@article {pmid40644525,
year = {2025},
author = {An, H and Fan, C and Kim, D and Bui, H and Park, Y},
title = {Discovery of oligodendrocyte enhancers that regulate Sox10 expression.},
journal = {PLoS genetics},
volume = {21},
number = {7},
pages = {e1011778},
doi = {10.1371/journal.pgen.1011778},
pmid = {40644525},
issn = {1553-7404},
abstract = {Oligodendrocytes (OLs) assemble myelin sheaths around axons in central nervous system (CNS). Myelin is essential for the saltatory conduction of action potentials and also performs other critical functions for the operation of the CNS. Sox10 (SRY-box containing gene 10) is a high-mobility group transcription factor that orchestrates the development of OLs. Despite its key role in OL biology, there is scant information on how the expression of Sox10 is regulated in OL lineage cells. Especially, OL enhancers that control its transcription remain elusive. We have recently developed an innovative method that rationally links OL enhancers to target genes. This study applied the new method to Sox10, uncovering two OL enhancers for it (termed Sox10-E1 and Sox10-E2). Epigenome editing analysis revealed that Sox10-E1 and Sox10-E2 regulate Sox10 expression non-redundantly. Luciferase assay and human and mouse brain multi-omics data show that, during the differentiation of OL precursor cells (OPCs) into OLs, the enhancer activity of Sox10-E1 does not change while that of Sox10-E2 decreases significantly. Chromatin interaction data indicate that the two Sox10 enhancers lie close to the border of the Sox10 topologically associating domain (TAD). Consistently, Pick1, a gene that is near the Sox10 TAD border, is also under the transcriptional control of Sox10-E1 and Sox10-E2. Hence, genomic deletions involving Sox10-E1 and Sox10-E2 would perturb not only SOX10, but also PICK1 and other genes, and may cause a pathology that is more complex than that of conventional Waardenburg-Shah syndrome that results from SOX10 coding mutations.},
}
@article {pmid40637236,
year = {2025},
author = {Ma, W and Wang, F and Fan, Y and Hao, G and Su, Y and Wong, KC and Li, X},
title = {DeepNanoHi-C: deep learning enables accurate single-cell nanopore long-read data analysis and 3D genome interpretation.},
journal = {Nucleic acids research},
volume = {53},
number = {13},
pages = {},
doi = {10.1093/nar/gkaf640},
pmid = {40637236},
issn = {1362-4962},
support = {62472195//China National Natural Science Foundation/ ; 62076109//China National Natural Science Foundation/ ; },
mesh = {*Deep Learning ; *Single-Cell Analysis/methods ; *Chromatin/genetics/chemistry ; Humans ; Nanopores ; *Nanopore Sequencing/methods ; *Genomics/methods ; Genome ; },
abstract = {Single-cell long-read concatemer sequencing (scNanoHi-C) technology provides unique insights into the higher-order chromatin structure across the genome in individual cells, crucial for understanding 3D genome organization. However, the lack of specialized analytical tools for scNanoHi-C data impedes progress, as existing methods, which primarily focus on scHi-C technologies, do not fully address the specific challenges of scNanoHi-C, such as sparsity, cell-specific variability, and complex chromatin interaction networks. Here, we introduce DeepNanoHi-C, a novel deep learning framework specifically designed for scNanoHi-C data, which leverages a multistep autoencoder and a Sparse Gated Mixture of Experts (SGMoE) to accurately predict chromatin interactions by imputing sparse contact maps, thereby capturing cell-specific structural features. DeepNanoHi-C effectively captures complex global chromatin contact patterns through the multistep autoencoder and dynamically selects the most appropriate expert from a pool of experts based on distinct chromatin contact patterns. Furthermore, DeepNanoHi-C integrates multiscale predictions through a dual-channel prediction net, refining complex interaction information and facilitating comprehensive downstream analyses of chromatin architecture. Experimental validation shows that DeepNanoHi-C outperforms existing methods in distinguishing cell types and demonstrates robust performance in data imputation tasks. Additionally, the framework identifies single-cell 3D genome features, such as cell-specific topologically associating domain (TAD) boundaries, further confirming its ability to accurately model chromatin interactions. Beyond single-cell analysis, DeepNanoHi-C also uncovers conserved genomic structures across species, providing insights into the evolutionary conservation of chromatin organization.},
}
@article {pmid40630581,
year = {2025},
author = {Trivellin, G and Sánchez-Gaya, V and Grasso, A and Pasińska, M and Stratakis, CA and Milnes, D and Kirk, EP and Beckers, A and Lania, AG and Pétrossians, P and Rada-Iglesias, A and Franke, M and Daly, AF},
title = {Distinguishing benign from pathogenic duplications involving GPR101 and VGLL1 -adjacent enhancers in the clinical setting with the bioinformatic tool POSTRE.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.06.27.25329768},
pmid = {40630581},
abstract = {BACKGROUND: Structural variants (SVs) that disrupt topologically associating domains (TADs) can cause disease by rewiring enhancer-promoter interactions. Duplications involving GPR101 are known to cause X-linked acrogigantism (X-LAG) by enabling aberrant expression of GPR101 through hijacking of enhancers at VGLL1 . However, not all GPR101 -containing duplications are pathogenic, presenting a diagnostic challenge, especially in the prenatal setting.<br><br>METHODS: We evaluated POSTRE, a tool designed to predict the regulatory impact of SVs, to distinguish pathogenic from benign GPR101 duplications. We analyzed six non-pathogenic duplications, and 27 known X-LAG associated pathogenic duplications. Tissue-specific enhancer maps built using H3K27ac ChIP-seq and ATAC-seq data as well as gene expression data derived from human anterior pituitary samples were integrated into POSTRE to enable predictions in a X-LAG relevant tissue context.<br><br>RESULTS: POSTRE correctly classified all 33 duplications as benign or pathogenic. In addition, one X-LAG case with mild clinical features (e.g., severe GH hypersecretion in the absence of pituitary tumorigenesis) was found to include only 2/5 VGLL1 enhancers (also predicted to be the weakest enhancers), whereas all 26 typical X-LAG cases had 24 enhancers duplicated. This suggests that milder enhancer hijacking at VGLL1 could explain the different clinical features of X-LAG in this individual.<br><br>CONCLUSIONS: These findings support the utility of POSTRE to support diagnostic pipelines when interpreting SVs affecting chromatin architecture in pituitary disease. By accurately modelling enhancer adoption in a cell type-specific context, POSTRE could help to reduce uncertainty in genetic counselling and offers a rapid alternative to performing chromatin conformation capture experiments.},
}
@article {pmid40629848,
year = {2025},
author = {Wei, J and Xue, Y and Gao, YQ},
title = {Hierarchical Prediction and Perturbation of Chromatin Organization Reveal How Loop Domains Mediate Higher-Order Architectures.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e04799},
doi = {10.1002/advs.202504799},
pmid = {40629848},
issn = {2198-3844},
support = {2022ZD0115001//National Science and Technology Major Project/ ; 92353304//National Natural Science Foundation of China/ ; T2495221//National Natural Science Foundation of China/ ; NCI202305//New Cornerstone Science Foundation/ ; },
abstract = {The genome is folded within the dense cell nucleus in a hierarchical manner, resulting in complex interactions between distinct folding strategies at various length scales. To elucidate how short-range loop domains regulate higher-order structures of the chromatin, such as topologically associating domains (TADs) and compartments, HiCGen is introduced as a hierarchical and cell-type-specific generator based on Swin-transformer architecture. HiCGen predicts genome organization across different spatial scales utilizing DNA sequence and genomic features as inputs. The model enables in silico screening through genetic or epigenetic perturbations on genome architecture, with resolution down to 1 kb. The analysis reveals unexpected linear correlations between loop properties and genome organization at various levels, including insulation degree, compartmentalization, and contact intensity over genomic distances exceeding 10 Mb. Regional or global perturbation conducted by HiCGen provides biological implications for such cross-scale correlations and their genome-function dependence. Notably, perturbation analysis of the human genome in sigmoid colon tissue demonstrates that modest activation of carcinogenesis-associated enhancers is sufficient to hijack nearby promoter, reshape TAD boundaries, and even flip compartment at mega-base scale.},
}
@article {pmid40628528,
year = {2025},
author = {Rahmaninejad, H and Xiao, Y and Tortora, MMC and Fudenberg, G},
title = {Dynamic barriers modulate cohesin positioning and genome folding at fixed occupancy.},
journal = {Genome research},
volume = {},
number = {},
pages = {},
doi = {10.1101/gr.280108.124},
pmid = {40628528},
issn = {1549-5469},
abstract = {In mammalian interphase cells, genomes are folded by cohesin loop extrusion limited by directional CTCF barriers. This process enriches cohesin at barriers, isolates neighboring topologically associating domains, and elevates contact frequency between convergent CTCF barriers across the genome. However, recent in vivo measurements present a puzzle: reported CTCF residence times on chromatin are in the range of a few minutes, whereas cohesin lifetimes are much longer. Can the observed features of genome folding result from relatively transient barriers? To address this question, we develop a dynamic barrier model, where CTCF sites switch between bound and unbound states. Using this model, we investigate how barrier dynamics would impact observables for a range of experimental genomic and imaging data sets, including ChIP-seq, Hi-C, and microscopy. We find the interplay of CTCF and cohesin binding timescales influence the strength of each of these features, leaving a signature of barrier dynamics even in the population-averaged snapshots offered by genomic data sets. First, in addition to barrier occupancy, barrier bound times are crucial for instructing features of genome folding. Second, the ratio of boundary to extruder lifetime greatly alters simulated ChIP-seq and simulated Hi-C. Third, large-scale changes in chromosome morphology observed experimentally after increasing extruder lifetime require dynamic barriers. By integrating multiple sources of experimental data, our biophysical model argues that CTCF barrier bound times effectively approach those of cohesin extruder lifetimes. Together, we demonstrate how models that are informed by biophysically measured protein dynamics broaden our understanding of genome folding.},
}
@article {pmid40626176,
year = {2025},
author = {Liehr, T and Cross, E and Kankel, S},
title = {Directional genomic hybridization (dGH™) identifies small inverted duplications in situ.},
journal = {Frontiers in genetics},
volume = {16},
number = {},
pages = {1604822},
pmid = {40626176},
issn = {1664-8021},
abstract = {Although fluorescence in situ hybridization (FISH) is a standard approach for characterizing the chromosomal structure involving a region of interest, FISH targeting single chromatids is not routinely performed. However, this latter approach seems principally well-suited to distinguish small, tandem inverted duplications from direct duplications in clinical cases. A commercially available single-chromatid FISH approach, called "directional genomic hybridization" (dGH™), was applied in this study to nine cases of small supernumerary marker chromosomes (sSMCs) known to contain inverted duplications. Successful detection of small inverted duplications has been demonstrated for the first time in this study using a custom KromaTiD dGH™ InSite Assay. In all five euchromatic sSMC cases, inversions were detected using the dGH single-chromatid molecular cytogenetic assay. Thus, the dGH method of FISH is a readily applicable, straightforward approach for identifying small inverted duplications that are undetectable by conventional (molecular) cytogenetic methods. This technique may be used to identify the presence of small inversions within regions presenting a copy number gain as detected by chromosome microarray. Distinguishing small inverted duplications from direct duplications may have an impact on topologically associating domains (TADs) and, thus, on clinical outcome.},
}
@article {pmid40598900,
year = {2025},
author = {Maestri, D and Caruso, LB and Cable, JM and Sklutuis, R and Preston-Alp, S and White, RE and Luftig, MA and Tempera, I},
title = {EBNA leader protein orchestrates chromatin architecture remodeling during Epstein-Barr virus-induced B cell transformation.},
journal = {Nucleic acids research},
volume = {53},
number = {12},
pages = {},
doi = {10.1093/nar/gkaf629},
pmid = {40598900},
issn = {1362-4962},
support = {P30 CA010815/CA/NCI NIH HHS/United States ; R01AI130209/GF/NIH HHS/United States ; R01AI182056/GF/NIH HHS/United States ; R01AI153508/GF/NIH HHS/United States ; P01 CA269043/GF/NIH HHS/United States ; P30 CA010815/GF/NIH HHS/United States ; R01CA140337/GF/NIH HHS/United States ; T32CA09171/GF/NIH HHS/United States ; T32CA288356/GF/NIH HHS/United States ; },
mesh = {Humans ; *Herpesvirus 4, Human/genetics/pathogenicity ; *B-Lymphocytes/virology/metabolism/pathology ; *Chromatin Assembly and Disassembly/genetics ; Chromatin/metabolism/genetics ; *Epstein-Barr Virus Nuclear Antigens/metabolism/genetics ; *Cell Transformation, Viral/genetics ; *Viral Proteins/metabolism/genetics ; Enhancer Elements, Genetic ; CCCTC-Binding Factor/metabolism ; Promoter Regions, Genetic ; Protein Binding ; Epstein-Barr Virus Infections/virology/genetics ; },
abstract = {Epstein-Barr virus Nuclear Antigen Leader Protein (EBNA-LP) plays a pivotal role in the transformation of B cells by Epstein-Barr virus (EBV), functioning independently of EBNA2 to regulate chromatin architecture and gene expression. Our study reveals that EBNA-LP binds to chromatin regions distinct from EBNA2 and facilitates the formation of long-distance chromatin loops by interacting with the cellular factor YY1. This interaction reconfigures the three-dimensional structure of the host genome, enhancing the integrity of topologically associating domains (TADs) and promoting the interaction between enhancers and promoters within these domains. In EBV-infected B cells, EBNA-LP strengthens YY1-mediated chromatin loops within TADs, which helps maintain stable regulatory programs essential for B cell transformation. Notably, EBNA-LP is crucial for establishing EBV-induced enhancers, yet it is not required for their maintenance once formed. Additionally, our data suggest a compensatory increase in CTCF binding in the absence of EBNA-LP, leading to more promiscuous chromatin interactions between TADs and a reduced TAD insulation at their boundaries. These findings provide new insights into the molecular mechanisms by which EBV reshapes the host genome chromatin architecture to support B cell transformation and highlight potential therapeutic targets for disrupting EBV-driven oncogenesis.},
}
@article {pmid40597210,
year = {2025},
author = {Bai, X and Tang, X and Wang, Y and Yue, S and Xu, X and Hu, P and Xu, J and Li, Y and Wang, J and Tao, H and Zheng, Y and Chen, B and Tian, M and Lin, L and Wang, R and Sun, Y and Ren, C and Bo, X and Li, H and Chen, H and Lu, M},
title = {The hierarchical folding dynamics of topologically associating domains during early embryo development.},
journal = {BMC biology},
volume = {23},
number = {1},
pages = {175},
pmid = {40597210},
issn = {1741-7007},
support = {62173338//National Natural Science Foundation of China/ ; 82001520//National Natural Science Foundation of China/ ; 20220484198//Beijing Nova Program of Science and Technology/ ; 20230484290//Beijing Nova Program of Science and Technology/ ; 62422318//National Natural Science Foundation of China/ ; 2024YFA1307700//National Key Research and Development Program of China/ ; 2023YFF0725500//National Key Research and Development Program of China/ ; },
mesh = {*Embryonic Development/genetics ; Animals ; *Chromatin/metabolism/chemistry ; *Gene Expression Regulation, Developmental ; Histones/metabolism ; Zygote/metabolism ; Mice ; },
abstract = {BACKGROUND: Recent research has indicated a close connection between the three-dimensional (3D) structure of chromatin and early embryo development, with precise higher-order chromatin folding playing a significant role in mediating gene expression. However, the specific role of 3D genomic hierarchical structure and its dynamics in early embryo development remains largely unknown.<br><br>RESULTS: In this study, we examined the hierarchical topological association domain (TAD) during early embryo development and its relationship with zygotic gene activation (ZGA), gene expression, and chromatin accessibility to gain a better understanding of the dynamics of TAD nesting levels during this developmental stage. Our findings show that ZGA precedes the establishment of hierarchical TAD, leading to widespread gene expression, an increase in the percentage of high-level TAD structures, and enhanced chromatin accessibility at higher hierarchical levels. Additionally, we utilized a deep neural network to investigate the formation of TAD boundaries and found that histone H3 lysine 4 trimethylation (H3K4me3) and histone H3 lysine trimethylation (H3K27me3) are key features in the establishment of TAD boundaries. Furthermore, we observed heterogeneous dynamics of hierarchical TAD among different species.<br><br>CONCLUSIONS: Overall, our study sheds light on the folding dynamics of hierarchical TADs during early embryo development and underscores their close relationship with transcriptional programs.},
}
@article {pmid40588575,
year = {2025},
author = {Sreenivasan, VKA and Yumiceba, V and Spielmann, M},
title = {Structural variants in the 3D genome as drivers of disease.},
journal = {Nature reviews. Genetics},
volume = {},
number = {},
pages = {},
pmid = {40588575},
issn = {1471-0064},
abstract = {The spatial organization of the genome within the nucleus - also known as genome architecture or 3D genome - is important to the regulation of gene expression. Disruption of the 3D genome, for example, by structural variation, can contribute to disease, including developmental disorders and cancer. Structural variants can rearrange higher-order chromatin structures, such as topologically associating domains, and disrupt interactions between cis-regulatory elements, which can lead to altered gene expression, a phenomenon known as position effects. New experimental and computational approaches are revealing the effect of structural variants on the 3D genome and gene expression and can help interpret their pathogenic potential, which has important implications for patients. Here, we review mechanisms of disease caused by position effects owing to disruptions of genome architecture, and more specifically topologically associating domains, as well as their consequences and clinical impact.},
}
@article {pmid40588507,
year = {2025},
author = {Wong, EWP and Sahin, M and Yang, R and Lee, U and Li, D and Zhan, YA and Misra, R and Tomas, F and Alomran, N and Polyzos, A and Lee, CJ and Trieu, T and Martinez-Fundichely, A and Wiesner, T and Rosowicz, A and Cheng, S and Liu, C and Lallo, M and Shoushtari, AN and Merghoub, T and Hamard, PJ and Koche, R and Khurana, E and Apostolou, E and Zheng, D and Chen, Y and Leslie, CS and Chi, P},
title = {Disruption of TAD hierarchy promotes LTR co-option in cancer.},
journal = {Nature genetics},
volume = {},
number = {},
pages = {},
pmid = {40588507},
issn = {1546-1718},
abstract = {Transposable elements (TEs) are abundant in the human genome, and they provide the source for genetic and functional diversity. Previous studies have suggested that TEs are repressed by DNA methylation and chromatin modifications. Here through integrating transcriptome and 3D genome architecture studies, we showed that haploinsufficient loss of NIPBL selectively activates alternative promoters (altPs) at the long terminal repeats (LTRs) of the TE subclasses. This activation occurs through the reorganization of topologically associating domain (TAD) hierarchical structures and the recruitment of proximal enhancers. These observations indicate that TAD hierarchy restricts transcriptional activation of LTRs that already possess open chromatin features. Perturbation of hierarchical chromatin topology can lead to co-option of LTRs as functional altPs, driving aberrant transcriptional activation of oncogenes. These data uncovered a new layer of regulatory mechanisms of TE expression and posit TAD hierarchy dysregulation as a new mechanism for altP-mediated oncogene activation and transcriptional diversity in cancer.},
}
@article {pmid40586163,
year = {2025},
author = {Xu, K and Yu, Z and Sun, C and Gou, C and Zhu, J and Wang, J and Bo, X and Yu, G and Li, H and Chen, H},
title = {ChromInSight: Revealing DNA Double-Strand Breaks Through Chromatin Structural Insights With an Interpretable Graph Neural Network Framework.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e04571},
doi = {10.1002/advs.202504571},
pmid = {40586163},
issn = {2198-3844},
support = {62422318//National Natural Science Foundation of China/ ; 62173338//National Natural Science Foundation of China/ ; 2024YFA1307700//National Key R&amp;D Program of China/ ; 2023YFF0725500//National Key R&amp;D Program of China/ ; },
abstract = {DNA double-strand breaks (DSBs) represent one of the most severe forms of genomic damage. Although substantial progress has been made in elucidating general patterns associated with DSBs, the influence of 3D chromatin structure on DSB formation remains underexplored, particularly concerning its spatial configuration. Here, the ChromInSight framework is introduced. Using standardized datasets,Hi-DSB is developed and deployed in ChromInSight, a genome-wide DSB prediction model based on graph contrastive learning (GCL), and applied advanced interpretability techniques to identify DSB-associated genomic patterns. The findings reveal that the spatial cluster-scene between hub nodes and DSB sites is predominantly shaped by the 3D conformation of chromatin, rather than by linear genomic distance. This phenomenon is validated at both the Loop and topologically associating domain (TAD) levels and proposed a "spatial isolation - damage containment" hypothesis, which illustrates the genome strategy for managing damage. These findings support the role of 3D genome architecture in genomic instability. Consequently, the framework provides a powerful tool for investigating the intricate relationship between chromatin structure and genomic stability.},
}
@article {pmid40579703,
year = {2025},
author = {Li, KY and Cao, Q and Chow, SH and Nicoletti, C and Puri, PL and Wang, H and Leung, D and Yip, KY},
title = {Regulatory roles of three-dimensional structures of chromatin domains.},
journal = {Genome biology},
volume = {26},
number = {1},
pages = {184},
pmid = {40579703},
issn = {1474-760X},
support = {U54AG079758/AG/NIA NIH HHS/United States ; U54AG079758/AG/NIA NIH HHS/United States ; General Research Fund 14107420//Research Grants Council, University Grants Committee/ ; General Research Fund 14107420//Research Grants Council, University Grants Committee/ ; General Research Fund 14107420//Research Grants Council, University Grants Committee/ ; General Research Fund 14107420//Research Grants Council, University Grants Committee/ ; 32100515//National Natural Science Foundation of China/ ; 2021.061//Chinese University of Hong Kong/ ; EDUC4-12813//California Institute for Regenerative Medicine/ ; P30CA030199/CA/NCI NIH HHS/United States ; },
mesh = {*Chromatin/chemistry/genetics/metabolism ; Humans ; *Gene Expression Regulation ; Enhancer Elements, Genetic ; Transcription Factors/metabolism ; Binding Sites ; Histones/metabolism ; },
abstract = {BACKGROUND: Transcriptional enhancers usually, but not always, regulate genes within the same topologically associating domain (TAD). We hypothesize that this incomplete insulation is partially due to three-dimensional structures of corresponding chromatin domains in individual cells: whereas enhancers and genes buried inside the core of a domain interact mostly with other regions in the same domain, those on the surface can more easily interact with the outside.<br><br>RESULTS: Here we show that a simple measure, the intra-TAD ratio, can quantify the coreness of a region with respect to the single-cell domains to which it belongs. We show that domain surfaces are permissive for high gene expression. Cell type-specific active cis-regulatory elements, active histone marks, and transcription factor binding sites are enriched on domain surfaces, most strongly in chromatin subcompartments typically considered inactive.<br><br>CONCLUSIONS: These findings suggest a model of gene regulation that involves positioning active cis-regulatory elements on domain surfaces. We also find that disease-associated non-coding variants are enriched on domain surfaces.},
}
@article {pmid40544603,
year = {2025},
author = {Liu, X and Tao, Y and Zhang, L and Liu, Y and Shi, D and Wang, J and Xue, P and Xu, B and Fang, W and Ran, Y},
title = {Caged-hypocrellin mediated photodynamic therapy induces chromatin remodeling and disrupts mitochondrial energy metabolism in multidrug-resistant Candida auris.},
journal = {Redox biology},
volume = {85},
number = {},
pages = {103708},
doi = {10.1016/j.redox.2025.103708},
pmid = {40544603},
issn = {2213-2317},
abstract = {Candida auris is a fungal pathogen with frequent development of multidrug-resistance or pan-drug resistance. Currently, the treatment options for Candida auris are limited. Therefore, there is an urgent need for alternative therapeutic strategies. Antimicrobial photodynamic therapy (aPDT), which generates reactive oxygen species (ROS) through light-activated photosensitizers, has shown promise against C. auris; however, its molecular mechanism remains unclear. To investigate COP1T-HA-mediated PDT-induced genomic alterations, we constructed a 3D genome map of Candida species, which uncovered the reorganization of chromatin architecture in response to PDT treatment. Our data showed that low-dose PDT causes subtle local adjustments in chromatin topology, whereas high-dose PDT leads to more pronounced changes in A/B compartmentalization, topologically associating domain (TAD) organization, and chromatin looping associated with key genes related to mitochondrial energy metabolism. Confocal imaging confirmed that high-dose COP1T-HA-mediated PDT induces localized ROS accumulation near the nucleus and a temporally ordered cellular stress response. Furthermore, functional validation through QCR10, NDUFA5, and MP knockouts confirmed the essential roles of these genes in mitochondrial integrity, ATP synthesis, ROS homeostasis, and biofilm formation. Mutants showed altered mitochondrial membrane potential, intracellular pH imbalance, and enhanced glycolytic compensation, highlighting the impact of electron transport disruption on energy metabolism. This study provides the first comprehensive insight into COP1T-HA-mediated PDT-induced chromatin reorganization in C. auris and establishes a direct connection between 3D genome remodeling and fungal energy metabolism, offering a foundation for chromatin-targeted antifungal strategies.},
}
@article {pmid40537528,
year = {2025},
author = {González-Almela, E and Castells-Garcia, A and Le Dily, F and Merino, MF and Carnevali, D and Cusco, P and Di Croce, L and Cosma, MP},
title = {Herpes simplex virus type 1 reshapes host chromatin architecture via transcription machinery hijacking.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {5313},
pmid = {40537528},
issn = {2041-1723},
support = {31971177//National Science Foundation of China | International Cooperation and Exchange Programme/ ; },
abstract = {Herpes simplex virus type 1 (HSV-1) remodels the host chromatin structure and induces a host-to-virus transcriptional switch during lytic infection. We combine super-resolution imaging and chromosome-capture technologies to identify the mechanism of remodeling. We show that the host chromatin undergoes massive condensation caused by the hijacking of RNA polymerase II (RNAP II) and topoisomerase I (TOP1). In addition, HSV-1 infection results in the rearrangement of topologically associating domains and loops, although the A/B compartments are maintained in the host. The position of viral genomes and their association with RNAP II and cohesin is determined nanometrically. We reveal specific host-HSV-1 genome interactions and enrichment of upregulated human genes in the most contacting regions. Finally, TOP1 inhibition fully blocks HSV-1 infection, suggesting possible antiviral strategies. This viral mechanism of host chromatin rewiring sheds light on the role of transcription in chromatin architecture.},
}
@article {pmid40513402,
year = {2025},
author = {Cetin, S and Sefer, E},
title = {The significance of chromosome conformation capture in 3D genome architecture comprehension.},
journal = {Computational biology and chemistry},
volume = {119},
number = {},
pages = {108534},
doi = {10.1016/j.compbiolchem.2025.108534},
pmid = {40513402},
issn = {1476-928X},
abstract = {Chromosomes are intricate macromolecules composed of chromatin that create three-dimensional structures within cells. The arrangement and interactions of chromosomes play a crucial role in shaping the genome's structure, function, and gene expression regulation. To fully grasp the architecture and adaptability of the genome, it is essential to understand the complex relationship between chromosomal structure and nucleotide sequences. Advances in our understanding of genome topology have been significantly driven by next-generation sequencing technologies designed for capturing chromatin conformation. The exploration of 3D genome organization has led to the development of high-throughput chromatin conformation capture (Hi-C) techniques. Hi-C is essential for revealing new aspects of genome architecture and for mapping genome-wide chromosomal interactions, both within individual chromosomes and between them. These interactions include chromosomal territories, topologically associating domains (TADs), and chromatin or gene loops. This review provides a comprehensive overview of the historical development and current state of 'C' technologies, in-depth insights into various Hi-C techniques, and the analysis of 3D genome structures. It concludes with a discussion on computational tools for analyzing high-resolution Hi-C data, the challenges in modeling 3D genome structures, and potential future advancements in the field.},
}
@article {pmid40501564,
year = {2025},
author = {Xu, W and Cui, J and Zhang, S and Lu, L and Liu, X and Li, Y and Jin, F},
title = {Map functional insulators with cross-platform Hi-C meta-analysis.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.05.26.656183},
pmid = {40501564},
issn = {2692-8205},
abstract = {CTCF forms the boundaries of topologically associating domains (TADs) but their insulating function in transcription is controversial. Here we report that functional insulators (FINs) shall be determined not only by their ability to form static loops or boundaries, but also by the dynamic context if their flanking sequences form new loops upon boundary loss. We performed a meta-analysis of nine independent Hi-C and micro-C datasets upon acute CTCF- or cohesin protein-depletion and found that only at several hundred loci, newly gained enhancers-promoters (E-P) loops can be reproducibly observed upon CTCF depletion. The new E-P loops are cohesin-dependent and associated with recurrent gene activation. These findings allow us to map FINs and define their direct target genes genome-wide. FINs are mostly present in euchromatin, do not overlap with TAD boundaries, and can be perturbed by Wapl -depletion or CTCF-displacement. We therefore conclude that FINs, but not TAD boundaries, are bona fide insulators.},
}
@article {pmid40495214,
year = {2025},
author = {Li, J and Xu, L and Wang, J and Wang, X and Lin, Y and Zou, AY and Ren, F and Wang, Y and Li, J and Chang, Z},
title = {CREPT is required for the metastasis of triple-negative breast cancer through a co-operational-chromatin loop-based gene regulation.},
journal = {Molecular cancer},
volume = {24},
number = {1},
pages = {170},
pmid = {40495214},
issn = {1476-4598},
support = {81230044, 81872249 and 81830092//National Natural Science Foundation of China/ ; 81230044, 81872249 and 81830092//National Natural Science Foundation of China/ ; 2016YFA0500301//Chinese National Major Scientific Research Program/ ; 7172213//Beijing Scientific Projects/ ; JFLKYXM202303AZ-203//Jinfeng Lab/ ; },
mesh = {*Triple Negative Breast Neoplasms/genetics/pathology/metabolism ; Humans ; Animals ; Female ; *Gene Expression Regulation, Neoplastic ; Mice ; *Chromatin/genetics/metabolism ; Neoplasm Metastasis ; Cell Line, Tumor ; Promoter Regions, Genetic ; Prognosis ; },
abstract = {Triple-negative breast cancer (TNBC) is recognized for its aggressiveness, yet the mechanism underlying metastasis remains unclear. Here, we report that CREPT/RPRD1B, which exhibits somatic gene copy-number amplifications and elevated expression, correlates with poor patient survival and drives TNBC metastasis. We demonstrate that CREPT alters three-dimensional genome structures in topologically-associating domain (TAD) status and chromatin loops via occupying promoters and enhancers. Specifically, CREPT mediates 1082 co-operational chromatin loops configured by enhancer-promoter and promoter-termination loops, which are validated by HiChIP analyses and visualized by Tn5-FISH experiments. These loops orchestrate RNAPII loading and recycling to enhance the metastatic gene expression. Disruption of these co-operational loops using CRISPR-dCas9 suppresses TNBC metastasis in vivo. Furthermore, depletion of CREPT using an AAV-based shRNA blocks TNBC metastasis in both preventative and therapeutic mouse models. We propose that targeting CREPT to disrupt the co-operational chromatin loop structures represents a promising therapeutic strategy for metastatic TNBC.},
}
@article {pmid40456819,
year = {2025},
author = {Zhang, K and Chen, M and Chen, M and Wang, Y and Liu, H and Li, Y and Guan, X and Lei, L and Tao, L and Liu, X and He, D and Fei, X},
title = {The 3D genome of plasma cells in multiple myeloma.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {19331},
pmid = {40456819},
issn = {2045-2322},
support = {2020YJ0438//The Science and Technology Department of Sichuan Province/ ; },
mesh = {Humans ; *Multiple Myeloma/genetics/pathology ; *Plasma Cells/metabolism/pathology ; Transcriptome ; Male ; Female ; Gene Expression Profiling ; Polymorphism, Single Nucleotide ; Aged ; *Genome, Human ; Gene Expression Regulation, Neoplastic ; Middle Aged ; Genomics/methods ; },
abstract = {Multiple myeloma (MM) is a hematological malignancy characterized by expanding clonal plasma cells in the bone marrow (BM) that produce monoclonal immunoglobulin. It is an incurable disease, accounting for about 10% of blood malignancies and the second most common hematologic malignancy. Therefore, in-depth research into the molecular mechanisms and therapeutic targets of the disease is crucial. For the first time, we performed high-throughput chromosome conformation capture (Hi-C) analysis of plasma cells in five multiple myeloma patients, and integrated it with genome resequencing and transcriptomic associated with genomic variation and gene expression. As a result, 19 specific TAD (Topologically Associating Domain) boundaries in MM samples related to the immune response and Wnt signaling pathways were identified. Additionally, Loop structures were also analyzed, revealing that promoter-enhancer-associated loops were the most prevalent. Genomic characteristics of MM patients were explored, identifying SNPs, InDels, and CNVs, with variations in the CDS region potentially affecting gene function. Transcriptome analysis showed differentially expressed genes in MM patients, mainly involved in p53 signaling and cell adhesion. Multi-omics analysis identified overlapping genes related to MM, including those involved in MHC class II protein complex assembly and antigen presentation. The study provides insights into the complex genomic and transcriptomic changes in MM plasma cells, potentially aiding in identifying therapeutic targets.},
}
@article {pmid40448401,
year = {2025},
author = {Yamasaki, YY and Toyoda, A and Kadota, M and Kuraku, S and Kitano, J},
title = {3D Genome Constrains Breakpoints of Inversions That Can Act as Barriers to Gene Flow in the Stickleback.},
journal = {Molecular ecology},
volume = {},
number = {},
pages = {e17814},
doi = {10.1111/mec.17814},
pmid = {40448401},
issn = {1365-294X},
support = {JPMJCR20S2//Core Research for Evolutional Science and Technology/ ; 16H06279//Japan Society for the Promotion of Science/ ; 20J01503//Japan Society for the Promotion of Science/ ; 21H02542//Japan Society for the Promotion of Science/ ; 22H04983//Japan Society for the Promotion of Science/ ; 22KK0105//Japan Society for the Promotion of Science/ ; },
abstract = {DNA within the nucleus is organised into a well-regulated three-dimensional (3D) structure. However, how such 3D genome structures influence speciation processes remains largely elusive. Recent studies have shown that 3D genome structures influence mutation rates, including the occurrence of chromosomal rearrangement. For example, breakpoints of chromosomal rearrangements tend to be located at topologically associating domain (TAD) boundaries. Here, we hypothesised that TAD structures may constrain the location of chromosomal inversions and thereby shape the genomic landscape of divergence between species with ongoing gene flow, given that inversions can act as barriers to gene flow. To test this hypothesis, we used a pair of Japanese stickleback species, Gasterosteus nipponicus (Japan Sea stickleback) and G. aculeatus (three-spined stickleback). We first constructed chromosome-scale genome assemblies of both species using high fidelity long reads and high-resolution proximity ligation data and identified several chromosomal inversions. Second, via population genomic analyses, we revealed higher genetic differentiation in inverted regions than in colinear regions and no gene flow within inversions, which contrasts with the significant gene flow in colinear regions. Third, using Hi-C data, we revealed 3D genome structures of sticklebacks, delineated by A/B compartments and TADs. Finally, we found that inversion breakpoints tend to be located at TAD boundaries. Thus, our study demonstrates that the 3D genome constrains breakpoints of inversions that can act as barriers to gene flow in the stickleback. Further integration of 3D genome analyses with population genomics could provide novel insights into how the 3D genome influences speciation.},
}
@article {pmid40436628,
year = {2025},
author = {Williamson, I and Graham, KA and Woolf, M and Becher, H and Hill, RE and Bickmore, WA and Lettice, LA},
title = {Bystander activation across a TAD boundary supports a cohesin-dependent transcription cluster model for enhancer function.},
journal = {Genes &amp; development},
volume = {},
number = {},
pages = {},
doi = {10.1101/gad.352648.125},
pmid = {40436628},
issn = {1549-5477},
abstract = {Mammalian enhancers can regulate genes over large genomic distances, often skipping over other genes. Despite this, precise developmental regulation suggests that mechanisms exist to ensure enhancers only activate their correct targets. Sculpting of three-dimensional chromosome organization through cohesin-dependent loop extrusion is thought to be important for facilitating and constraining enhancer action. The boundaries of topologically associating domains (TADs) are thought to prevent enhancers acting on genes in adjacent TADs. However, there are examples where enhancers appear to act across TAD boundaries, but it has remained unclear whether a single enhancer can simultaneously activate genes in different TADs. Here we show that some Shh enhancers can activate transcription concurrently not only at Shh but also at Mnx1 located in an adjacent TAD. This occurs in the context of a chromatin conformation maintaining genes and enhancers in close proximity and is influenced by cohesin. To our knowledge, this is the first report of two endogenous mammalian genes transcribed concurrently under the control of the same enhancer and across a TAD boundary. These findings have implications for understanding the design rules of gene regulatory landscapes and are consistent with a transcription cluster model of enhancer-promoter communication.},
}
@article {pmid40405503,
year = {2025},
author = {Xu, Y and Wu, D and Zhao, M and Tang, W and Cheng, X and Hu, Q and Liu, Z and Gan, J and Hua, J and Zou, G and Lu, A and Yang, C and Zheng, Y and Li, W and Li, J and Wang, X and Ma, C},
title = {The rice AT-rich pincer-like element family of conserved noncoding sequences regulates chromatin loop formation.},
journal = {Plant physiology},
volume = {},
number = {},
pages = {},
doi = {10.1093/plphys/kiaf211},
pmid = {40405503},
issn = {1532-2548},
abstract = {The comprehensive annotation of regulatory elements in linear genomes is needed to elucidate the molecular mechanisms underlying chromatin loop formation in plants. Here, we characterized a novel family of conserved noncoding sequences (CNSs) in the rice (Oryza sativa) genome. These sequences, known as AT-rich pincer-like elements (APEs), are composed of 13-bp repeat unit arrays in a reverse-forward configuration. Our findings revealed that there are 611 APE copies across the japonica genome. Deletion of single APEs disrupted the long-range chromatin loops anchoring target APE regions and moderately remodeled the profile of A/B compartments, topologically associating domains (TADs), and chromatin loops, thereby rewiring the expression of looped gene(s) including those controlling important agronomic traits. Thus, APEs function as hub motifs directly mediating chromatin looping and maintaining 3D genome integrity and stability at the levels of compartments, TADs, and loops. Moreover, neighboring genomic regions harboring numerous paired non-APE (NA) CNSs were more likely to interact with each other. This finding suggests that NA CNS pairs might play a helper role in determining loop frequency in a dose-dependent manner, likely by ensuring the pairing selectivity of anchor sites. Our study highlights the importance of APEs and NA CNSs in maintaining 3D genome structure, thereby providing the framework required to link many noncoding repetitive elements to their molecular functions in plants.},
}
@article {pmid40391535,
year = {2025},
author = {Lee, H and Seo, PJ},
title = {Deciphering the 3D structures of plant genomes: Building blocks of hierarchically organized chromatin domains.},
journal = {Journal of experimental botany},
volume = {},
number = {},
pages = {},
doi = {10.1093/jxb/eraf218},
pmid = {40391535},
issn = {1460-2431},
abstract = {The spatial arrangement of chromatin within the nucleus is intricately regulated and acts as a key determinant of gene expression. Advanced high-resolution chromatin conformation capture techniques have revealed that plant genomes exhibit hierarchical organization within the nucleus, into large A and B compartments, intermediate topologically associating domain (TAD)-like domains, and fine gene-scale chromatin domains. In this review, we highlight recent findings demonstrating that TAD-like domains are closely associated with distinct epigenetic states, which are modulated by cohesin components. In addition, we underscore the significance of gene-scale chromatin domains, which are established by RNA polymerase II and accessible chromatin structures at gene borders. These fine-scale chromatin domains likely serve as the fundamental structural units for higher-order chromatin organization. Examining the chromatin structures at different levels of the hierarchy allows us to elucidate their epigenetic features and the molecular mechanisms for domain formation, providing insights into the three-dimensional organization of plant genomes.},
}
@article {pmid40390127,
year = {2025},
author = {Zhang, Y and Dali, R and Blanchette, M},
title = {RobusTAD: reference panel based annotation of nested topologically associating domains.},
journal = {Genome biology},
volume = {26},
number = {1},
pages = {129},
pmid = {40390127},
issn = {1474-760X},
abstract = {Topologically associating domains (TADs) are fundamental units of 3D genomes and play essential roles in gene regulation. Hi-C data suggests a hierarchical organization of TADs. Accurately annotating nested TADs from Hi-C data remains challenging, both in terms of the precise identification of boundaries and the correct inference of hierarchies. While domain boundary is relatively well conserved across cells, few approaches have taken advantage of this fact. Here, we present RobusTAD to annotate TAD hierarchies. It incorporates additional Hi-C data to refine boundaries annotated from the study sample. RobusTAD outperforms existing tools at boundary and domain annotation across several benchmarking tasks.},
}
@article {pmid40390095,
year = {2025},
author = {Hou, C and Tian, GG and Hu, S and Chen, B and Li, X and Xu, B and Cao, Y and Le, W and Hu, R and Chen, H and Zhang, Y and Fang, Q and Zhang, M and Wang, Z and Zhang, Z and Zhang, J and Wei, Z and Yao, G and Wang, Y and Yin, P and Guo, Y and Tong, G and Teng, X and Sun, Y and Cao, Y and Wu, J},
title = {RNA polymerase I is essential for driving the formation of 3D genome in early embryonic development in mouse, but not in human.},
journal = {Genome medicine},
volume = {17},
number = {1},
pages = {57},
pmid = {40390095},
issn = {1756-994X},
support = {2022YFA0806301//National Key Research and Development Program of China/ ; 82201780//National Nature Science Foundation of China/ ; 23JC1402800//the Scientific and Technological Innovation Action program of Shanghai/ ; },
abstract = {BACKGROUND: Three-dimensional (3D) chromatin architecture undergoes dynamic reorganization during mammalian gametogenesis and early embryogenesis. While mouse studies have shown species-specific patterns as well as mechanisms underlying de novo organization, these remain poorly characterized in humans. Although RNA polymerases II and III have been shown to regulate chromatin structure, the potential role of RNA polymerase I (Pol I), which drives ribosomal RNA production, in shaping 3D genome organization during these developmental transitions has not been investigated.<br><br>METHODS: We employed a modified low-input in situ Hi-C approach to systematically compare 3D genome architecture dynamics from gametogenesis through early embryogenesis in human and mouse. Complementary Smart-seq2 for low-input transcriptomics, CUT&amp;Tag for Pol I profiling, and Pol I functional inhibition assays were performed to elucidate the mechanisms governing chromatin organization.<br><br>RESULTS: Our study revealed an extensive reorganization of the 3D genome from human oogenesis to early embryogenesis, displaying significant differences with the mouse, including dramatically attenuated topologically associating domains (TADs) at germinal vesicle (GV) stage oocytes. The 3D genome reconstruction timing is a fundamental difference between species. In human, reconstruction initiates at the 4-cell stage embryo in human, while in mouse, it commences at the 2-cell stage embryo. We discovered that Pol I is crucial for establishing the chromatin structures during mouse embryogenesis, but not in human embryos. Intriguingly, the absence of Pol I transcription weakens TAD structure in mouse female germline stem cells, whereas it fortifies it in human counterparts.<br><br>CONCLUSIONS: These observed interspecies distinctions in chromatin organization dynamics provide novel insights into the evolutionary divergence of chromatin architecture regulation during early mammalian development. Our findings provide mechanistic insights into species-specific chromatin organization during germ cell and embryonic development and have potential implications for fertility preservation and birth defect prevention.},
}
@article {pmid40384625,
year = {2025},
author = {Kurbidaeva, A and Gupta, S and Zaidem, M and Castanera, R and Sato, Y and Joly-Lopez, Z and Casacuberta, JM and Purugganan, MD},
title = {Topologically associating domains and the evolution of three-dimensional genome architecture in rice.},
journal = {The Plant journal : for cell and molecular biology},
volume = {122},
number = {4},
pages = {e70139},
doi = {10.1111/tpj.70139},
pmid = {40384625},
issn = {1365-313X},
support = {//National Science Foundation/ ; //Tamkeen/NYU Abu Dhabi Research Institute/ ; //Zegar Family Foundation/ ; //European Social Fund Plus/ ; //Ministerio de Ciencia e Innovaci&#xf3;n/ ; //Severo Ochoa Center of Excellence/ ; },
mesh = {*Oryza/genetics ; *Genome, Plant/genetics ; *Evolution, Molecular ; Chromatin/genetics ; DNA Transposable Elements/genetics ; Chromosomes, Plant/genetics ; },
abstract = {We examined the nature and evolution of three-dimensional (3D) genome conformation, including topologically associating domains (TADs), in five genomes within the genus Oryza. These included three varieties from subspecies within domesticated Asian rice O. sativa as well as their closely related wild relatives O. rufipogon and O. meridionalis. We used the high-resolution chromosome conformation capture technique Micro-C, which we modified for use in rice. Our analysis of rice TADs shows that TAD boundaries have high transcriptional activity, low methylation levels, low transposable element (TE) content, and increased gene density. We also find a significant correlation of expression levels for genes within TADs, suggesting that they do function as genomic domains with shared regulatory features. Our findings indicate that animal and plant TADs may share more commonalities than were initially thought, as evidenced by similar genetic and epigenetic signatures associated with TADs and boundaries. To examine 3D genome divergence, we employed a computer vision-based algorithm for the comparison of chromatin contact maps and complemented this analysis by assessing the evolutionary conservation of individual TADs and their boundaries. We conclude that overall chromatin organization is conserved in rice, and 3D structural divergence correlates with evolutionary distance between genomes. We also note that individual TADs are not well conserved, even at short evolutionary timescales.},
}
@article {pmid40382218,
year = {2025},
author = {Li, X and Liu, N},
title = {Advances in understanding LINE-1 regulation and function in the human genome.},
journal = {Trends in genetics : TIG},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tig.2025.04.011},
pmid = {40382218},
issn = {0168-9525},
abstract = {LINE-1 (long interspersed nuclear element 1, L1) retrotransposons constitute ~17% of human DNA (~0.5 million genomic L1 copies) and exhibit context-dependent expression in different cell lines. Recent studies reveal that L1 is under multilayered control by diverse factors that either collaborate or compete with each other to ensure precise L1 activity. Remarkably, L1s have been co-opted as various transcription-dependent regulatory elements, such as promoters, enhancers, and topologically associating domain (TAD) boundaries, that regulate gene expression in zygotic genome activation, aging, cancer, and other disorders. This review highlights the regulation of L1 and its regulatory functions that influence disease and development.},
}
@article {pmid40375066,
year = {2025},
author = {Yin, H and Zhao, Q and Yang, L and Yi, G and Yao, W and Fang, L and Bai, L},
title = {A multi-tissue and -breed catalogue of chromatin conformations and their implications in gene regulation in pigs.},
journal = {BMC genomics},
volume = {26},
number = {1},
pages = {484},
pmid = {40375066},
issn = {1471-2164},
support = {2021YFF1000600//National Key Research and Developmental Program of China/ ; 2021YFF1000600//National Key Research and Developmental Program of China/ ; 2021YFF1000600//National Key Research and Developmental Program of China/ ; 2021YFF1000600//National Key Research and Developmental Program of China/ ; 2021YFF1000600//National Key Research and Developmental Program of China/ ; 31972539//National Natural Science Foundation of China/ ; 31972539//National Natural Science Foundation of China/ ; 31501933//National Natural Science Foundation of China/ ; CJGJZD20210408092402006//Science and Technology Program of Shenzhen/ ; 2021YFD301201//National Key R&amp;D Program of China/ ; 2021YFD301201//National Key R&amp;D Program of China/ ; 2021YFD301201//National Key R&amp;D Program of China/ ; 2021YFD301201//National Key R&amp;D Program of China/ ; },
mesh = {Animals ; *Chromatin/chemistry/genetics ; Swine/genetics ; Quantitative Trait Loci ; *Gene Expression Regulation ; Organ Specificity ; Breeding ; },
abstract = {BACKGROUND: Topologically associating domains (TADs) are functional units that organize chromosomes into 3D structures of interacting chromatin, and play a crucial role in regulating gene expression by constraining enhancer-promoter contacts. Evidence suggests that deletion of TAD boundaries can lead to aberrant expression of neighboring genes. In our study, we analyzed high-throughput chromatin conformation capture (Hi-C) datasets from publicly available sources, integrating 71 datasets across five tissues in six pig breeds.<br><br>RESULTS: Our comprehensive analysis revealed 65,843 TADs in pigs, and we found that TAD boundaries are enriched for expression Quantitative Trait Loci (eQTL), splicing Quantitative Trait Loci (sQTL), Loss-of-Function variants (LoFs), and other regulatory variants. Genes within conserved TADs are associated with fundamental biological functions, while those in dynamic TADs may have tissue-specific roles. Specifically, we observed differential expression of the NCOA2 gene within dynamic TADs. This gene is highly expressed in adipose tissue, where it plays a crucial role in regulating lipid metabolism and maintaining energy homeostasis. Additionally, differential expression of the BMPER gene within dynamic TADs is associated with its role in modulating the activities of bone morphogenetic proteins (BMPs)-critical growth factors involved in bone and cartilage development.<br><br>CONCLUSION: Our investigations have shed light on the pivotal roles of TADs in governing gene expression and even influencing traits. Our study has unveiled a holistic interplay between chromatin interactions and gene regulation across various tissues and pig breeds. Furthermore, we anticipate that incorporating markers, such as structural variants (SVs), and phenotypes will enhance our understanding of their intricate interactions.},
}
@article {pmid40374602,
year = {2025},
author = {Sept, CE and Tak, YE and Goel, V and Bhakta, MS and Cerda-Smith, CG and Hutchinson, HM and Blanchette, M and Eyler, CE and Johnstone, SE and Joung, JK and Hansen, AS and Aryee, MJ},
title = {High-resolution CTCF footprinting reveals impact of chromatin state on cohesin extrusion.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {4506},
pmid = {40374602},
issn = {2041-1723},
support = {RM1HG009490//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; R35GM118158//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; T32GM135117//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; NNF21SA0072102//Novo Nordisk Fonden (Novo Nordisk Foundation)/ ; },
mesh = {*CCCTC-Binding Factor/metabolism/genetics ; Cohesins ; *Chromosomal Proteins, Non-Histone/metabolism/genetics ; *Cell Cycle Proteins/metabolism/genetics ; *Chromatin/metabolism/genetics/chemistry ; Humans ; Binding Sites ; Enhancer Elements, Genetic ; *DNA Footprinting/methods ; Promoter Regions, Genetic ; Protein Binding ; },
abstract = {Cohesin-mediated DNA loop extrusion enables gene regulation by distal enhancers through the establishment of chromosome structure and long-range enhancer-promoter interactions. The best characterized cohesin-related structures, such as topologically associating domains (TADs) anchored at convergent CTCF binding sites, represent static conformations. Consequently, loop extrusion dynamics remain poorly understood. To better characterize static and dynamically extruding chromatin loop structures, we use MNase-based 3D genome assays to simultaneously determine CTCF and cohesin localization as well as the 3D contacts they mediate. Here we present CTCF Analyzer (with) Multinomial Estimation (CAMEL), a tool that identifies CTCF footprints at near base-pair resolution in CTCF MNase HiChiP. We also use Region Capture Micro-C to identify a CTCF-adjacent footprint that is attributed to cohesin occupancy. We leverage this substantial advance in resolution to determine that the fully extruded (CTCF-CTCF loop) state is rare genome-wide with locus-specific variation from ~1-10%. We further investigate the impact of chromatin state on loop extrusion dynamics and find that active regulatory elements impede cohesin extrusion. These findings support a model of topological regulation whereby the transient, partially extruded state facilitates enhancer-promoter contacts that can regulate transcription.},
}
@article {pmid40340859,
year = {2025},
author = {Denaud, S and Sabarís, G and Di Stefano, M and Papadopoulos, GL and Schuettengruber, B and Cavalli, G},
title = {Determining the functional relationship between epigenetic and physical chromatin domains in Drosophila.},
journal = {Genome biology},
volume = {26},
number = {1},
pages = {116},
pmid = {40340859},
issn = {1474-760X},
mesh = {Animals ; *Chromatin/genetics/metabolism/chemistry ; *Epigenesis, Genetic ; Histones/metabolism ; Drosophila Proteins/genetics/metabolism ; *Drosophila melanogaster/genetics ; *Drosophila/genetics ; Histone Code ; Polycomb-Group Proteins/genetics ; },
abstract = {The tight correlation between topologically associating domains (TADs) and epigenetic domains in Drosophila suggests that the epigenome contributes to define TADs. However, it is still unknown whether histone modifications are essential for TAD formation and structure. By either deleting or shifting key regulatory elements needed to establish the epigenetic signature of Polycomb TADs, we show that the epigenome is not a major driving force for the establishment of TADs. On the other hand, physical domains have an important impact on the formation of epigenetic domains, as they can restrict the spreading of repressive histone marks and looping between cis-regulatory elements.},
}
@article {pmid40332394,
year = {2025},
author = {Blotas, C and Le Nabec, A and Collobert, M and Bulcaen, M and Carlon, MS and Férec, C and Moisan, S},
title = {Cis-Regulation of the CFTR Gene in Pancreatic Cells.},
journal = {International journal of molecular sciences},
volume = {26},
number = {8},
pages = {},
doi = {10.3390/ijms26083788},
pmid = {40332394},
issn = {1422-0067},
support = {RF20210502832//Vaincre la mucoviscidose/ ; 2020-J1810150-E015//Mucovereniging Belgium/ ; US_172749169_6//Emily's Entourage/ ; 1SE8122N//FWO-SB/ ; },
mesh = {*Cystic Fibrosis Transmembrane Conductance Regulator/genetics/metabolism ; Humans ; *Pancreas/metabolism/cytology ; Promoter Regions, Genetic ; Chromatin/genetics/metabolism ; *Gene Expression Regulation ; Cell Line ; Transcription Factors/metabolism/genetics ; *Regulatory Sequences, Nucleic Acid ; Cystic Fibrosis/genetics ; },
abstract = {Genome organization is essential for precise spatial and temporal gene expression and relies on interactions between promoters and distal cis-regulatory elements (CREs), which constitute ~8% of the human genome. For the cystic fibrosis transmembrane conductance regulator (CFTR) gene, tissue-specific expression, especially in the pancreas, remains poorly understood. Unraveling its regulation could clarify the clinical heterogeneity observed in cystic fibrosis and CFTR-related disorders. To understand the role of 3D chromatin architecture in establishing tissue-specific expression of the CFTR gene, we mapped chromatin interactions and epigenomic regulation in Capan-1 pancreatic cells. Candidate CREs are validated by luciferase reporter assay and CRISPR knock-out. We identified active CREs not only around the CFTR gene but also outside the topologically associating domain (TAD). We demonstrate the involvement of multiple CREs upstream and downstream of the CFTR gene and reveal a cooperative effect of the -44 kb, -35 kb, +15.6 kb, and +37.7 kb regions, which share common predicted transcription factor (TF) motifs. We also extend our analysis to compare 3D chromatin conformation in intestinal and pancreatic cells, providing valuable insights into the tissue specificity of CREs in regulating CFTR gene expression.},
}
@article {pmid40329044,
year = {2025},
author = {Irastorza-Azcarate, I and Kukalev, A and Kempfer, R and Thieme, CJ and Mastrobuoni, G and Markowski, J and Loof, G and Sparks, TM and Brookes, E and Natarajan, KN and Sauer, S and Fisher, AG and Nicodemi, M and Ren, B and Schwarz, RF and Kempa, S and Pombo, A},
title = {Extensive folding variability between homologous chromosomes in mammalian cells.},
journal = {Molecular systems biology},
volume = {},
number = {},
pages = {},
pmid = {40329044},
issn = {1744-4292},
support = {U54DK107977//HHS | National Institutes of Health (NIH)/ ; 1UM1HG011585-03//HHS | National Institutes of Health (NIH)/ ; 422841138//Deutsche Forschungsgemeinschaft (DFG)/ ; EXC-2049 - 390688087//Deutsche Forschungsgemeinschaft (DFG)/ ; PITN-GA-2007-214902//EC | Seventh Framework Programme (FP7)/ ; MC_U120061476//UKRI | Medical Research Council (MRC)/ ; MC_U120027516//UKRI | Medical Research Council (MRC)/ ; MC_UP_1605/12//UKRI | Medical Research Council (MRC)/ ; MRC Centenary grant//UKRI | Medical Research Council (MRC)/ ; Long-Term Fellowship//Federation of European Biochemical Societies (FEBS)/ ; 01IS18025A 01IS18037A//Helmholtz-Gemeinschaft/ ; M4C2 CN00000041 CUP E63C22000940007, MUR PRIN 2022 CUP E53D23001810006, MUR PRIN PNRR 2022 CUP E53D2//EC | NextGenerationEU (NGEU)/ ; },
abstract = {Genetic variation and 3D chromatin structure have major roles in gene regulation. Due to challenges in mapping chromatin conformation with haplotype-specific resolution, the effects of genetic sequence variation on 3D genome structure and gene expression imbalance remain understudied. Here, we applied Genome Architecture Mapping (GAM) to a hybrid mouse embryonic stem cell (mESC) line with high density of single-nucleotide polymorphisms (SNPs). GAM resolved haplotype-specific 3D genome structures with high sensitivity, revealing extensive allelic differences in chromatin compartments, topologically associating domains (TADs), long-range enhancer-promoter contacts, and CTCF loops. Architectural differences often coincide with allele-specific differences in gene expression, and with Polycomb occupancy. We show that histone genes are expressed with allelic imbalance in mESCs, and are involved in haplotype-specific chromatin contacts marked by H3K27me3. Conditional knockouts of Polycomb enzymatic subunits, Ezh2 or Ring1, show that one-third of ASE genes, including histone genes, is regulated through Polycomb repression. Our work reveals highly distinct 3D folding structures between homologous chromosomes, and highlights their intricate connections with allelic gene expression.},
}
@article {pmid40315272,
year = {2025},
author = {Han, J and Hu, G and Dai, Y and Zhang, X and Tian, J and Zhou, J and Xu, X and Chen, Q and Kou, X and Xu, L and Wu, X and Sun, Z and Geng, J and Li, L and Qiu, C and Mehari, TG and Wang, B and Zhang, H and Shen, X and Xu, Z and Wendel, JF and Wang, K},
title = {Centromere-size reduction and chromatin state dynamics following intergenomic hybridization in cotton.},
journal = {PLoS genetics},
volume = {21},
number = {5},
pages = {e1011689},
doi = {10.1371/journal.pgen.1011689},
pmid = {40315272},
issn = {1553-7404},
abstract = {Centromeres are pivotal for accurate chromosome segregation, yet their regulation and evolutionary dynamics remain poorly understood. Here, we investigate centromeres of the diploid species Gossypium anomalum (Ga, B-genome) that were transferred into tetraploid cotton G. hirsutum (Gh, AD-genome) as either an additional or integrated chromosome, as well as in synthetic allohexaploid (AABBDD) lines. We demonstrate consistent size reduction for all Ga centromeres in the Gh background. Histone modification profiling across 10 marks revealed heightened levels of both active and repressive chromatin marks within the Ga centromeres when transferred into the Gh background, particularly for H3K36me2. The centromeric histone modification perturbation extended into pericentromeric regions, with variable CENH3-binding domains consistently exhibiting a more pronounced increase in histone modification levels compared to stable centromere regions, highlighting the role of histone modification elevation in centromere dynamics. In addition, we observed enhanced chromatin accessibility and the presence of non-B-form DNA motifs, such as A-phased DNA repeats within stable centromere domains that are correlated with centromere stability. Hi-C analysis reveals a reorganized 3D chromatin architecture within the introgression line centromeres, including the formation of new topologically associating domains linked to H3K36me2 dynamics, emphasizing the importance of H3K36me2 in centromere organization. Together, these findings elucidate epigenetic mechanisms underlying centromere composition following intergenomic hybridization and allopolyploid formation, offering insights into centromere evolution in plants and its myriad epigenetic and potentially functional dimensions.},
}
@article {pmid40308064,
year = {2025},
author = {Yang, Q and Wu, T and Liu, M and Zhang, X and Sun, X and Feng, D and Lu, Y and Chen, X and Hong, Y and Ma, W and Zhao, J},
title = {An integrative 3D-genome database for plants.},
journal = {Plant communications},
volume = {},
number = {},
pages = {101346},
doi = {10.1016/j.xplc.2025.101346},
pmid = {40308064},
issn = {2590-3462},
abstract = {High-throughput sequencing technologies have revolutionized studies of 3D-genome structures, revealing unprecedented insights into the complexity of genome-wide gene regulation in eukaryotes. To analyze and compare 3D-genome structures, we developed the 3D-genome database for plants, 3D-GDP, for interspecies comparative functional genomics (http://www.3d-gdp.com/). 3D-GDP encompasses all publicly available plant 3D-genome sequences. It offers detailed analyses and comparisons of 3D-genome structures among 26 plant species, with comprehensive information on topologically associating domains (TADs), loops and compartments, as well as gene annotations. 3D-GDP also provides a range of bioinformatic tools such as genome browser, TAD function prediction, and specialized modules for predicting and systematically comparing chromatin structures across species to identify conserved TADs and loop structures. Taken together, the 3D-genome database for plants (3D-GDP) represents a resourceful integrating database and innovative platform that can be used to reveal evolutionary conservation of 3D-genome structures and their relevance to genome-wide gene regulation in plants and beyond.},
}
@article {pmid40278067,
year = {2025},
author = {Wu, C and Fan, J and Hu, D and Sun, H and Lu, G and Wang, Y and Yang, Y},
title = {The Three-Dimensional Structure of the Genome of the Dark Septate Endophyte Exophiala tremulae and Its Symbiosis Effect on Alpine Meadow Plant Growth.},
journal = {Journal of fungi (Basel, Switzerland)},
volume = {11},
number = {4},
pages = {},
doi = {10.3390/jof11040246},
pmid = {40278067},
issn = {2309-608X},
support = {U23A2043//the National Natural Science Foundation of China/ ; },
abstract = {The establishment of artificial grassland is a good pathway for resolving serious social and economic problems in the Qinghai-Tibet Plateau. Some beneficial indigenous microbes may be used to improve productivity in artificial grassland. The genome of the indigenous dark septate fungus, Exophiala tremulae CICC2537, was sequenced and assembled at the chromosome level using the PacBio sequencing platform, with the assistance of the Hi-C technique for scaffolding, and its 3D genome structures were investigated. The genome size of E. tremulae is 51.903848 Mb, and it contains eight chromosomes. A total of 12,277 protein-coding genes were predicted, and 11,932 genes (97.19%) were annotated. As for the distribution of exon and intron number and the distribution of gene GC and CDS GC, E. tremulae showed similar distribution patterns to the other investigated members of the genus Exophiala. The analysis of carbohydrate-active enzymes showed that E. tremulae possesses the greatest number of enzymes with auxiliary activities and the lowest number of enzymes with carbohydrate-binding modules among the investigated fungi. The total number of candidate effector proteins was 3337, out of which cytoplasmic and apoplastic effector proteins made up 3100 and 163, respectively. The whole genome of E. tremulae contained 40 compartment As and 76 compartment Bs, and there was no significant difference in GC content in its compartment As and Bs. The whole genome of E. tremulae was predicted to contain 155 topologically associating domains (TADs), and their average length was 250,000 bp, but there were no significant differences in the numbers of genes and the GC content per bin localized within the boundaries and interiors of TADs. Comparative genome analysis showed that E. tremulae diverged from Exophiala mesophila about 34.1 (30.0-39.1) Myr ago, and from Exophiala calicioides about 85.6 (76.1-90.6) Myr ago. Compared with all the investigated fungi, the numbers of contraction and expansion gene families in the E. tremulae genome were 13 and 89, respectively, and the numbers of contraction and expansion genes were 14 and 670, respectively. Our work provides a basis for the use of the dark septate fungus in alpine artificial grassland and further research into its symbiosis mechanisms, which may improve the growth of plant species used in the Qinghai-Tibet Plateau.},
}
@article {pmid40269984,
year = {2025},
author = {Sandås, K and Spindola, L and Løkhammer, S and Stavrum, AK and Andreassen, O and Tesfaye, M and Hellard, SL},
title = {Using LDpred2 to adapt polygenic risk score techniques for methylation score creation.},
journal = {BMC research notes},
volume = {18},
number = {1},
pages = {190},
pmid = {40269984},
issn = {1756-0500},
mesh = {Humans ; *DNA Methylation/genetics ; *Genome-Wide Association Study/methods ; *Schizophrenia/genetics ; *Multifactorial Inheritance/genetics ; *Genetic Predisposition to Disease ; *Software ; Models, Genetic ; Genetic Risk Score ; },
abstract = {OBJECTIVE: This study sought to determine if the R package LDpred2, designed for polygenic risk score creation for genome-wide association studies using summary statistics, could be adapted for deriving DNA methylation scores from methylome-wide association studies. Recognizing that linkage disequilibrium, used as prior in LDpred2, does not apply to methylation, we explored co-methylated regions and topologically associating domains as alternative structural priors for correlation between methylation sites. A genomic sliding-window approach was also tested. The performance of the LDpred2-based models was evaluated on methylation data from schizophrenia and control samples (N = 1,227).<br><br>RESULTS: LDpred2 models employing topologically associating domains and sliding window clusters as priors performed similarly to existing methods, explaining approximately 3.6% of schizophrenia phenotypic variance. The co-methylated regions model underperformed due to insufficient clustering of probes. The similarity in performance between the model using topologically associating domains and a null model consisting of random clusters suggests that the structural information provided by these domains enhances performance only marginally. In conclusion, while LDpred2 can be adapted for methylation data, it does not substantially enhance methylation score performance over existing methods, and the choice of structural prior may not be a critical factor.},
}
@article {pmid40268951,
year = {2025},
author = {Xu, H and Chi, Y and Yin, C and Li, C and Chen, Y and Liu, Z and Liu, X and Xie, H and Chen, ZJ and Zhao, H and Wu, K and Zhao, S and Xing, D},
title = {Three-dimensional genome structures of single mammalian sperm.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {3805},
pmid = {40268951},
issn = {2041-1723},
support = {32430061//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {The three-dimensional (3D) organization of chromosomes is crucial for packaging a large mammalian genome into a confined nucleus and ensuring proper nuclear functions in somatic cells. However, the packaging of the much more condensed sperm genome is challenging to study with traditional imaging or sequencing approaches. In this study, we develop an enhanced chromosome conformation capture assay, and resolve the 3D whole-genome structures of single mammalian sperm. The reconstructed genome structures accurately delineate the species-specific nuclear morphologies for both human and mouse sperm. We discover that sperm genomes are divided into chromosomal territories and A/B compartments, similarly to somatic cells. However, neither human nor mouse sperm chromosomes contain topologically associating domains or chromatin loops. These results suggest that the fine-scale chromosomal organization of mammalian sperm fundamentally differs from that of somatic cells. The discoveries and methods established in this work will be valuable for future studies of sperm related infertility.},
}
@article {pmid40007120,
year = {2025},
author = {Lee, S and Liu, X and Ziabkin, I and Zidovska, A},
title = {Image-based analysis of the genome's fractality during the cell cycle.},
journal = {Biophysical journal},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.bpj.2025.02.014},
pmid = {40007120},
issn = {1542-0086},
support = {R01 GM145924/GM/NIGMS NIH HHS/United States ; },
abstract = {The human genome consists of about 2 m of DNA packed inside the cell nucleus barely 10 μm in diameter. DNA is complexed with histones, forming chromatin fiber, which folds inside the nucleus into loops, topologically associating domains, A/B compartments, and chromosome territories. This organization is knot-free and self-similar across length scales, leading to a hypothesis that the genome presents a fractal globule, which was corroborated by chromosome conformation capture experiments. In addition, many microscopy techniques have been used to obtain the fractal dimension of the genome's spatial distribution from its images. However, different techniques often required that different definitions of fractal dimension be adapted, making the comparison of these results not trivial. In this study, we use spinning disk confocal microscopy to collect high-resolution images of nuclei in live human cells during the cell cycle. We then systematically compare existing image-based fractal analyses-including mass-scaling, box-counting, lacunarity, and multifractal spectrum-by applying them to images of human cell nuclei and investigate changes in the genome's spatial organization during the cell cycle. Our data reveal that different image-based fractal measurements offer distinct metrics, highlighting different features of the genome's spatial organization. Yet, all these metrics consistently indicate the following trend for the changes in the genome's organization during the cell cycle: the genome being compactly packed in early G1 phase, followed by a decondensation throughout the G1 phase, and a subsequent condensation in the S and G2 phases. Our comprehensive comparison of image-based fractal analyses reconciles the perceived discrepancies between different methods. Moreover, our results offer new insights into the physical principles underlying the genome's organization and its changes during the cell cycle.},
}
@article {pmid40250193,
year = {2025},
author = {Vargas, LCZ and Ortíz-Ortíz, J and Martínez, YA and Viguri, GEC and Rojas, FIT and Ávila-López, PA},
title = {Identification of ZNF384 as a regulator of epigenome in leukemia.},
journal = {Leukemia research},
volume = {153},
number = {},
pages = {107691},
doi = {10.1016/j.leukres.2025.107691},
pmid = {40250193},
issn = {1873-5835},
abstract = {Leukemia is a complex hematologic cancer driven by genetic and epigenetic changes that impact gene expression. Understanding these molecular mechanisms is essential for improving leukemia diagnosis and prognosis. This study examines the role of the zinc finger protein ZNF384 in the epigenome and its influence on gene regulation in leukemia. We analyzed next-generation sequencing data from The Encyclopedia of DNA Elements (ENCODE), integrating datasets such as chromatin immunoprecipitation sequencing (ChIP-seq) of ZNF384 and regulatory histone marks, RNA sequencing (RNA-seq), and Hi-C data from K562 and GM12878 cells. Additionally, we used RNA-seq from K562 ZNF384 knock-down (KD) cells generated via CRISPR interference (CRISPRi) to validate our findings. This enabled us to explore the chromatin interaction patterns of ZNF384 and its regulatory impact. Our results demonstrate that ZNF384 associates with promoters and enhancers in K562 and GM12878 cells, facilitating increased transcription levels. We also found ZNF384 enriched at topologically associating domain (TAD) boundaries and chromatin loops, suggesting a role in three-dimensional (3D) chromatin organization. Furthermore, we identified a significant binding of ZNF384 at SINE-Alu elements in both K562 and GM12878 cells. In summary, this study highlights the regulatory role of ZNF384 in the leukemia epigenome and its impact on gene expression. Understanding the oncogenic implications of ZNF384 may improve leukemia diagnosis and prognosis.},
}
@article {pmid40247362,
year = {2025},
author = {Zhou, H and Liu, Y and Tian, GG and Wu, J},
title = {Nicotinamide mononucleotide promotes female germline stem cell proliferation by activating the H4K16ac-Hmgb1-Fyn-PLD signaling pathway through epigenetic remodeling.},
journal = {Cell &amp; bioscience},
volume = {15},
number = {1},
pages = {48},
pmid = {40247362},
issn = {2045-3701},
support = {2022YFA0806301//the National Key Research and Development Program of China/ ; 23JC1402800//the Scientific and Technological Innovation Action Program of Shanghai/ ; },
abstract = {BACKGROUND: Nicotinamide mononucleotide (NMN), an endogenous nucleotide essential for various physiological processes, has an unclear role and regulatory mechanisms in female germline stem cell (FGSC) development.<br><br>RESULTS: We demonstrate that NMN significantly enhances FGSC viability and proliferation. Quantitative acetylation proteomics revealed that NMN markedly increases the acetylation of histone H4 at lysine 16 (H4K16ac). Subsequent chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) identified high mobility group box 1 (Hmgb1) as a downstream target of H4K16ac, a finding further validated by ChIP-qPCR. Knockdown of Hmgb1 reduced FGSC proliferation by disrupting cell cycle progression, inducing apoptosis, and decreasing chromatin accessibility. High-throughput chromosome conformation capture (Hi-C) analysis showed that Hmgb1 knockdown induced A/B compartment switching, increased the number of topologically associating domains (TADs), and decreased chromatin loop formation in FGSCs. Notably, the chromatin loop at the promoter region of Fyn proto-oncogene (Fyn) disappeared following Hmgb1 knockdown. ChIP-qPCR and dual-luciferase reporter assays further confirmed the interaction between Hmgb1 and the Fyn promoter. Importantly, Fyn overexpression reversed the inhibitory effects of Hmgb1 knockdown on FGSC proliferation. Proteomic analysis suggested this rescue was mediated through the phospholipase D (PLD) signaling pathway, as Fyn overexpression selectively enhanced the phosphorylation of PLD1 at threonine 147 without affecting serine 561. Furthermore, treatment with 5-fluoro-2-indolyldechlorohaloamide, a PLD inhibitor, nullified the pro-proliferative effects of Fyn overexpression.<br><br>CONCLUSIONS: Our findings reveal that NMN promotes FGSC proliferation by activating the H4K16ac-Hmgb1-Fyn-PLD signaling pathway through epigenetic remodeling. These results deepen our understanding of FGSC proliferation and highlight potential therapeutic avenues for advancing FGSC applications in reproductive medicine.},
}
@article {pmid40236218,
year = {2025},
author = {Li, C and Mowlaei, ME and , and Carnevale, V and Kumar, S and Shi, X},
title = {TRUHiC: A TRansformer-embedded U-2 Net to enhance Hi-C data for 3D chromatin structure characterization.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.03.29.646133},
pmid = {40236218},
issn = {2692-8205},
abstract = {High-throughput chromosome conformation capture sequencing (Hi-C) is a key technology for studying the three-dimensional (3D) structure of genomes and chromatin folding. Hi-C data reveals important patterns of genome organization such as topologically associating domains (TADs) and chromatin loops with critical roles in transcriptional regulation and disease etiology and progression. However, the relatively low resolution of existing Hi-C data often hinders robust and reliable inference of 3D structures. Hence, we propose TRUHiC, a new computational method that leverages recent state-of-the-art deep generative modeling to augment low-resolution Hi-C data for the characterization of 3D chromatin structures. Applying TRUHiC to publically available Hi-C data for human and mice, we demonstrate that the augmented data significantly improves the characterization of TADs and loops across diverse cell lines and species. We further present a pre-trained TRUHiC on human lymphoblastoid cell lines that can be adaptable and transferable to improve chromatin characterization of various cell lines, tissues, and species.},
}
@article {pmid40235997,
year = {2025},
author = {Liang, H and Berger, B and Singh, R},
title = {Tracing the Shared Foundations of Gene Expression and Chromatin Structure.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.03.31.646349},
pmid = {40235997},
issn = {2692-8205},
abstract = {UNLABELLED: The three-dimensional organization of chromatin into topologically associating domains (TADs) may impact gene regulation by bringing distant genes into contact. However, many questions about TADs' function and their influence on transcription remain unresolved due to technical limitations in defining TAD boundaries and measuring the direct effect that TADs have on gene expression. Here, we develop consensus TAD maps for human and mouse with a novel "bag-of-genes" approach for defining the gene composition within TADs. This approach enables new functional interpretations of TADs by providing a way to capture species-level differences in chromatin organization. We also leverage a generative AI foundation model computed from 33 million transcriptomes to define contextual similarity, an embedding-based metric that is more powerful than co-expression at representing functional gene relationships. Our analytical framework directly leads to testable hypotheses about chromatin organization across cellular states. We find that TADs play an active role in facilitating gene co-regulation, possibly through a mechanism involving transcriptional condensates. We also discover that the TAD-linked enhancement of transcriptional context is strongest in early developmental stages and systematically declines with aging. Investigation of cancer cells show distinct patterns of TAD usage that shift with chemotherapy treatment, suggesting specific roles for TAD-mediated regulation in cellular development and plasticity. Finally, we develop "TAD signatures" to improve statistical analysis of single-cell transcriptomic data sets in predicting cancer cell-line drug response. These findings reshape our understanding of cellular plasticity in development and disease, indicating that chromatin organization acts through probabilistic mechanisms rather than deterministic rules.<br><br>SOFTWARE AVAILABILITY: https://singhlab.net/tadmap.},
}
@article {pmid40210441,
year = {2025},
author = {Kim, J and Wang, H and Ercan, S},
title = {Cohesin organizes 3D DNA contacts surrounding active enhancers in C. elegans.},
journal = {Genome research},
volume = {},
number = {},
pages = {},
doi = {10.1101/gr.279365.124},
pmid = {40210441},
issn = {1549-5469},
abstract = {In mammals, cohesin and CTCF organize the 3D genome into topologically associating domains (TADs) to regulate communication between cis-regulatory elements. Many organisms, including S. cerevisiae, C. elegans, and A. thaliana contain cohesin but lack CTCF. Here, we used C. elegans to investigate the function of cohesin in 3D genome organization in the absence of CTCF. Using Hi-C data, we observe cohesin-dependent features called "fountains," which have also been reported in zebrafish and mice. These are population average reflections of DNA loops originating from distinct genomic regions and are ∼20-40 kb in C. elegans Hi-C analysis upon cohesin and WAPL-1 depletion supports the idea that cohesin is preferentially loaded at sites bound by the C. elegans ortholog of NIPBL and loop extrudes in an effectively two-sided manner. ChIP-seq analyses show that cohesin translocation along the fountain trajectory depends on a fully intact complex and is extended upon WAPL-1 depletion. Hi-C contact patterns at individual fountains suggest that cohesin processivity is unequal on each side, possibly owing to collision with cohesin loaded from surrounding sites. The putative cohesin loading sites are closest to active enhancers, and fountain strength is associated with transcription. Compared with mammals, the average processivity of C. elegans cohesin is about 10-fold shorter, and the binding of NIPBL ortholog does not depend on cohesin. We propose that preferential loading and loop extrusion by cohesin is an evolutionarily conserved mechanism that regulates the 3D interactions of enhancers in animal genomes.},
}
@article {pmid40200588,
year = {2025},
author = {Hu, A and Zhou, W and Luo, X and Qiu, R and Li, J},
title = {Correlation Between DNA Double-Strand Break Distribution in 3D Genome and Ionizing Radiation-Induced Cell Death.},
journal = {Radiation research},
volume = {},
number = {},
pages = {},
doi = {10.1667/RADE-24-00277.1},
pmid = {40200588},
issn = {1938-5404},
abstract = {The target theory is the most classical hypothesis explaining radiation-induced cell death, yet the physical or biological nature of the "target" remains ambiguous. This study hypothesizes that the distribution of DNA double-strand breaks (DSBs) within the 3D genome is a pivotal factor affecting the probability of radiation-induced cell death. We propose that clustered DSBs in DNA segments with high-interaction frequencies are more susceptible to leading to cell death than isolated DSBs. Topologically associating domains (TAD) can be regarded as the reference unit for evaluating the impact of DSB clustering in the 3D genome. To quantify this correlation between the DSB distribution in 3D genome and radiation-induced effect, we developed a simplified model considering the DSB distribution across TADs. Utilizing track-structure Monte Carlo codes to simulate the electron and carbon ion irradiation, and we calculated the incidence of each DSB case across a variety of radiation doses and linear energy transfers (LETs). Our simulation results indicate that DSBs in TADs with frequent interactions (case 3) are significantly more likely to induce cell death than clustered DSBs within a single TAD (case 2). Moreover, case 2 is significantly more likely to induce cell death than isolated DSBs (case 1). The curves of the incidence of cases 2 and 3 compared with LETs have a similar shape to the radiation quality factor (Q) used in radiation protection. This indicates that these two cases are also associated with the stochastic effects induced by high-LET radiation. Our study underscores the crucial significance of the 3D genome structure in the fundamental mechanisms of radiobiological effects. The hypothesis in our research offers novel perspectives on the mechanisms that regulate radiobiological effects. Moreover, it serves as a valuable reference for the establishment of mechanistic models that can predict cell survival under different doses and LETs.},
}
@article {pmid40196636,
year = {2025},
author = {Qiu, J and Jadali, A and Martinez, E and Song, Z and Ni, JZ and Kwan, KY},
title = {CHD7 binds to insulators during neuronal differentiation.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.03.28.646031},
pmid = {40196636},
issn = {2692-8205},
abstract = {Spiral ganglion neurons (SGNs) are crucial for hearing, and the loss of SGNs causes hearing loss. Stem cell-based therapies offer a promising approach for SGN regeneration and require understanding the mechanisms governing SGN differentiation. We investigated the chromatin remodeler CHD7 in neuronal differentiation using immortalized multipotent otic progenitor (iMOP) cells. We demonstrated that CHD7 knockdown impaired neuronal differentiation. Genome-wide analysis revealed CHD7 binding at diverse cis -regulatory elements, with notable enrichment at sites marked by the insulator-binding protein CTCF between topologically associating domains (TADs). Insulators marked by the enrichment of CHD7 and CTCF resided near genes critical for neuronal differentiation, including Mir9-2 . Targeting these regulatory regions in iMOPs with CRISPR interference (CRISPRi) and activation (CRISPRa) increased miR-9 transcription, irrespective of the method. Blocking the CHD7 and CTCF marked sites suggested that the elements function as insulators to regulate gene expression. The study highlights CHD7 activity at insulators and underscores an unreported mechanism for promoting neuronal differentiation.},
}
@article {pmid40131313,
year = {2025},
author = {Wang, X and Luo, J and Wu, L and Luo, H and Guo, F},
title = {deepTAD: an approach for identifying topologically associated domains based on convolutional neural network and transformer model.},
journal = {Briefings in bioinformatics},
volume = {26},
number = {2},
pages = {},
doi = {10.1093/bib/bbaf127},
pmid = {40131313},
issn = {1477-4054},
support = {62372156//National Natural Science Foundation of China/ ; 232102211046//Henan Provincial Department of Science and Technology Research Project/ ; },
mesh = {*Neural Networks, Computer ; Humans ; Computational Biology/methods ; Algorithms ; Chromatin/chemistry/genetics ; Software ; Genomics/methods ; },
abstract = {MOTIVATION: Topologically associated domains (TADs) play a key role in the 3D organization and function of genomes, and accurate detection of TADs is essential for revealing the relationship between genomic structure and function. Most current methods are developed to extract features in Hi-C interaction matrix to identify TADs. However, due to complexities in Hi-C contact matrices, it is difficult to directly extract features associated with TADs, which prevents current methods from identifying accurate TADs.<br><br>RESULTS: In this paper, a novel method is proposed, deepTAD, which is developed based on a convolutional neural network (CNN) and transformer model. First, based on Hi-C contact matrix, deepTAD utilizes CNN to directly extract features associated with TAD boundaries. Next, deepTAD takes advantage of the transformer model to analyze the variation features around TAD boundaries and determines the TAD boundaries. Second, deepTAD uses the Wilcoxon rank-sum test to further identify false-positive boundaries. Finally, deepTAD computes cosine similarity among identified TAD boundaries and assembles TAD boundaries to obtain hierarchical TADs. The experimental results show that TAD boundaries identified by deepTAD have a significant enrichment of biological features, including structural proteins, histone modifications, and transcription start site loci. Additionally, when evaluating the completeness and accuracy of identified TADs, deepTAD has a good performance compared with other methods. The source code of deepTAD is available at https://github.com/xiaoyan-wang99/deepTAD.},
}
@article {pmid40117347,
year = {2025},
author = {Li, SH and Liang, YC and Jiang, TX and Jea, WC and Chih-Kuan Chen, and Lu, J and Núñez-León, D and Yu, Z and Lai, YC and Widelitz, RB and Andersson, L and Wu, P and Chuong, CM},
title = {Skin regional specification and higher-order HoxC regulation.},
journal = {Science advances},
volume = {11},
number = {12},
pages = {eado2223},
doi = {10.1126/sciadv.ado2223},
pmid = {40117347},
issn = {2375-2548},
mesh = {Animals ; *Homeodomain Proteins/genetics/metabolism ; *Feathers ; *Chickens/genetics ; *Skin/metabolism ; Gene Expression Regulation, Developmental ; },
abstract = {The integument plays a critical role in functional adaptation, with macro-regional specification forming structures like beaks, combs, feathers, and scales, while micro-regional specification modifies skin appendage shapes. However, the molecular mechanisms remain largely unknown. Craniofacial integument displays dramatic diversity, exemplified by the Polish chicken (PC) with a homeotic transformation of comb-to-crest feathers, caused by a 195-base pair (bp) duplication in HoxC10 intron. Micro-C analyses show that HoxC-containing topologically associating domain (TAD) is normally closed in the scalp but open in the dorsal and tail regions, allowing multiple long-distance contacts. In the PC scalp, the TAD is open, resulting in high HoxC expression. CRISPR-Cas9 deletion of the 195-bp duplication reduces crest feather formation, and HoxC misexpression alters feather shapes. The 195-bp sequence is found only in Archelosauria (crocodilians and birds) and not in mammals. These findings suggest that higher-order regulation of the HoxC cluster modulates gene expression, driving the evolution of adaptive integumentary appendages in birds.},
}
@article {pmid40098664,
year = {2025},
author = {Xu, S and Shan, L and Tian, R and Yu, Z and Sun, D and Zhang, Z and Seim, I and Zhou, M and Sun, L and Liang, N and Zhang, Q and Chai, S and Yin, D and Deme, L and Wu, T and Chen, Y and Xu, Z and Zheng, Y and Ren, W and Yang, G},
title = {Multi-level genomic convergence of secondary aquatic adaptation in marine mammals.},
journal = {Innovation (Cambridge (Mass.))},
volume = {6},
number = {3},
pages = {100798},
pmid = {40098664},
issn = {2666-6758},
abstract = {Marine mammals provide a valuable model for studying the molecular basis of convergent evolution during secondary aquatic adaptation. Using multi-omics data and functional experiments, including CRISPR-Cas9 mouse models and luciferase reporter assays, this study explored the molecular mechanisms driving this transition across coding regions, regulatory elements, and genomic architecture. Convergent amino acid substitutions in APPL1 [P378L] and NEIL1 [E71G] were found to promote lipid accumulation and suppress cancer cell proliferation, likely contributing to the evolution of extensive blubber layers and cancer resistance. Convergently evolved conserved non-exonic elements (CNEs) and lineage-specific regulatory variations were shown to influence the activity of nearby genes (e.g., NKX3-2, SOX9, HAND2), shaping cetacean limb phenotypes. Additionally, convergent shifts in topologically associating domains (TADs) across cetaceans and pinnipeds were implicated in the regulation of ASXL3 and FAM43B expression, playing a role in the formation of thickened blubber layers and mitigating cancer susceptibility. Structural variations within conserved TADs were associated with the expression of neuronal genes, including NUP153 and ID4, potentially driving cognitive and social adaptations. These findings provide novel insights into the molecular foundations of the convergent evolution of secondary aquatic adaptations in mammals.},
}
@article {pmid40092712,
year = {2025},
author = {Ning, D and Deng, Y and Tian, SZ},
title = {Chromatin structure and gene transcription of recombinant p53 adenovirus vector within host.},
journal = {Frontiers in molecular biosciences},
volume = {12},
number = {},
pages = {1562357},
pmid = {40092712},
issn = {2296-889X},
abstract = {INTRODUCTION: The recombinant human p53 adenovirus (Ad-p53) offers a promising approach for cancer therapy, yet its chromatin structure and effects on host chromatin organization and gene expression are not fully understood.<br><br>METHODS: In this study, we employed in situ ChIA-PET to investigate the colorectal cancer cell line HCT116 with p53 knockout, comparing them to cells infected with the adenovirus-vector expressing p53. We examined alterations in chromatin interactions and gene expression following treatment with the anti-cancer drug 5-fluorouracil (5-FU).<br><br>RESULTS: Our results indicate that Ad-p53 forms a specific chromatin architecture within the vector and mainly interacts with repressive or inactive regions of host chromatin, without significantly affecting the expression of associated genes. Additionally, Ad-p53 does not affect topologically associating domains (TADs) or A/B compartments in the host genome.<br><br>DISCUSSION: These findings suggest that while Ad-p53 boosts p53 expression, enhancing drug sensitivity without substantially altering host HCT116 chromatin architecture.},
}
@article {pmid40063813,
year = {2025},
author = {Papale, A and Segueni, J and El Maroufi, H and Noordermeer, D and Holcman, D},
title = {Insulation between adjacent TADs is controlled by the width of their boundaries through distinct mechanisms.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {122},
number = {11},
pages = {e2413112122},
doi = {10.1073/pnas.2413112122},
pmid = {40063813},
issn = {1091-6490},
support = {882673//ERC/ ; 19CS145-00//plan cancer/ ; AnalysisSpectralEEG//Agence national recherche/ ; ANR-21-CE12-0034//Agence national recherche/ ; ANR-22-CE12-0016//Agence national recherche/ ; ANR-22-CE14-0021//Agence national recherche/ ; },
mesh = {*CCCTC-Binding Factor/metabolism/genetics ; *Chromatin/metabolism/genetics ; Animals ; Binding Sites ; Humans ; Enhancer Elements, Genetic ; Promoter Regions, Genetic ; Cohesins ; Cell Cycle Proteins/metabolism/genetics ; Chromosomal Proteins, Non-Histone/metabolism/genetics ; Insulator Elements/genetics ; Genome ; },
abstract = {Topologically associating domains (TADs) are sub-Megabase regions in vertebrate genomes with enriched intradomain interactions that restrict enhancer-promoter contacts across their boundaries. However, the mechanisms that separate TADs remain incompletely understood. Most boundaries between TADs contain CTCF binding sites (CBSs), which individually contribute to the blocking of Cohesin-mediated loop extrusion. Using genome-wide classification, here we show that the width of TAD boundaries forms a continuum from narrow to highly extended and correlates with CBSs distribution, chromatin features, and gene regulatory elements. To investigate how these boundary widths emerge, we modified the random crosslinker polymer model to incorporate specific boundary configurations, enabling us to evaluate the differential impact of boundary composition on TAD insulation. Our analysis, using three generic boundary categories, identifies differential influence on TAD insulation, with varying local and distal effects on neighboring domains. Notably, we find that increasing boundary width reduces long-range inter-TAD contacts, as confirmed by Hi-C data. While blocking loop extrusion at boundaries indirectly promotes spurious intermingling of neighboring TADs, extended boundaries counteract this effect, emphasizing their role in establishing genome organization. In conclusion, TAD boundary width not only enhances the efficiency of loop extrusion blocking but may also modulate enhancer-promoter contacts over long distances across TAD boundaries, providing a further mechanism for transcriptional regulation.},
}
@article {pmid40060486,
year = {2025},
author = {Tastemel, M and Jussila, A and Saravanan, B and Huang, H and Xie, Y and Zhu, Q and Jiang, Y and Armand, E and Ren, B},
title = {Context-Dependent and Gene-Specific Role of Chromatin Architecture Mediated by Histone Modifiers and Loop-extrusion Machinery.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.02.21.639596},
pmid = {40060486},
issn = {2692-8205},
abstract = {Loop-extrusion machinery, comprising the cohesin complex and CCCTC-binding factor CTCF, organizes the interphase chromosomes into topologically associating domains (TADs) and loops, but acute depletion of components of this machinery results in variable transcriptional changes in different cell types, highlighting the complex relationship between chromatin organization and gene regulation. Here, we systematically investigated the role of 3D genome architecture in gene regulation in mouse embryonic stem cells under various perturbation conditions. We found that acute depletion of cohesin or CTCF disrupts the formation of TADs, but affects gene regulation in a gene-specific and context-dependent manner. Furthermore, the loop extrusion machinery was dispensable for transcription from most genes in steady state, consistent with prior results, but became critical for a large number of genes during transition of cellular states. Through a genome-wide CRISPR screen, we uncovered multiple factors that can modulate the role of loop extrusion machinery in gene regulation in a gene-specific manner. Among them were the MORF acetyltransferase complex members (Kat6b, Ing5, Brpf1), which could antagonize the transcriptional insulation mediated by CTCF and cohesin complex at developmental genes. Interestingly, inhibition of Kat6b partially rescues the insulator defects in cells lacking the cohesin loader Nipbl, mutations of which are responsible for the developmental disorder Cornelia de Lange syndrome. Taken together, our findings uncovered interplays between the loop extrusion machinery and histone modifying complex that underscore the context-dependent and gene-specific role of the 3D genome.},
}
@article {pmid40058875,
year = {2025},
author = {Lee, J and Mo, HL and Ha, Y and Nam, DY and Lim, G and Park, JW and Park, S and Choi, WY and Lee, HJ and Rhee, JK},
title = {Unraveling the three-dimensional genome structure using machine learning.},
journal = {BMB reports},
volume = {},
number = {},
pages = {},
pmid = {40058875},
issn = {1976-670X},
abstract = {The study of chromatin interactions has advanced considerably with technologies such as high-throughput chromosome conformation capture (Hi-C) sequencing, providing a genome-wide view of physical interactions within the nucleus. These techniques have revealed the existence of hierarchical chromatin structures such as compartments, topologically associating domains (TADs), and chromatin loops, which are crucial in genome organization and regulation. However, identifying and analyzing these structural features require advanced computational methods. In recent years, machine learning approaches, particularly deep learning, have emerged as powerful tools for detecting and analyzing structural information. In this review, we present an overview of various machine learning-based techniques for determining chromosomal organization. Starting with the progress in predicting interactions from DNA sequences, we describe methods for identifying various hierarchical structures from Hi-C data. Additionally, we present advances in enhancing the chromosome contact frequency map resolution to overcome the limitations of Hi-C data. Finally, we identify the remaining challenges and propose potential solutions and future directions.},
}
@article {pmid40053568,
year = {2025},
author = {Kearly, A and Saelee, P and Bard, J and Sinha, S and Satterthwaite, A and Garrett-Sinha, LA},
title = {Sequences within and upstream of the mouse Ets1 gene drive high level expression in B cells, but are not sufficient for consistent expression in T cells.},
journal = {PloS one},
volume = {20},
number = {3},
pages = {e0308896},
doi = {10.1371/journal.pone.0308896},
pmid = {40053568},
issn = {1932-6203},
mesh = {*Proto-Oncogene Protein c-ets-1/genetics/metabolism ; Animals ; *B-Lymphocytes/metabolism/immunology ; Mice ; *T-Lymphocytes/metabolism/immunology ; Gene Expression Regulation ; Chromatin/metabolism/genetics ; Humans ; Enhancer Elements, Genetic ; },
abstract = {The levels of transcription factor Ets1 are high in resting B and T cells, but are downregulated by signaling through antigen receptors and Toll-like receptors (TLRs). Loss of Ets1 in mice leads to excessive immune cell activation and development of an autoimmune syndrome and reduced Ets1 expression has been observed in human PBMCs in the context of autoimmune diseases. In B cells, Ets1 serves to prevent premature activation and differentiation to antibody-secreting cells. Given these important roles for Ets1 in the immune response, stringent control of Ets1 gene expression levels is required for homeostasis. However, the genetic regulatory elements that control expression of the Ets1 gene remain relatively unknown. Here we identify a topologically-associating domain (TAD) in the chromatin of B cells that includes the mouse Ets1 gene locus and describe an interaction hub that extends over 100 kb upstream and into the gene body. Additionally, we compile epigenetic datasets to find several putative regulatory elements within the interaction hub by identifying regions of high DNA accessibility and enrichment of active enhancer histone marks. Using reporter constructs, we determine that DNA sequences within this interaction hub are sufficient to direct reporter gene expression in lymphoid tissues of transgenic mice. Further analysis indicates that the reporter construct drives faithful expression of the reporter gene in mouse B cells, but variegated expression in T cells, suggesting the existence of T cell regulatory elements outside this region. To investigate how the downregulation of Ets1 transcription is associated with alterations in the epigenetic landscape of stimulated B cells, we performed ATAC-seq in resting and BCR-stimulated primary B cells and identified four regions within and upstream of the Ets1 locus that undergo changes in chromatin accessibility that correlate to Ets1 gene expression. Interestingly, functional analysis of several putative Ets1 regulatory elements using luciferase constructs suggested a high level of functional redundancy. Taken together our studies reveal a complex network of regulatory elements and transcription factors that coordinate the B cell-specific expression of Ets1.},
}
@article {pmid40022213,
year = {2025},
author = {Yang, X and Cheng, L and Xin, Y and Zhang, J and Chen, X and Xu, J and Zhang, M and Feng, R and Hyle, J and Qi, W and Rosikiewicz, W and Xu, B and Li, C and Xu, P},
title = {CTCF is selectively required for maintaining chromatin accessibility and gene expression in human erythropoiesis.},
journal = {Genome biology},
volume = {26},
number = {1},
pages = {44},
pmid = {40022213},
issn = {1474-760X},
support = {82170119//National Natural Science Foundation of China/ ; BK20210714//Jiangsu Province National Science and Technology grant/ ; ZXL2022443//Suzhou Municipality Gusu Leading Talents grant/ ; },
mesh = {Humans ; *CCCTC-Binding Factor/metabolism/genetics ; *Erythropoiesis/genetics ; *Chromatin/metabolism ; Cell Line ; Gene Expression Regulation ; Erythroid Precursor Cells/metabolism/cytology ; },
abstract = {BACKGROUND: CTCF is considered as the most essential transcription factor regulating chromatin architecture and gene expression. However, genome-wide impact of CTCF on erythropoiesis has not been extensively investigated.<br><br>RESULTS: Using a state-of-the-art human erythroid progenitor cell model (HUDEP-2 and HEL cell lines), we systematically investigate the effects of acute CTCF loss by an auxin-inducible degron system on transcriptional programs, chromatin accessibility, CTCF genome occupancy, and genome architecture. By integrating multi-omics datasets, we reveal that acute CTCF loss notably disrupts genome-wide chromatin accessibility and the transcription network. We detect over thousands of decreased chromatin accessibility regions but only a few hundred increased regions after CTCF depletion in HUDEP-2 and HEL lines, suggesting the role of CTCF in maintaining proper chromatin openness in the erythroid lineage. CTCF depletion in the erythroid context notably disrupts the boundary integrity of topologically associating domains and chromatin loops but does not affect nuclear compartmentalization. We find erythroid lineage-specific genes, including some metabolism-related genes, are suppressed at immature and mature stages. Notably, we find a subset of genes whose transcriptional levels increase upon CTCF depletion, accompanied by decreased chromatin accessibility regions enriched with the GATA motif. We further decipher the molecular mechanism underlying the CTCF/GATA2 repression axis through distal non-coding chromatin regions. These results suggest a suppressive role of CTCF in gene expression during erythroid lineage specification.<br><br>CONCLUSIONS: Our study reveals a novel role of CTCF in regulating erythroid differentiation by maintaining its proper chromatin openness and gene expression network, which extends our understanding of CTCF biology.},
}
@article {pmid40017784,
year = {2025},
author = {Zhang, S and Xie, X and Zhang, H and Zhao, Z and Xia, K and Song, H and Li, Q and Li, M and Ge, Z},
title = {Visualizing Reactive Oxygen Species-Induced DNA Damage Process in Higher-Ordered Origami Nanostructures.},
journal = {JACS Au},
volume = {5},
number = {2},
pages = {965-974},
pmid = {40017784},
issn = {2691-3704},
abstract = {The genetic information on organisms is stored in the cell nucleus in the form of higher-ordered DNA structures. Here, we use DNA framework nanostructures (DFNs) to simulate the compaction and stacking density of nucleosome DNA for precise conformational and structure determination, particularly the dynamic structural changes, preferential reaction regions, and sites of DFNs during the reactive oxygen species (ROS) reaction process. By developing an atomic force microscopy-based single-particle analysis (SPA) data reconstruction method to collect and reanalyze imaging information, we demonstrate that the geometric morphology of DFNs constrains their reaction kinetics with ROS, where local mechanical stress and regional base distribution are two key factors affecting their kinetics. Furthermore, we plot the reaction process diagram for ROS and DFNs, showing the reaction process and intermediate products with individual activation energies. This SPA method offers new research tools and insights for studying the dynamic changes of highly folded and organized DNA structural domains within the nucleus and helps to reveal the key mechanisms behind their functional differences in topologically associating domains.},
}
@article {pmid40011778,
year = {2025},
author = {Zhao, H and Shu, L and Qin, S and Lyu, F and Liu, F and Lin, E and Xia, S and Wang, B and Wang, M and Shan, F and Lin, Y and Zhang, L and Gu, Y and Blobel, GA and Huang, K and Zhang, H},
title = {Extensive mutual influences of SMC complexes shape 3D genome folding.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {40011778},
issn = {1476-4687},
abstract = {Mammalian genomes are folded through the distinct actions of structural maintenance of chromosome (SMC) complexes, which include the chromatin loop-extruding cohesin (extrusive cohesin), the sister chromatid cohesive cohesin and the mitotic chromosome-associated condensins[1-3]. Although these complexes function at different stages of the cell cycle, they exist together on chromatin during the G2-to-M phase transition, when the genome structure undergoes substantial reorganization[1,2]. Yet, how the different SMC complexes affect each other and how their interactions orchestrate the dynamic folding of the three-dimensional genome remain unclear. Here we engineered all possible cohesin and condensin configurations on mitotic chromosomes to delineate the concerted, mutually influential action of SMC complexes. We show that condensin disrupts the binding of extrusive cohesin at CCCTC-binding factor (CTCF) sites, thereby promoting the disassembly of interphase topologically associating domains (TADs) and loops during mitotic progression. Conversely, extrusive cohesin impedes condensin-mediated mitotic chromosome spiralization. Condensin reduces peaks of cohesive cohesin, whereas cohesive cohesin antagonizes condensin-mediated longitudinal shortening of mitotic chromosomes. The presence of both extrusive and cohesive cohesin synergizes these effects and inhibits mitotic chromosome condensation. Extrusive cohesin positions cohesive cohesin at CTCF-binding sites. However, cohesive cohesin by itself cannot be arrested by CTCF molecules and is insufficient to establish TADs or loops. Moreover, it lacks loop-extrusion capacity, which indicates that cohesive cohesin has nonoverlapping functions with extrusive cohesin. Finally, cohesive cohesin restricts chromatin loop expansion mediated by extrusive cohesin. Collectively, our data describe a three-way interaction among major SMC complexes that dynamically modulates chromatin architecture during cell cycle progression.},
}
@article {pmid39999165,
year = {2025},
author = {Meng, L and Sheong, FK and Luo, Q},
title = {Linking DNA-packing density distribution and TAD boundary locations.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {122},
number = {9},
pages = {e2418456122},
doi = {10.1073/pnas.2418456122},
pmid = {39999165},
issn = {1091-6490},
support = {2022M721203//China Postdoctoral Science Foundation (China Postdoctoral Foundation Project)/ ; No. 20173326//The Construction Plan of Guangdong Province High-level Universities and the Research Start-up Funds for the High-level Talent Introduction Project of South China Agricultural University/ ; 22403033//MOST | National Natural Science Foundation of China (NSFC)/ ; },
mesh = {Humans ; *DNA/chemistry/metabolism ; *Chromatin/metabolism/chemistry/genetics ; Genome, Human ; Chromatin Assembly and Disassembly ; },
abstract = {DNA is heterogeneously packaged into chromatin, which is further organized into topologically associating domains (TADs) with sharp boundaries. These boundary locations are critical for genome regulation. Here, we explore how the distribution of DNA-packing density across chromatin affects the TAD boundary locations. We develop a polymer-physics-based model that utilizes DNA accessibility data to parameterize DNA-packing density along chromosomes, treating them as heteropolymers, and simulates the stochastic folding of these heteropolymers within a nucleus to yield a conformation ensemble. Such an ensemble reproduces a subset (over 60%) of TAD boundaries across the human genome, as confirmed by Hi-C data. Additionally, it reproduces the spatial distance matrices of 2-Mb genomic regions provided by FISH experiments. Furthermore, our model suggests that utilizing DNA accessibility data alone as input is sufficient to predict the emergence and disappearance of key TADs during early T cell differentiation. We show that stochastic folding of heteropolymers in a confined space can replicate both the prevalence of chromatin domain structures and the cell-to-cell variation in domain boundary positions observed in single-cell experiments. Furthermore, regions of lower DNA-packing density preferentially form domain boundaries, and this preference drives the emergence of TAD boundaries observed in ensemble-averaged Hi-C maps. The enrichment of TAD boundaries at CTCF binding sites can be attributed to the influence of CTCF binding on local DNA-packing density in our model. Collectively, our findings establish a strong link between TAD boundaries and regions of lower DNA-packing density, providing insights into the mechanisms underlying TAD formation.},
}
@article {pmid39983729,
year = {2025},
author = {Sakata, T and Tei, S and Izumi, K and Krantz, ID and Bando, M and Shirahige, K},
title = {A common molecular mechanism underlying Cornelia de Lange and CHOPS syndromes.},
journal = {Current biology : CB},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cub.2025.01.044},
pmid = {39983729},
issn = {1879-0445},
abstract = {The cohesin protein complex is essential for the formation of topologically associating domains (TADs) and chromatin loops on interphase chromosomes.[1,2,3,4,5] For the loading onto chromosomes, cohesin requires the cohesin loader complex formed by NIPBL[6,7,8] and MAU2.[9] Cohesin localizes at enhancers and gene promoters with NIPBL in mammalian cells[10,11,12,13,14] and forms enhancer-promoter loops.[15,16] Cornelia de Lange syndrome (CdLS) is a rare, genetically heterogeneous disorder affecting multiple organs and systems during development,[17,18] caused by mutations in the cohesin loader NIPBL gene (>60% of patients),[19,20,21,22,23] as well as in genes encoding cohesin, a chromatin regulator, BRD4, and cohesin-related factors.[24,25,26,27] We also reported CHOPS syndrome that phenotypically overlaps with CdLS[28,29] and is caused by gene mutations of a super elongation complex (SEC) core component, AFF4. Although these syndromes are associated with transcriptional dysregulation,[24,28,30,31,32] the underlying mechanism remains unclear. In this study, we provide the first comprehensive analysis of chromosome architectural changes caused by these mutations using cell lines derived from CdLS and CHOPS syndrome patients. In both patient cells, we found a decrease in cohesin, NIPBL, BRD4, and acetylation of lysine 27 on histone H3 (H3K27ac)[33,34,35] in most enhancers with enhancer-promoter loop attenuation. By contrast, TADs were maintained in both patient cells. These findings reveal a shared molecular mechanism in these syndromes and highlight unexpected roles for cohesin, cohesin loaders, and the SEC in maintaining the enhancer complexes. These complexes are crucial for recruiting transcriptional regulators, sustaining active histone modifications, and facilitating enhancer-promoter looping.},
}
@article {pmid39972127,
year = {2025},
author = {Sebastian, R and Sun, EG and Fedkenheuer, M and Fu, H and Jung, S and Thakur, BL and Redon, CE and Pegoraro, G and Tran, AD and Gross, JM and Mosavarpour, S and Kusi, NA and Ray, A and Dhall, A and Pongor, LS and Casellas, R and Aladjem, MI},
title = {Mechanism for local attenuation of DNA replication at double-strand breaks.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {39972127},
issn = {1476-4687},
abstract = {DNA double-strand breaks (DSBs) disrupt the continuity of the genome, with consequences for malignant transformation. Massive DNA damage can elicit a cellular checkpoint response that prevents cell proliferation[1,2]. However, how highly aggressive cancer cells, which can tolerate widespread DNA damage, respond to DSBs alongside continuous chromosome duplication is unknown. Here we show that DSBs induce a local genome maintenance mechanism that inhibits replication initiation in DSB-containing topologically associating domains (TADs) without affecting DNA synthesis at other genomic locations. This process is facilitated by mediators of replication and DSBs (MRDs). In normal and cancer cells, MRDs include the TIMELESS-TIPIN complex and the WEE1 kinase, which actively dislodges the TIMELESS-TIPIN complex from replication origins adjacent to DSBs and prevents initiation of DNA synthesis at DSB-containing TADs. Dysregulation of MRDs, or disruption of 3D chromatin architecture by dissolving TADs, results in inadvertent replication in damaged chromatin and increased DNA damage in cancer cells. We propose that the intact MRD cascade precedes DSB repair to prevent genomic instability, which is otherwise observed when replication is forced, or when genome architecture is challenged, in the presence of DSBs[3-5]. These observations reveal a previously unknown vulnerability in the DNA replication machinery that may be exploited to therapeutically target cancer cells.},
}
@article {pmid39971902,
year = {2025},
author = {Yamaura, K and Takemata, N and Kariya, M and Osaka, A and Ishino, S and Yamauchi, M and Tamura, T and Hamachi, I and Takada, S and Ishino, Y and Atomi, H},
title = {Chromosomal domain formation by archaeal SMC, a roadblock protein, and DNA structure.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {1312},
pmid = {39971902},
issn = {2041-1723},
support = {JP21K20636, JP23H04281//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP20H05934//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP19K22289//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JPMJPR20K7, JPMJFR224V//MEXT | Japan Science and Technology Agency (JST)/ ; JPMJFS2123, JPMJSP2110//MEXT | Japan Science and Technology Agency (JST)/ ; },
mesh = {*Archaeal Proteins/metabolism/genetics/chemistry ; *Thermococcus/genetics/metabolism ; *DNA, Archaeal/genetics/metabolism ; *Chromosomes, Archaeal/genetics ; Nucleic Acid Conformation ; Genome, Archaeal ; Cell Cycle Proteins/metabolism/genetics/chemistry ; },
abstract = {In eukaryotes, structural maintenance of chromosomes (SMC) complexes form topologically associating domains (TADs) by extruding DNA loops and being stalled by roadblock proteins. It remains unclear whether a similar mechanism of domain formation exists in prokaryotes. Using high-resolution chromosome conformation capture sequencing, we show that an archaeal homolog of the bacterial Smc-ScpAB complex organizes the genome of Thermococcus kodakarensis into TAD-like domains. We find that TrmBL2, a nucleoid-associated protein that forms a stiff nucleoprotein filament, stalls the T. kodakarensis SMC complex and establishes a boundary at the site-specific recombination site dif. TrmBL2 stalls the SMC complex at tens of additional non-boundary loci with lower efficiency. Intriguingly, the stalling efficiency is correlated with structural properties of underlying DNA sequences. Our study illuminates a eukaryotic-like mechanism of domain formation in archaea and a role of intrinsic DNA structure in large-scale genome organization.},
}
@article {pmid39946792,
year = {2025},
author = {Gómora-García, JC and Furlan-Magaril, M},
title = {Pioneer factors outline chromatin architecture.},
journal = {Current opinion in cell biology},
volume = {93},
number = {},
pages = {102480},
doi = {10.1016/j.ceb.2025.102480},
pmid = {39946792},
issn = {1879-0410},
abstract = {Pioneer factors are transcription factors capable of binding to nucleosomal DNA, initiating chromatin opening, and facilitating gene expression. By overcoming nucleosomes, pioneer factors enable cellular reprogramming, tissue-specific gene expression, and genome response to external stimuli. Here we discuss the recent literature on how pioneer factors modulate chromatin architecture at multiple levels, from local chromatin accessibility to large-scale genome organization, including chromatin compartments, topologically associating domains, and enhancer-promoter looping. Understanding the mechanisms by which pioneer factors modulate chromatin organization dynamics is key to understand their broader impact on gene expression regulation.},
}
@article {pmid39910043,
year = {2025},
author = {Kaya, VO and Adebali, O},
title = {UV-induced reorganization of 3D genome mediates DNA damage response.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {1376},
pmid = {39910043},
issn = {2041-1723},
mesh = {*Ultraviolet Rays/adverse effects ; *DNA Damage/radiation effects ; *DNA Repair/radiation effects ; Humans ; Genome, Human/radiation effects ; Genome ; Gene Expression Regulation/radiation effects ; Chromatin/radiation effects/metabolism/genetics ; },
abstract = {While it is well-established that UV radiation threatens genomic integrity, the precise mechanisms by which cells orchestrate DNA damage response and repair within the context of 3D genome architecture remain unclear. Here, we address this gap by investigating the UV-induced reorganization of the 3D genome and its critical role in mediating damage response. Employing temporal maps of contact matrices and transcriptional profiles, we illustrate the immediate and holistic changes in genome architecture post-irradiation, emphasizing the significance of this reconfiguration for effective DNA repair processes. We demonstrate that UV radiation triggers a comprehensive restructuring of the 3D genome organization at all levels, including loops, topologically associating domains and compartments. Through the analysis of DNA damage and excision repair maps, we uncover a correlation between genome folding, gene regulation, damage formation probability, and repair efficacy. We show that adaptive reorganization of the 3D genome is a key mediator of the damage response, providing new insights into the complex interplay of genomic structure and cellular defense mechanisms against UV-induced damage, thereby advancing our understanding of cellular resilience.},
}
@article {pmid39887949,
year = {2025},
author = {Dautle, MA and Chen, Y},
title = {Single-Cell Hi-C Technologies and Computational Data Analysis.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e2412232},
doi = {10.1002/advs.202412232},
pmid = {39887949},
issn = {2198-3844},
support = {DBI-2239350//National Science Foundation/ ; },
abstract = {Single-cell chromatin conformation capture (scHi-C) techniques have evolved to provide significant insights into the structural organization and regulatory mechanisms in individual cells. Although many scHi-C protocols have been developed, they often involve intricate procedures and the resulting data are sparse, leading to computational challenges for systematic data analysis and limited applicability. This review provides a comprehensive overview, quantitative evaluation of thirteen protocols and practical guidance on computational topics. It is first assessed the efficiency of these protocols based on the total number of contacts recovered per cell and the cis/trans ratio. It is then provided systematic considerations for scHi-C quality control and data imputation. Additionally, the capabilities and implementations of various analysis methods, covering cell clustering, A/B compartment calling, topologically associating domain (TAD) calling, loop calling, 3D reconstruction, scHi-C data simulation and differential interaction analysis is summarized. It is further highlighted key computational challenges associated with the specific complexities of scHi-C data and propose potential solutions.},
}
@article {pmid39863579,
year = {2025},
author = {Zhao, M and Jankovic, D and Link, VM and Souza, COS and Hornick, KM and Oyesola, O and Belkaid, Y and Lack, J and Loke, P},
title = {Genetic variation in IL-4 activated tissue resident macrophages determines strain-specific synergistic responses to LPS epigenetically.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {1030},
pmid = {39863579},
issn = {2041-1723},
mesh = {Animals ; *Lipopolysaccharides/pharmacology ; *Interleukin-4/pharmacology/genetics/metabolism ; Male ; *Mice, Inbred C57BL ; *Epigenesis, Genetic ; Mice ; *Mice, Inbred BALB C ; *Genetic Variation ; Macrophages/metabolism/drug effects ; Macrophage Activation/genetics/drug effects ; Species Specificity ; NF-kappa B/metabolism ; Macrophages, Peritoneal/metabolism/drug effects ; },
abstract = {How macrophages in the tissue environment integrate multiple stimuli depends on the genetic background of the host, but this is still poorly understood. We investigate IL-4 activation of male C57BL/6 and BALB/c strain specific in vivo tissue-resident macrophages (TRMs) from the peritoneal cavity. C57BL/6 TRMs are more transcriptionally responsive to IL-4 stimulation, with induced genes associated with more super enhancers, induced enhancers, and topologically associating domains (TAD) boundaries. IL-4-directed epigenomic remodeling reveals C57BL/6 specific enrichment of NF-κB, IRF, and STAT motifs. Additionally, IL-4-activated C57BL/6 TRMs demonstrate an augmented synergistic response upon in vitro lipopolysaccharide (LPS) exposure, despite naïve BALB/c TRMs displaying a more robust transcriptional response to LPS. Single-cell RNA sequencing (scRNA-seq) analysis of mixed bone marrow chimeras indicates that transcriptional differences and synergy are cell intrinsic within the same tissue environment. Hence, genetic variation alters IL-4-induced cell intrinsic epigenetic reprogramming resulting in strain specific synergistic responses to LPS exposure.},
}
@article {pmid39849544,
year = {2025},
author = {Li, H and Xing, C and Li, J and Zhan, Y and Luo, M and Wang, P and Sheng, Y and Peng, H},
title = {Aberrant c-AMP signalling in richter syndrome revealed by single-cell transcriptome and 3D chromatin analysis.},
journal = {Biomarker research},
volume = {13},
number = {1},
pages = {15},
pmid = {39849544},
issn = {2050-7771},
support = {2024JJ6549//Natural Science Foundation of Hunan Province/ ; 2024JJ6566//Natural Science Foundation of Hunan Province/ ; 2023JJ60427//Natural Science Foundation of Hunan Province/ ; 32270791//National Natural Science Foundation of China/ ; 82070175//National Natural Science Foundation of China/ ; 2022RC1205//Huxiang Youth Talent Support Program/ ; CRP/CHN22-03_EC//International Centre for Genetic Engineering and Biotechnology/ ; C202303046332//the Scientific Research Project of Hunan Provincial Health Commission/ ; 23A0018//the Scientific Research Project of Hunan Provincial Department of Education/ ; },
abstract = {Richter syndrome (RS), characterized by aggressive lymphoma arising from chronic lymphocytic leukaemia (CLL), presents a poor response to treatment and grim prognosis. To elucidate RS mechanisms, paired samples from a patient with DLBCL-RS were subjected to single-cell RNA sequencing (scRNA-seq) and high-throughput chromosome conformation capture (Hi-C) sequencing. Over 10,000 cells were profiled via scRNA-seq, revealing the comprehensive B cell transformation in RS. Hi-C sequencing exposed a unique chromatin architecture in RS, with increased proximal and decreased distal interactions. At the compartment scale, the interaction between B compartments was strengthened in DLBCL cells, while topologically associating domains (TADs) in DLBCL had elevated intra-TAD and reduced inter-TAD contacts. Differentially expressed genes at TAD borders between CLL and DLBCL cells highlighted an enrichment of cAMP-mediated signalling. To substantiate the functional relevance of ATF1 and CAP1, the genes involve in cAMP-mediated signalling, in the context of cell proliferation, we have performed gain- and loss-of-function experiments in relevant cell lines. Collectively, integrated scRNA-seq and Hi-C data suggest that chromatin reorganization and altered cAMP signalling drive RS transformation.},
}
@article {pmid39827577,
year = {2025},
author = {Qi, S and Shi, Z and Yu, H},
title = {Genome folding by cohesion.},
journal = {Current opinion in genetics &amp; development},
volume = {91},
number = {},
pages = {102310},
doi = {10.1016/j.gde.2025.102310},
pmid = {39827577},
issn = {1879-0380},
abstract = {Chromosomes in eukaryotic cells undergo compaction at multiple levels and are folded into hierarchical structures to fit into the nucleus with limited dimensions. Three-dimensional genome organization needs to be coordinated with chromosome-templated processes, including DNA replication and gene transcription. As an ATPase molecular machine, the cohesin complex is a major driver of genome folding, which regulates transcription by modulating promoter-enhancer contacts. Here, we review our current understanding of genome folding by cohesin. We summarize the available evidence supporting a role of loop extrusion by cohesin in forming chromatin loops and topologically associating domains. We describe different conformations of cohesin and discuss the regulation of loop extrusion by cohesin-binding factors and loop-extrusion barriers. Finally, we propose a dimeric inchworm model for cohesin-mediated loop extrusion.},
}
@article {pmid39820353,
year = {2025},
author = {Wei, K and Li, R and Zhao, X and Xie, B and Xie, T and Sun, Q and Chen, Y and Wei, P and Xu, W and Guo, X and Zhao, Z and Feng, H and Ni, L and Dong, C},
title = {TRIM28 is an essential regulator of three-dimensional chromatin state underpinning CD8[+] T cell activation.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {750},
pmid = {39820353},
issn = {2041-1723},
mesh = {*CD8-Positive T-Lymphocytes/immunology/metabolism ; *Tripartite Motif-Containing Protein 28/metabolism/genetics ; Animals ; *Chromatin/metabolism ; Mice ; *Lymphocyte Activation ; *Chromosomal Proteins, Non-Histone/metabolism/genetics ; Cell Cycle Proteins/metabolism/genetics ; CCCTC-Binding Factor/metabolism/genetics ; RNA Polymerase II/metabolism ; Interleukin-2/metabolism/genetics ; Cohesins ; Mice, Knockout ; Mice, Inbred C57BL ; },
abstract = {T cell activation is accompanied by extensive changes in epigenome. However, the high-ordered chromatin organization underpinning CD8[+] T cell activation is not fully known. Here, we show extensive changes in the three-dimensional genome during CD8[+] T cell activation, associated with changes in gene transcription. We show that CD8[+] T-cell-specific deletion of Trim28 in mice disrupts autocrine IL-2 production and leads to impaired CD8[+] T cell activation in vitro and in vivo. Mechanistically, TRIM28 binds to regulatory regions of genes associated with the formation of chromosomal loops during activation. At the loop anchor regions, TRIM28-occupancy overlaps with that of CTCF, a factor known for defining the boundaries of topologically associating domains and for forming of the loop anchors. In the absence of Trim28, RNA Pol II and cohesin binding to these regions diminishes, and the chromosomal structure required for the active state is disrupted. These results thus identify a critical role for TRIM28-dependent chromatin topology in gene transcription in activated CD8[+] T cells.},
}
@article {pmid39778075,
year = {2025},
author = {Li, M and Yang, Y and Wu, R and Gong, H and Yuan, Z and Wang, J and Long, E and Zhang, X and Chen, Y},
title = {SEE: A Method for Predicting the Dynamics of Chromatin Conformation Based on Single-Cell Gene Expression.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e2406413},
doi = {10.1002/advs.202406413},
pmid = {39778075},
issn = {2198-3844},
support = {2022YFC2504003//National Key R&amp;D Program of China/ ; 2022YFC2504002//National Key R&amp;D Program of China/ ; 2021-I2M-1-020//CAMS Innovation Fund for Medical Sciences/ ; 2022-I2M-1-020//CAMS Innovation Fund for Medical Sciences/ ; 2021-RC310-007//CAMS Innovation Fund for Medical Sciences/ ; },
abstract = {The dynamics of chromatin conformation involve continuous and reversible changes within the nucleus of a cell, which participate in regulating processes such as gene expression, DNA replication, and damage repair. Here, SEE is introduced, an artificial intelligence (AI) method that utilizes autoencoder and transformer techniques to analyze chromatin dynamics using single-cell RNA sequencing data and a limited number of single-cell Hi-C maps. SEE is employed to investigate chromatin dynamics across different scales, enabling the detection of (i) rearrangements in topologically associating domains (TADs), and (ii) oscillations in chromatin interactions at gene loci. Additionally, SEE facilitates the interpretation of disease-associated single-nucleotide polymorphisms (SNPs) by leveraging the dynamic features of chromatin conformation. Overall, SEE offers a single-cell, high-resolution approach to analyzing chromatin dynamics in both developmental and disease contexts.},
}
@article {pmid39777468,
year = {2025},
author = {Sun, Q and Zhou, Q and Qiao, Y and Chen, X and Sun, H and Wang, H},
title = {Pervasive RNA-binding protein enrichment on TAD boundaries regulates TAD organization.},
journal = {Nucleic acids research},
volume = {53},
number = {1},
pages = {},
doi = {10.1093/nar/gkae1271},
pmid = {39777468},
issn = {1362-4962},
support = {82172436//National Natural Science Foundation of China/ ; 2022YFA0806003//National Key R&amp;D Program of China/ ; 14103522//Research Grants Council (RGC) of the Hong Kong Special Administrative Region, China/ ; 10210906//Health Bureau of the Hong Kong Special Administrative Region, China/ ; //Government of the Hong Kong SAR, China/ ; //Chinese University of Hong Kong/ ; //Strategic Seed Funding for Collaborative Research Scheme/ ; 2024A1515030291//Natural Science Foundation of Guangdong Province/ ; },
mesh = {Humans ; K562 Cells ; *RNA-Binding Proteins/metabolism/genetics ; *RNA Splicing Factors/metabolism/genetics ; *Promoter Regions, Genetic ; Hep G2 Cells ; Protein Binding ; CCCTC-Binding Factor/metabolism/genetics ; Animals ; Cell Differentiation/genetics ; Mice ; Chromatin/metabolism ; Myoblasts/metabolism ; Transcription, Genetic ; Repressor Proteins ; },
abstract = {Mammalian genome is hierarchically organized by CTCF and cohesin through loop extrusion mechanism to facilitate the organization of topologically associating domains (TADs). Mounting evidence suggests additional factors/mechanisms exist to orchestrate TAD formation and maintenance. In this study, we investigate the potential role of RNA-binding proteins (RBPs) in TAD organization. By integrated analyses of global RBP binding and 3D genome mapping profiles from both K562 and HepG2 cells, our study unveils the prevalent enrichment of RBPs on TAD boundaries and define boundary-associated RBPs (baRBPs). We found that baRBP binding is correlated with enhanced TAD insulation strength and in a CTCF-independent manner. Moreover, baRBP binding is associated with nascent promoter transcription. Additional experimental testing was performed using RBFox2 as a paradigm. Knockdown of RBFox2 in K562 cells causes mild TAD reorganization. Moreover, RBFox2 enrichment on TAD boundaries is a conserved phenomenon in C2C12 myoblast (MB) cells. RBFox2 is downregulated and its bound boundaries are remodeled during MB differentiation into myotubes. Finally, transcriptional inhibition indeed decreases RBFox2 binding and disrupts TAD boundary insulation. Altogether, our findings demonstrate that RBPs can play an active role in modulating TAD organization through co-transcriptional association and synergistic actions with nascent promoter transcripts.},
}
@article {pmid39757126,
year = {2025},
author = {Ren, X and Shi, Y and Xiao, B and Su, X and Shi, H and He, G and Chen, P and Wu, D and Shi, Y},
title = {Gene Doping Detection From the Perspective of 3D Genome.},
journal = {Drug testing and analysis},
volume = {},
number = {},
pages = {},
doi = {10.1002/dta.3850},
pmid = {39757126},
issn = {1942-7611},
support = {2022YFE0125300//Key Research and Development Plan of the Ministry of Science and Technology/ ; YG2023ZD26//Shanghai Jiao Tong University STAR/ ; YG2022ZD024//Shanghai Jiao Tong University STAR/ ; YG2022QN111//Shanghai Jiao Tong University STAR/ ; //Shanghai Gaofeng and Gaoyuan Project for the University Academic Program Development/ ; },
abstract = {Since the early 20th century, the concept of doping was first introduced. To achieve better athletic performance, chemical substances were used. By the mid-20th century, it became gradually recognized that the illegal use of doping substances can seriously endangered athletes' health and compromised the fairness of sports competitions. Over the past 30 years, the World Anti-Doping Agency (WADA) has established corresponding rules and regulations to prohibit athletes from using doping substances or restrict the use of certain drugs, and isotope, chromatography, and mass spectrometry techniques were accredited to detect doping substances. With the development of gene editing technology, many genetic diseases have been effectively treated, but enabled by the same technology, doping has also the potential to pose a threat to sports in the form of gene doping. WADA has explicitly indicated gene doping in the Prohibited List as a prohibited method (M3) and approved qPCR detection. However, gene doping can easily evade detection, if the target genes' upstream regulatory elements are considered, the task became more challenging. Hi-C experiment driven 3D genome technology, through perspectives such as topologically associating domain (TAD) and chromatin loop, provides a more comprehensive and in-depth understanding of gene regulation and expression, thereby better preventing the potential use of 3D genome level gene doping. In this work, we will explore gene doping from a different perspective by analyzing recent studies on gene doping and explore related genes under 3D genome.},
}
@article {pmid39741350,
year = {2024},
author = {Wang, D and Xiao, S and Shu, J and Luo, L and Yang, M and Calonje, M and He, H and Song, B and Zhou, Y},
title = {Promoter capture Hi-C identifies promoter-related loops and fountain structures in Arabidopsis.},
journal = {Genome biology},
volume = {25},
number = {1},
pages = {324},
pmid = {39741350},
issn = {1474-760X},
mesh = {*Arabidopsis/genetics ; *Promoter Regions, Genetic ; *Arabidopsis Proteins/genetics/metabolism ; *Chromatin/metabolism/genetics ; *Gene Expression Regulation, Plant ; Cohesins ; Histones/metabolism ; Cell Cycle Proteins/metabolism/genetics ; Chromosomal Proteins, Non-Histone/metabolism/genetics ; Enhancer Elements, Genetic ; },
abstract = {BACKGROUND: Promoters serve as key elements in the regulation of gene transcription. In mammals, loop interactions between promoters and enhancers increase the complexity of the promoter-based regulatory networks. However, the identification of enhancer-promoter or promoter-related loops in Arabidopsis remains incomplete.<br><br>RESULTS: Here, we use promoter capture Hi-C to identify promoter-related loops in Arabidopsis, which shows that gene body, proximal promoter, and intergenic regions can interact with promoters, potentially functioning as distal regulatory elements or enhancers. We find that promoter-related loops mainly repress gene transcription and are associated with ordered chromatin structures, such as topologically associating domains and fountains-chromatin structures not previously identified in Arabidopsis. Cohesin binds to the center of fountains and is involved in their formation. Moreover, fountain strength is positively correlated with the number of promoter-related loops, and the maintenance of these loops is linked to H3K4me3. In atxr3 mutants, which lack the major H3K4me3 methyltransferases in Arabidopsis, the number of promoter-related loops at fountains is reduced, leading to upregulation of fountain-regulated genes.<br><br>CONCLUSIONS: We identify promoter-related loops associated with ordered chromatin structures and reveal the molecular mechanisms involved in fountain formation and maintenance.},
}
@article {pmid39731323,
year = {2024},
author = {Ma, N and Li, X and Ci, D and Zeng, HY and Zhang, C and Xie, X and Zhong, C and Deng, XW and Li, D and He, H},
title = {Chromatin Topological Domains Associate With the Rapid Formation of Tandem Duplicates in Plants.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e2408861},
doi = {10.1002/advs.202408861},
pmid = {39731323},
issn = {2198-3844},
support = {ZR202211070163//Key R&amp;D Program of Shandong Province/ ; 32230006//National Natural Science Foundation of China/ ; 2021hszd017//Hubei Hongshan Laboratory/ ; 2023AFA075//Hubei Province Natural Science Fund Project for Outstanding Youth/ ; },
abstract = {In eukaryotes, chromatin is compacted within nuclei under the principle of compartmentalization. On top of that, condensin II establishes eukaryotic chromosome territories, while cohesin organizes the vertebrate genome by extruding chromatin loops and forming topologically associating domains (TADs). Thus far, the formation and roles of these chromatin structures in plants remain poorly understood. This study integrates Hi-C data from diverse plant species, demonstrating that nuclear DNA content influences large-scale chromosome conformation and affects the finer details of compartmental patterns. These contrasting compartmental patterns are distinguished by gene-to-gene loops and validated through cytological observations. Additionally, a novel chromatin domain type associated with tandem duplicate gene clusters is identified. These domains are independent of H3K27me3-mediated chromatin compartmentalization and exhibit evolutionary conservation across species. Gene pairs within TAD-like domains are younger and show higher levels of coexpression. These domains potentially promote the formation of tandem duplicates, a property appears unique to the Actinidia family. Overall, this study reveals functional chromatin domains in plants and provides evidence for the role of three-dimensional chromatin architecture in gene regulation and genome evolution.},
}
@article {pmid39727192,
year = {2024},
author = {Dang, D and Zhang, SW and Dong, K and Duan, R and Zhang, S},
title = {Uncovering topologically associating domains from three-dimensional genome maps with TADGATE.},
journal = {Nucleic acids research},
volume = {},
number = {},
pages = {},
doi = {10.1093/nar/gkae1267},
pmid = {39727192},
issn = {1362-4962},
support = {2019YFA0709501//National Key Research and Development Program of China/ ; 62173271//National Natural Science Foundation of China/ ; 2023K0602//R&amp;D project of Pazhou Lab/ ; YSBR-034//CAS Project for Young Scientists in Basic Research/ ; },
abstract = {Topologically associating domains (TADs) are essential components of three-dimensional (3D) genome organization and significantly influence gene transcription regulation. However, accurately identifying TADs from sparse chromatin contact maps and exploring the structural and functional elements within TADs remain challenging. To this end, we develop TADGATE, a graph attention auto-encoder that can generate imputed maps from sparse Hi-C contact maps while adaptively preserving or enhancing the underlying topological structures, thereby facilitating TAD identification. TADGATE captures specific attention patterns with two types of units within TADs and demonstrates TAD organization relates to chromatin compartmentalization with diverse biological properties. We identify many structural and functional elements within TADs, with their abundance reflecting the overall properties of these domains. We applied TADGATE to sparse and noisy Hi-C contact maps from 21 human tissues or cell lines. That improved the clarity of TAD structures, allowing us to investigate conserved and cell-type-specific boundaries and uncover cell-type-specific transcriptional regulatory mechanisms associated with topological domains. We also demonstrated TADGATE's capability to fill in sparse single-cell Hi-C contact maps and identify TAD-like domains within them, revealing the specific domain boundaries with distinct heterogeneity and the shared backbone boundaries characterized by strong CTCF enrichment and high gene expression levels.},
}
@article {pmid39682078,
year = {2024},
author = {Ren, H and Zhong, H and Zhang, J and Lu, Y and Hu, G and Duan, W and Ma, N and Yao, H},
title = {CTCF Point Mutation at R567 Disrupts Mouse Heart Development via 3D Genome Rearrangement and Transcription Dysregulation.},
journal = {Cell proliferation},
volume = {},
number = {},
pages = {e13783},
doi = {10.1111/cpr.13783},
pmid = {39682078},
issn = {1365-2184},
support = {31925009//National Natural Science Foundation of China/ ; U21A20195//National Natural Science Foundation of China/ ; 32300477//National Natural Science Foundation of China/ ; 32430016//National Natural Science Foundation of China/ ; 2021YFA1100300//National Key R&amp;D Program of China/ ; 2023B03J1230//Guangzhou Key R&amp;D Program/ ; 2022ZDLSF02-01//Key R&amp;D Program of Shaanxi Province/ ; 2023JC-XJ-11//Special Support Project for Basic Research of Shaanxi Province/ ; },
abstract = {CTCF plays a vital role in shaping chromatin structure and regulating gene expression. Clinical studies have associated CTCF mutations with congenital developmental abnormalities, including congenital cardiomyopathy. In this study, we investigated the impact of the homozygous CTCF-R567W (Ctcf[R567W/R567W]) mutation on cardiac tissue morphogenesis during mouse embryonic development. Our results reveal significant impairments in heart development, characterised by ventricular muscle trabecular hyperplasia and reduced ventricular cavity sizes. We also observe a marked downregulation of genes involved in sarcomere assembly, calcium ion transport, and mitochondrial function in heart tissues from homozygous mice. Furthermore, the Ctcf[R567W/R567W] mutation disrupts CTCF's interaction with chromatin, resulting in alterations to topologically associating domain (TAD) structure within specific genomic regions and diminishing crucial promoter-enhancer interactions necessary for cardiac development. Additionally, we find that the heterozygous CTCF-R567W (Ctcf[+/R567W]) mutation significantly compromises cardiac contractility in 8-week-old mice. This study elucidates the mechanism by which the CTCF-R567W mutation hampers cardiac development, underscoring the essential role of CTCF-R567 in embryonic heart development and maturation.},
}
@article {pmid39669613,
year = {2024},
author = {Wolujewicz, P and Aguiar-Pulido, V and Thareja, G and Suhre, K and Elemento, O and Finnell, RH and Ross, ME},
title = {Integrative computational analyses implicate regulatory genomic elements contributing to spina bifida.},
journal = {Genetics in medicine open},
volume = {2},
number = {},
pages = {101894},
pmid = {39669613},
issn = {2949-7744},
abstract = {PURPOSE: Spina bifida (SB) arises from complex genetic interactions that converge to interfere with neural tube closure. Understanding the precise patterns conferring SB risk requires a deep exploration of the genomic networks and molecular pathways that govern neurulation. This study aims to delineate genome-wide regulatory signatures underlying SB pathophysiology.<br><br>METHODS: An untargeted, genome-wide approach was used to interrogate regulatory regions for rare single-nucleotide and copy-number variants (rSNVs and rCNVs, respectively) predicted to affect gene expression, comparing results from SB patients with healthy controls. Qualifying variants were subjected to a deep learning prioritization framework to identify the most functionally relevant variants, as well as the likely target genes affected by these rare regulatory variants.<br><br>RESULTS: This ensemble of computational tools identified rSNVs in specific transcription factor binding sites (TFBSs) that distinguish SB cases from controls. rSNV enrichment was found in specific TFBSs, especially CCCTC-binding factor binding sites. These TFBSs were subjected to a deep learning prioritization framework to identify the most functionally relevant variants, as well as the likely target genes affected by these rSNVs. The functional pathways or modules implicated by these regulated genes serve protein transport, cilia assembly, and central nervous system development. Moreover, the detected rare copy-number variants in SB cases are positioned to disrupt gene regulatory networks and alter 3-dimensional genomic architectures, including brain-specific enhancers and topologically associated domain boundaries of relevant cell types.<br><br>CONCLUSION: Our study provides a resource for identifying and interpreting genomic regulatory DNA variant contributions to human SB genetic predisposition.},
}
@article {pmid39638559,
year = {2024},
author = {Li, C and Bonder, MJ and Syed, S and Jensen, M and , and , and Gerstein, MB and Zody, MC and Chaisson, MJP and Talkowski, ME and Marschall, T and Korbel, JO and Eichler, EE and Lee, C and Shi, X},
title = {An integrative TAD catalog in lymphoblastoid cell lines discloses the functional impact of deletions and insertions in human genomes.},
journal = {Genome research},
volume = {},
number = {},
pages = {},
doi = {10.1101/gr.279419.124},
pmid = {39638559},
issn = {1549-5469},
abstract = {The human genome is packaged within a three-dimensional (3D) nucleus and organized into structural units known as compartments, topologically associating domains (TADs), and loops. TAD boundaries, separating adjacent TADs, have been found to be well conserved across mammalian species and more evolutionarily constrained than TADs themselves. Recent studies show that structural variants (SVs) can modify 3D genomes through the disruption of TADs, which play an essential role in insulating genes from outside regulatory elements' aberrant regulation. However, how SV affects the 3D genome structure and their association among different aspects of gene regulation and candidate cis-regulatory elements (cCREs) have rarely been studied systematically. Here, we assess the impact of SVs intersecting with TAD boundaries by developing an integrative Hi-C analysis pipeline, which enables the generation of an in-depth catalog of TADs and TAD boundaries in human lymphoblastoid cell lines (LCLs) to fill the gap of limited resources. Our catalog contains 18,865 TADs, including 4596 sub-TADs, with 185 SVs (TAD-SVs) that alter chromatin architecture. By leveraging the ENCODE registry of cCREs in humans, we determine that 34 of 185 TAD-SVs intersect with cCREs and observe significant enrichment of TAD-SVs within cCREs. This study provides a database of TADs and TAD-SVs in the human genome that will facilitate future investigations of the impact of SVs on chromatin structure and gene regulation in health and disease.},
}
@article {pmid39634272,
year = {2024},
author = {Mao, R and Cai, Z and Wang, T and Li, Y and Tian, S and Li, D and Li, P},
title = {Comparative study of the three-dimensional genomes of granulosa cells in germinal vesicle and metaphase II follicles.},
journal = {Frontiers in genetics},
volume = {15},
number = {},
pages = {1480153},
pmid = {39634272},
issn = {1664-8021},
abstract = {INTRODUCTION: Follicle development is a critical process in the female reproductive system, with significant implications for fertility and reproductive health. Germinal vesicle (GV) oocytes are primary oocytes that are arrested in the dictyate stage, also known as the diplotene stage of meiotic prophase I. Metaphase II (MII) is the stage at which the oocyte is typically retrieved for assisted reproductive technologies such as in vitro fertilization (IVF). The granulosa cells play a pivotal role in follicle development processes. 3D chromatin organization is a fundamental aspect of cellular biology that has significant implications for gene regulation and cellular function.<br><br>METHODS: In this study, we investigated 3D chromatin organization in granulosacells from GV and MII follicles, which is essential for understanding the regulatory mechanisms governing oocyte development.<br><br>RESULTS: The results revealed distinct compartmentalization patterns,including stable genomic regions and transitions during oocyte maturation. Notably, there was a significant shift in functional gene activation, particularly in processes related to hormone metabolic pathways. Furthermore, alterations in topologically associating domains (TADs) were observed, with differential expression observed in genes that are involved in crucial biological processes. The analysis also identified a subset of genes with altered promoter-enhancer interactions (PEIs), reflecting a regulatory shift in gene expression related to reproductive processes.<br><br>DISCUSSION: These findings provide valuable insights into 3D genome organization in granulosa cells with implications for reproductive health and the development of assisted reproductive technologies. Understanding spatial genome organization at different stages of follicular development may help realize novel strategies for enhancing success rates in assisted reproductive technologies.},
}
@article {pmid39617879,
year = {2024},
author = {Shen, W and Zhang, P and Jiang, Y and Tao, H and Zi, Z and Li, L},
title = {HTAD: a human-in-the-loop framework for supervised chromatin domain detection.},
journal = {Genome biology},
volume = {25},
number = {1},
pages = {302},
pmid = {39617879},
issn = {1474-760X},
mesh = {Humans ; *Chromatin ; Genome, Human ; Supervised Machine Learning ; Machine Learning ; Software ; },
abstract = {Topologically associating domains (TADs) are essential units of genome architecture, influencing transcriptional regulation and diseases. Despite numerous methods proposed for TAD identification, it remains challenging due to complex background and nested TAD structures. We introduce HTAD, a human-in-the-loop TAD caller that combines machine learning with human supervision to achieve high accuracy. HTAD begins with feature extraction for potential TAD border pairs, followed by an interactive labeling process through active learning. Performance assessments using public curation and synthetic datasets demonstrate HTAD's superiority over other state-of-the-art methods and reveal highly hierarchical TAD structures, offering a human-in-the-loop solution for detecting complex genomic patterns.},
}
@article {pmid39614448,
year = {2024},
author = {Popenko, V and Spirin, P and Prassolov, V and Leonova, O},
title = {Chromomeres, Topologically Associating Domains and Structural Organization of Chromatin Bodies in Somatic Nuclei (Macronuclei) of Ciliates.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {29},
number = {11},
pages = {378},
doi = {10.31083/j.fbl2911378},
pmid = {39614448},
issn = {2768-6698},
support = {22-14-00353//Russian Science Foundation/ ; 075-15-2019-1660//Ministry of Science and Higher Education of the Russian Federation/ ; },
mesh = {*Chromatin/ultrastructure/metabolism/genetics ; *Ciliophora/genetics/ultrastructure ; Macronucleus/genetics/metabolism/ultrastructure ; Cell Nucleus/ultrastructure/metabolism ; Chromosomes/ultrastructure/genetics ; },
abstract = {BACKGROUND: In the twentieth century, the textbook idea of packaging genomic material in the cell nucleus and metaphase chromosomes was the presence of a hierarchy of structural levels of chromatin organization: nucleosomes - nucleosomal fibrils -30 nm fibrils - chromomeres - chromonemata - mitotic chromosomes. Chromomeres were observed in partially decondensed chromosomes and interphase chromatin as ~100 nm globular structures. They were thought to consist of loops of chromatin fibres attached at their bases to a central protein core. However, Hi-C and other related methods led to a new concept of chromatin organization in the nuclei of higher eukaryotes, according to which nucleosomal fibrils themselves determine the spatial configuration of chromatin in the form of topologically associating domains (TADs), which are formed by a loop extrusion process and are regions whose DNA sequences preferentially contact each other. Somatic macronuclei of ciliates are transcriptionally active, highly polyploid nuclei. A feature of macronuclei is that their genome is represented by a large number of "gene-sized" (~1-25 kb) or of "subchromosomal" (~50-1700 kb) size minichromosomes. The inactive macronuclear chromatin of "subchromosomal" ciliates usually looks like bodies 100-200 nm in size. The aim of this work was to find out which of the models (chromomeres or TADs) is more consistent with the confocal and electron microscopic data on structural organization of chromatin bodies.<br><br>METHODS: Macronuclear chromatin of four "subchromosomal" ciliate species (Bursaria truncatella, Paramecium multimicronucleatum, Didinium nasutum, Climacostomum virens) was examined using electron microscopy and confocal microscopy during regular growth, starvation and encystment.<br><br>RESULTS: Chromatin bodies ~70-200 nm in size observed in the interphase macronuclei consisted of tightly packed nucleosomes. Some of them were interconnected by one or more chromatin fibrils. Under hypotonic conditions in vitro, chromatin bodies decompacted, forming rosette-shaped structures of chromatin fibrils around an electron-dense centre. When the activity of the macronucleus decreased during starvation or encystment, chromatin bodies assembled into chromonema-like fibrils 100-300 nm thick. This data allows us to consider chromatin bodies as analogues of chromomeres. On the other hand, most likely, the formation of DNA loops in chromatin bodies occurs by the loop extrusion as in TADs.<br><br>CONCLUSIONS: The data obtained is well explained by the model, according to which the chromatin bodies of ciliate macronuclei combine features inherent in both chromomeres and TADs; that is, they can be considered as chromomeres with loops packed in the same way as the loops in TADs.},
}
@article {pmid39605346,
year = {2024},
author = {Hanafiah, A and Geng, Z and Liu, T and Tai, YT and Cai, W and Wang, Q and Christensen, N and Liu, Y and Yue, F and Gao, Z},
title = {PRC1 and CTCF-Mediated Transition from Poised to Active Chromatin Loops Drives Bivalent Gene Activation.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.11.13.623456},
pmid = {39605346},
issn = {2692-8205},
abstract = {Polycomb Repressive Complex 1 (PRC1) and CCCTC-binding factor (CTCF) are critical regulators of 3D chromatin architecture that influence cellular transcriptional programs. Spatial chromatin structures comprise conserved compartments, topologically associating domains (TADs), and dynamic, cell-type-specific chromatin loops. Although the role of CTCF in chromatin organization is well-known, the involvement of PRC1 is less understood. In this study, we identified an unexpected, essential role for the canonical Pcgf2-containing PRC1 complex (cPRC1.2), a known transcriptional repressor, in activating bivalent genes during differentiation. Our Hi-C analysis revealed that cPRC1.2 forms chromatin loops at bivalent promoters, rendering them silent yet poised for activation. Using mouse embryonic stem cells (ESCs) with CRISPR/Cas9-mediated gene editing, we found that the loss of Pcgf2, though not affecting the global level of H2AK119ub1, disrupts these cPRC1.2 loops in ESCs and impairs the transcriptional induction of crucial target genes necessary for neuronal differentiation. Furthermore, we identified CTCF enrichment at cPRC1.2 loop anchors and at Polycomb group (PcG) bodies, nuclear foci with concentrated PRC1 and its tethered chromatin domains, suggesting that PRC1 and CTCF cooperatively shape chromatin loop structures. Through virtual 4C and other genomic analyses, we discovered that establishing neuronal progenitor cell (NPC) identity involves a switch from cPRC1.2-mediated chromatin loops to CTCF-mediated active loops, enabling the expression of critical lineage-specific factors. This study uncovers a novel mechanism by which pre-formed PRC1 and CTCF loops at lineage-specific genes maintain a poised state for subsequent gene activation, advancing our understanding of the role of chromatin architecture in controlling cell fate transitions.},
}
@article {pmid39605341,
year = {2024},
author = {Frederick, J and Virk, RKA and Ye, IC and Almassalha, LM and Wodarcyk, GM and VanDerway, D and Carrillo Gonzalez, P and Nap, RJ and Agrawal, V and Anthony, NM and Carinato, J and Li, WS and Dunton, CL and Medina, KI and Kakkaramadam, R and Jain, S and Shahabi, S and Ameer, G and Szleifer, IG and Backman, V},
title = {Leveraging chromatin packing domains to target chemoevasion in vivo.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.11.14.623612},
pmid = {39605341},
issn = {2692-8205},
abstract = {Cancer cells exhibit a remarkable resilience to cytotoxic stress, often adapting through transcriptional changes linked to alterations in chromatin structure. In several types of cancer, these adaptations involve epigenetic modifications and restructuring of topologically associating domains (TADs). However, the underlying principles by which chromatin architecture facilitates such adaptability across different cancers remain poorly understood. To investigate the role of chromatin in this process, we developed a physics-based mechanistic model that connects chromatin organization to cell fate decisions, specifically survival following chemotherapy. Our model builds on the observation that chromatin forms packing domains, which influence transcriptional efficiency through macromolecular crowding. The model accurately predicts chemoevasion in vitro , suggesting that changes in packing domains affect the likelihood of survival. Consistent results across diverse cancer types indicate that the model captures fundamental principles of chromatin-mediated adaptation, independent of the specific cancer or chemotherapy mechanisms involved. Based on these insights, we hypothesized that compounds capable of modulating packing domains, termed Transcriptional Plasticity Regulators (TPRs), could prevent cellular adaptation to chemotherapy. Using live-cell chromatin imaging, we conducted a compound screen that identified several TPRs which synergistically enhanced chemotherapyinduced cell death. The most effective TPR significantly improved therapeutic outcomes in a patient-derived xenograft (PDX) model of ovarian cancer. These findings underscore the central role of chromatin in cellular adaptation to cytotoxic stress and present a novel framework for enhancing cancer therapies, with broad potential across multiple cancer types.},
}
@article {pmid39574698,
year = {2024},
author = {Gjoni, K and Ren, X and Everitt, A and Shen, Y and Pollard, KS},
title = {De novo structural variants in autism spectrum disorder disrupt distal regulatory interactions of neuronal genes.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.11.06.621353},
pmid = {39574698},
issn = {2692-8205},
abstract = {Three-dimensional genome organization plays a critical role in gene regulation, and disruptions can lead to developmental disorders by altering the contact between genes and their distal regulatory elements. Structural variants (SVs) can disturb local genome organization, such as the merging of topologically associating domains upon boundary deletion. Testing large numbers of SVs experimentally for their effects on chromatin structure and gene expression is time and cost prohibitive. To address this, we propose a computational approach to predict SV impacts on genome folding, which can help prioritize causal hypotheses for functional testing. We developed a weighted scoring method that measures chromatin contact changes specifically affecting regions of interest, such as regulatory elements or promoters, and implemented it in the SuPreMo-Akita software (Gjoni and Pollard 2024). With this tool, we ranked hundreds of de novo SVs (dnSVs) from autism spectrum disorder (ASD) individuals and their unaffected siblings based on predicted disruptions to nearby neuronal regulatory interactions. This revealed that putative cis-regulatory element interactions (CREints) are more disrupted by dnSVs from ASD probands versus unaffected siblings. We prioritized candidate variants that disrupt ASD CREints and validated our top-ranked locus using isogenic excitatory neurons with and without the dnSV, confirming accurate predictions of disrupted chromatin contacts. This study establishes disrupted genome folding as a potential genetic mechanism in ASD and provides a general strategy for prioritizing variants predicted to disrupt regulatory interactions across tissues.},
}
@article {pmid39572529,
year = {2024},
author = {de Luca, KL and Rullens, PMJ and Karpinska, MA and de Vries, SS and Gacek-Matthews, A and Pongor, LS and Legube, G and Jachowicz, JW and Oudelaar, AM and Kind, J},
title = {Genome-wide profiling of DNA repair proteins in single cells.},
journal = {Nature communications},
volume = {15},
number = {1},
pages = {9918},
pmid = {39572529},
issn = {2041-1723},
mesh = {Humans ; *DNA Repair ; *Single-Cell Analysis/methods ; *DNA Breaks, Double-Stranded ; *Chromatin/metabolism ; Genome, Human ; Genomic Instability ; Protein Binding ; DNA Damage ; DNA-Binding Proteins/metabolism/genetics ; },
abstract = {Accurate repair of DNA damage is critical for maintenance of genomic integrity and cellular viability. Because damage occurs non-uniformly across the genome, single-cell resolution is required for proper interrogation, but sensitive detection has remained challenging. Here, we present a comprehensive analysis of repair protein localization in single human cells using DamID and ChIC sequencing techniques. This study reports genome-wide binding profiles in response to DNA double-strand breaks induced by AsiSI, and explores variability in genomic damage locations and associated repair features in the context of spatial genome organization. By unbiasedly detecting repair factor localization, we find that repair proteins often occupy entire topologically associating domains, mimicking variability in chromatin loop anchoring. Moreover, we demonstrate the formation of multi-way chromatin hubs in response to DNA damage. Notably, larger hubs show increased coordination of repair protein binding, suggesting a preference for cooperative repair mechanisms. Together, our work offers insights into the heterogeneous processes underlying genome stability in single cells.},
}
@article {pmid39545685,
year = {2024},
author = {Lee, D and Kang, J and Kim, A},
title = {TAD-dependent sub-TAD is required for enhancer-promoter interaction enabling the β-globin transcription.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {38},
number = {22},
pages = {e70181},
doi = {10.1096/fj.202401526RR},
pmid = {39545685},
issn = {1530-6860},
support = {NRF-2020R1I1A3054808//National Research Foundation of Korea (NRF)/ ; 2022R1C1C2006355//National Research Foundation of Korea (NRF)/ ; },
abstract = {Topologically associating domains (TADs) are chromatin domains in the eukaryotic genome. TADs often comprise several sub-TADs. The boundaries of TADs and sub-TADs are enriched in CTCF, an architectural protein. Deletion of CTCF-binding motifs at one boundary disrupts the domains, often resulting in a transcriptional decrease in genes inside the domains. However, it is not clear how TAD and sub-TAD affect each other in the domain formation. Unaffected gene transcription was observed in the β-globin locus when one boundary of TAD or sub-TAD was destroyed. Here, we disrupted β-globin TAD and sub-TAD by deleting CTCF motifs at both boundaries in MEL/ch11 cells. Disruption of TAD impaired sub-TAD, but sub-TAD disruption did not affect TAD. Both TAD and sub-TAD disruption compromised the β-globin transcription, accompanied by the loss of enhancer-promoter interactions. However, histone H3 occupancy and H3K27ac were largely maintained across the β-globin locus. Genome-wide analysis showed that putative enhancer-promoter interactions and gene transcription were decreased by the disruption of CTCF-mediated topological domains in neural progenitor cells. Collectively, our results indicate that there is unequal relationship between TAD and sub-TAD formation. TAD is likely not sufficient for gene transcription, and, therefore, sub-TAD appears to be required. TAD-dependently formed sub-TADs are considered to provide chromatin environments for enhancer-promoter interactions enabling gene transcription.},
}
@article {pmid39543681,
year = {2024},
author = {Yuan, T and Yan, H and Li, KC and Surovtsev, I and King, MC and Mochrie, SGJ},
title = {Cohesin distribution alone predicts chromatin organization in yeast via conserved-current loop extrusion.},
journal = {Genome biology},
volume = {25},
number = {1},
pages = {293},
pmid = {39543681},
issn = {1474-760X},
support = {1830904//Division of Emerging Frontiers and Multidisciplinary Activities/ ; 1830904//Division of Emerging Frontiers and Multidisciplinary Activities/ ; 1830904//Division of Emerging Frontiers and Multidisciplinary Activities/ ; 1830904//Division of Emerging Frontiers and Multidisciplinary Activities/ ; 1830904//Division of Emerging Frontiers and Multidisciplinary Activities/ ; 1830904//Division of Emerging Frontiers and Multidisciplinary Activities/ ; 2412859//Division of Physics/ ; 2412859//Division of Physics/ ; 2412859//Division of Physics/ ; 2412859//Division of Physics/ ; 2412859//Division of Physics/ ; },
abstract = {BACKGROUND: Inhomogeneous patterns of chromatin-chromatin contacts within 10-100-kb-sized regions of the genome are a generic feature of chromatin spatial organization. These features, termed topologically associating domains (TADs), have led to the loop extrusion factor (LEF) model. Currently, our ability to model TADs relies on the observation that in vertebrates TAD boundaries are correlated with DNA sequences that bind CTCF, which therefore is inferred to block loop extrusion. However, although TADs feature prominently in their Hi-C maps, non-vertebrate eukaryotes either do not express CTCF or show few TAD boundaries that correlate with CTCF sites. In all of these organisms, the counterparts of CTCF remain unknown, frustrating comparisons between Hi-C data and simulations.<br><br>RESULTS: To extend the LEF model across the tree of life, here, we propose the conserved-current loop extrusion (CCLE) model that interprets loop-extruding cohesin as a nearly conserved probability current. From cohesin ChIP-seq data alone, we derive a position-dependent loop extrusion rate, allowing for a modified paradigm for loop extrusion, that goes beyond solely localized barriers to also include loop extrusion rates that vary continuously. We show that CCLE accurately predicts the TAD-scale Hi-C maps of interphase Schizosaccharomyces pombe, as well as those of meiotic and mitotic Saccharomyces cerevisiae, demonstrating its utility in organisms lacking CTCF.<br><br>CONCLUSIONS: The success of CCLE in yeasts suggests that loop extrusion by cohesin is indeed the primary mechanism underlying TADs in these systems. CCLE allows us to obtain loop extrusion parameters such as the LEF density and processivity, which compare well to independent estimates.},
}
@article {pmid39537822,
year = {2024},
author = {Zhang, R and Sun, J and Liu, S and Ding, J and Xiang, M},
title = {Multiscale 3D genome rewiring during PTF1A-mediated somatic cell reprogramming into neural stem cells.},
journal = {Communications biology},
volume = {7},
number = {1},
pages = {1505},
pmid = {39537822},
issn = {2399-3642},
support = {2021ZD0202603//Ministry of Science and Technology of the People&apos;s Republic of China (Chinese Ministry of Science and Technology)/ ; 81970794, 81721003//National Natural Science Foundation of China (National Science Foundation of China)/ ; 2023B1212060018//Guangdong Science and Technology Department (Science and Technology Department, Guangdong Province)/ ; },
mesh = {*Neural Stem Cells/metabolism/cytology ; *Transcription Factors/metabolism/genetics ; Animals ; *Cellular Reprogramming/genetics ; Mice ; Genome ; Chromatin/metabolism/genetics ; Cell Transdifferentiation/genetics ; Fibroblasts/metabolism/cytology ; },
abstract = {The genome is intricately folded into chromatin compartments, topologically associating domains (TADs) and loops unique to each cell type. How this higher-order genome organization regulates cell fate transition remains elusive. Here we show how a single non-neural progenitor transcription factor, PTF1A, reorchestrates the 3D genome during fibroblast transdifferentiation into neural stem cells (NSCs). Multiomics analyses integrating Hi-C data, PTF1A and CTCF DNA-binding profiles, H3K27ac modification, and gene expression, demonstrate that PTF1A binds to subTAD boundaries subsequently associated with elevated CTCF binding and enhanced boundary insulation, and reorganizes chromatin loops, leading to gene expression changes that drive transdifferentiation into NSCs. Moreover, PTF1A activates enhancers and super-enhancers near low-insulation boundaries and modulates H3K27ac deposition, promoting cell fate transitions. Together, our data implicate an involvement of 3D genome in transcriptional and cell fate alterations, and highlight an essential role for PTF1A in gene expression control and multiscale 3D genome remodeling during cell reprogramming.},
}
@article {pmid39507620,
year = {2024},
author = {de Bruijn, SE and Panneman, DM and Weisschuh, N and Cadena, EL and Boonen, EGM and Holtes, LK and Astuti, GDN and Cremers, FPM and Leijsten, N and Corominas, J and Gilissen, C and Skowronska, A and Woodley, J and Beggs, AD and Toulis, V and Chen, D and Cheetham, ME and Hardcastle, AJ and McLaren, TL and Lamey, TM and Thompson, JA and Chen, FK and de Roach, JN and Urwin, IR and Sullivan, LS and Roosing, S},
title = {Identification of novel 3D-genome altering and complex structural variants underlying retinitis pigmentosa type 17 through a multistep and high-throughput approach.},
journal = {Frontiers in genetics},
volume = {15},
number = {},
pages = {1469686},
doi = {10.3389/fgene.2024.1469686},
pmid = {39507620},
issn = {1664-8021},
abstract = {INTRODUCTION: Autosomal dominant retinitis pigmentosa type 17 (adRP, type RP17) is caused by complex structural variants (SVs) affecting a locus on chromosome 17 (chr17q22). The SVs disrupt the 3D regulatory landscape by altering the topologically associating domain (TAD) structure of the locus, creating novel TAD structures (neo-TADs) and ectopic enhancer-gene contacts. Currently, screening for RP17-associated SVs is not included in routine diagnostics given the complexity of the variants and a lack of cost-effective detection methods. The aim of this study was to accurately detect novel RP17-SVs by establishing a systematic and efficient workflow.<br><br>METHODS: Genetically unexplained probands diagnosed with adRP (n = 509) from an international cohort were screened using a smMIPs or genomic qPCR-based approach tailored for the RP17 locus. Suspected copy number changes were validated using high-density SNP-array genotyping, and SV breakpoint characterization was performed by mutation-specific breakpoint PCR, genome sequencing and, if required, optical genome mapping. In silico modeling of novel SVs was performed to predict the formation of neo-TADs and whether ectopic contacts between the retinal enhancers and the GDPD1-promoter could be formed.<br><br>RESULTS: Using this workflow, potential RP17-SVs were detected in eight probands of which seven were confirmed. Two novel SVs were identified that are predicted to cause TAD rearrangement and retinal enhancer-GDPD1 contact, one from Germany (DE-SV9) and three with the same SV from the United States (US-SV10). Previously reported RP17-SVs were also identified in three Australian probands, one with UK-SV2 and two with SA-SV3.<br><br>DISCUSSION: In summary, we describe a validated multi-step pipeline for reliable and efficient RP17-SV discovery and expand the range of disease-associated SVs. Based on these data, RP17-SVs can be considered a frequent cause of adRP which warrants the inclusion of RP17-screening as a standard diagnostic test for this disease.},
}
@article {pmid39481374,
year = {2024},
author = {Lee, JJY and Johnston, MJ and Farooq, H and Chen, HM and Younes, ST and Suarez, R and Zwaig, M and Juretic, N and Weiss, WA and Ragoussis, J and Jabado, N and Taylor, MD and Gallo, M},
title = {3D genome topology distinguishes molecular subgroups of medulloblastoma.},
journal = {American journal of human genetics},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ajhg.2024.10.003},
pmid = {39481374},
issn = {1537-6605},
abstract = {Four main medulloblastoma (MB) molecular subtypes have been identified based on transcriptional, DNA methylation, and genetic profiles. However, it is currently not known whether 3D genome architecture differs between MB subtypes. To address this question, we performed in situ Hi-C to reconstruct the 3D genome architecture of MB subtypes. In total, we generated Hi-C and matching transcriptome data for 28 surgical specimens and Hi-C data for one patient-derived xenograft. The average resolution of the Hi-C maps was 6,833 bp. Using these data, we found that insulation scores of topologically associating domains (TADs) were effective at distinguishing MB molecular subgroups. TAD insulation score differences between subtypes were globally not associated with differential gene expression, although we identified few exceptions near genes expressed in the lineages of origin of specific MB subtypes. Our study therefore supports the notion that TAD insulation scores can distinguish MB subtypes independently of their transcriptional differences.},
}
@article {pmid39468060,
year = {2024},
author = {Göbel, AM and Zhou, S and Wang, Z and Tzourtzou, S and Himmelbach, A and Zheng, S and Pradillo, M and Liu, C and Jiang, H},
title = {Mutations of PDS5 genes enhance TAD-like domain formation Arabidopsis thaliana.},
journal = {Nature communications},
volume = {15},
number = {1},
pages = {9308},
pmid = {39468060},
issn = {2041-1723},
support = {JI347/6-1//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; LI 2862/8-1//Deutsche Forschungsgemeinschaft (German Research Foundation)/ ; 100489995//Bundesministerium f&#xfc;r Bildung und Forschung (Federal Ministry of Education and Research)/ ; 757600//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; },
mesh = {*Arabidopsis/genetics ; *Arabidopsis Proteins/genetics/metabolism ; *Mutation ; *Gene Expression Regulation, Plant ; *Chromatin/metabolism/genetics ; *Genome, Plant ; Chromatin Assembly and Disassembly/genetics ; },
abstract = {In eukaryotes, topologically associating domains (TADs) organize the genome into functional compartments. While TAD-like structures are common in mammals and many plants, they are challenging to detect in Arabidopsis thaliana. Here, we demonstrate that Arabidopsis PDS5 proteins play a negative role in TAD-like domain formation. Through Hi-C analysis, we show that mutations in PDS5 genes lead to the widespread emergence of enhanced TAD-like domains throughout the Arabidopsis genome, excluding pericentromeric regions. These domains exhibit increased chromatin insulation and enhanced chromatin interactions, without significant changes in gene expression or histone modifications. Our results suggest that PDS5 proteins are key regulators of genome architecture, influencing 3D chromatin organization independently of transcriptional activity. This study provides insights into the unique chromatin structure of Arabidopsis and the broader mechanisms governing plant genome folding.},
}
@article {pmid39457417,
year = {2024},
author = {Houchens, D and Chowdhury, HMAM and Oluwadare, O},
title = {coiTAD: Detection of Topologically Associating Domains Based on Clustering of Circular Influence Features from Hi-C Data.},
journal = {Genes},
volume = {15},
number = {10},
pages = {},
doi = {10.3390/genes15101293},
pmid = {39457417},
issn = {2073-4425},
support = {R35GM150402/NH/NIH HHS/United States ; },
mesh = {*Algorithms ; Humans ; Chromatin/genetics ; Cluster Analysis ; Computational Biology/methods ; Chromatin Assembly and Disassembly ; },
abstract = {BACKGROUND/OBJECTIVES: Topologically associating domains (TADs) are key structural units of the genome, playing a crucial role in gene regulation. TAD boundaries are enriched with specific biological markers and have been linked to genetic diseases, making consistent TAD detection essential. However, accurately identifying TADs remains challenging due to the lack of a definitive validation method. This study aims to develop a novel algorithm, termed coiTAD, which introduces an innovative approach for preprocessing Hi-C data to improve TAD prediction. This method employs a proposed "circle of influence" (COI) approach derived from Hi-C contact matrices.<br><br>METHODS: The coiTAD algorithm is based on the creation of novel features derived from the circle of influence in input contact matrices, which are subsequently clustered using the HDBSCAN clustering algorithm. The TADs are extracted from the clustered features based on intra-cluster interactions, thereby providing a more accurate method for identifying TADs.<br><br>RESULTS: Rigorous tests were conducted using both simulated and real Hi-C datasets. The algorithm's validation included analysis of boundary proteins such as H3K4me1, RNAPII, and CTCF. coiTAD consistently matched other TAD prediction methods.<br><br>CONCLUSIONS: The coiTAD algorithm represents a novel approach for detecting TADs. At its core, the circle-of-influence methodology introduces an innovative strategy for preparing Hi-C data, enabling the assessment of interaction strengths between genomic regions. This approach facilitates a nuanced analysis that effectively captures structural variations within chromatin. Ultimately, the coiTAD algorithm enhances our understanding of chromatin organization and offers a robust tool for genomic research. The source code for coiTAD is publicly available, and the URL can be found in the Data Availability Statement section.},
}
@article {pmid39416077,
year = {2024},
author = {Rahmaninejad, H and Xiao, Y and Tortora, MMC and Fudenberg, G},
title = {Dynamic barriers modulate cohesin positioning and genome folding at fixed occupancy.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.10.08.617113},
pmid = {39416077},
issn = {2692-8205},
abstract = {In mammalian interphase cells, genomes are folded by cohesin loop extrusion limited by directional CTCF barriers. This interplay leads to the enrichment of cohesin at barriers, isolation between neighboring topologically associating domains, and elevated contact frequency between convergent CTCF barriers across the genome. However, recent in vivo measurements present a puzzle: reported residence times for CTCF on chromatin are in the range of a few minutes, while lifetimes for cohesin are much longer. Can the observed features of genome folding result from the action of relatively transient barriers? To address this question, we developed a dynamic barrier model, where CTCF sites switch between bound and unbound states with rates that can be directly compared with biophysical measurements. Using this model, we investigated how barrier dynamics would impact observables for a range of experimental genomic and imaging datasets, including ChIP-seq, Hi-C, and microscopy. We found the interplay of CTCF and cohesin binding timescales influence the strength of each of these features, leaving a signature of barrier dynamics even in the population-averaged snapshots offered by genomic datasets. First, in addition to barrier occupancy, barrier bound times are crucial for instructing features of genome folding. Second, the ratio of boundary to extruder lifetime greatly alters simulated ChIP-seq and simulated Hi-C. Third, large-scale changes in chromosome morphology observed experimentally after increasing extruder lifetime require dynamic barriers. By integrating multiple sources of experimental data, our biophysical model argues that CTCF barrier bound times effectively approach those of cohesin extruder lifetimes. Together, we demonstrate how models that are informed by biophysically measured protein dynamics broaden our understanding of genome folding.},
}
@article {pmid39394698,
year = {2024},
author = {Ding, T and Fu, S and Zhang, X and Yang, F and Zhang, J and Xu, H and Yang, J and Chen, C and Shi, Y and Bai, Y and Li, W and Chang, X and Wang, S and Zhang, C and Liu, Q and Zhang, H},
title = {Inter3D: Capture of TAD Reorganization Endows Variant Patterns of Gene Transcription.},
journal = {Genomics, proteomics &amp; bioinformatics},
volume = {22},
number = {3},
pages = {},
doi = {10.1093/gpbjnl/qzae034},
pmid = {39394698},
issn = {2210-3244},
mesh = {Humans ; *Transcription, Genetic/genetics ; Chromatin Assembly and Disassembly/genetics ; },
abstract = {Topologically associating domain (TAD) reorganization commonly occurs in the cell nucleus and contributes to gene activation and inhibition through the separation or fusion of adjacent TADs. However, functional genes impacted by TAD alteration and the underlying mechanism of TAD reorganization regulating gene transcription remain to be fully elucidated. Here, we first developed a novel approach termed Inter3D to specifically identify genes regulated by TAD reorganization. Our study revealed that the segregation of TADs led to the disruption of intrachromosomal looping at the myosin light chain 12B (MYL12B) locus, via the meticulous reorganization of TADs mediating epigenomic landscapes within tumor cells, thereby exhibiting a significant correlation with the down-regulation of its transcriptional activity. Conversely, the fusion of TADs facilitated intrachromosomal interactions, suggesting a potential association with the activation of cytochrome P450 family 27 subfamily B member 1 (CYP27B1). Our study provides comprehensive insight into the capture of TAD rearrangement-mediated gene loci and moves toward understanding the functional role of TAD reorganization in gene transcription. The Inter3D pipeline developed in this study is freely available at https://github.com/bm2-lab/inter3D and https://ngdc.cncb.ac.cn/biocode/tool/BT7399.},
}
@article {pmid39392751,
year = {2024},
author = {Tsaytler, P and Blaess, G and Scholze-Wittler, M and Meierhofer, D and Wittler, L and Koch, F and Herrmann, BG},
title = {SRF promotes long-range chromatin loop formation and stem cell pluripotency.},
journal = {Cell reports},
volume = {43},
number = {10},
pages = {114846},
doi = {10.1016/j.celrep.2024.114846},
pmid = {39392751},
issn = {2211-1247},
abstract = {Serum response factor (SRF) is a transcription factor essential for cell proliferation, differentiation, and migration and is required for primitive streak and mesoderm formation in the embryo. The canonical roles of SRF are mediated by a diverse set of context-dependent cofactors. Here, we show that SRF physically interacts with CTCF and cohesin subunits at topologically associating domain (TAD) boundaries and loop anchors. SRF promotes long-range chromatin loop formation and contributes to TAD insulation. In embryonic stem cells (ESCs), SRF associates with SOX2 and NANOG and contributes to the formation of three-dimensional (3D) pluripotency hubs. Our findings reveal additional roles of SRF in higher-order chromatin organization.},
}
@article {pmid39383545,
year = {2024},
author = {Bondarieva, A and Tachibana, K},
title = {Genome folding and zygotic genome activation in mammalian preimplantation embryos.},
journal = {Current opinion in genetics &amp; development},
volume = {89},
number = {},
pages = {102268},
doi = {10.1016/j.gde.2024.102268},
pmid = {39383545},
issn = {1879-0380},
abstract = {The totipotent one-cell embryo, or zygote, gives rise to all germ layers and extraembryonic tissues that culminate in the development of a new organism. A zygote is produced at fertilisation by the fusion of differentiated germ cells, egg and sperm. The chromatin of parental genomes is reprogrammed and spatially reorganised in the early embryo. The 3D chromatin organisation is established de novo after fertilisation by a cohesin-dependent mechanism of loop extrusion that forms chromatin loops and topologically associating domains (TADs). Strengthening of TAD insulation is concomitant with the transcriptional 'awakening' of the embryo known as zygotic genome activation (ZGA). Whether and how these processes are causally linked remains poorly understood. In this review, we discuss recent findings of 3D chromatin organisation in mammalian gametes and embryos and how these are potentially related to ZGA.},
}
@article {pmid39322849,
year = {2024},
author = {Lee, Y and Park, SH and Lee, H},
title = {Prediction of the 3D cancer genome from whole-genome sequencing using InfoHiC.},
journal = {Molecular systems biology},
volume = {},
number = {},
pages = {},
pmid = {39322849},
issn = {1744-4292},
support = {2019-0-00567//Institute of Information &amp; communications technology planning &amp; evaluation/ ; 2019-0-01842//Institute of Information &amp; communications technology planning &amp; evaluation/ ; },
abstract = {The 3D genome prediction in cancer is crucial for uncovering the impact of structural variations (SVs) on tumorigenesis, especially when they are present in noncoding regions. We present InfoHiC, a systemic framework for predicting the 3D cancer genome directly from whole-genome sequencing (WGS). InfoHiC utilizes contig-specific copy number encoding on the SV contig assembly, and performs a contig-to-total Hi-C conversion for the cancer Hi-C prediction from multiple SV contigs. We showed that InfoHiC can predict 3D genome folding from all types of SVs using breast cancer cell line data. We applied it to WGS data of patients with breast cancer and pediatric patients with medulloblastoma, and identified neo topologically associating domains. For breast cancer, we discovered super-enhancer hijacking events associated with oncogenic overexpression and poor survival outcomes. For medulloblastoma, we found SVs in noncoding regions that caused super-enhancer hijacking events of medulloblastoma driver genes (GFI1, GFI1B, and PRDM6). In addition, we provide trained models for cancer Hi-C prediction from WGS at https://github.com/dmcb-gist/InfoHiC , uncovering the impacts of SVs in cancer patients and revealing novel therapeutic targets.},
}
@article {pmid39322282,
year = {2024},
author = {Hristov, BH and Noble, WS and Bertero, A},
title = {Systematic identification of interchromosomal interaction networks supports the existence of specialized RNA factories.},
journal = {Genome research},
volume = {},
number = {},
pages = {},
doi = {10.1101/gr.278327.123},
pmid = {39322282},
issn = {1549-5469},
abstract = {Most studies of genome organization have focused on intrachromosomal (cis) contacts because they harbor key features such as DNA loops and topologically associating domains. Interchromosomal (trans) contacts have received much less attention, and tools for interrogating potential biologically relevant trans structures are lacking. Here, we develop a computational framework that uses Hi-C data to identify sets of loci that jointly interact in trans This method, trans-C, initiates probabilistic random walks with restarts from a set of seed loci to traverse an input Hi-C contact network, thereby identifying sets of trans-contacting loci. We validate trans-C in three increasingly complex models of established trans contacts: the Plasmodium falciparum var genes, the mouse olfactory receptor "Greek islands", and the human RBM20 cardiac splicing factory. We then apply trans-C to systematically test the hypothesis that genes coregulated by the same trans-acting element (i.e., a transcription or splicing factor) colocalize in three dimensions to form "RNA factories" that maximize the efficiency and accuracy of RNA biogenesis. We find that many loci with multiple binding sites of the same DNA binding proteins interact with one another in trans, especially those bound by factors with intrinsically disordered domains. Similarly, clustered binding of a subset of RNA-binding proteins correlates with trans interaction of the encoding loci. Intriguingly, we observe that these trans-interacting loci are close to nuclear speckles. Our findings support the existence of trans interacting chromatin domains (TIDs) driven by RNA biogenesis. Trans-C provides an efficient computational framework for studying these and other types of trans interactions, empowering studies of a poorly understood aspect of genome architecture.},
}
@article {pmid39293448,
year = {2024},
author = {Erjavec, E and Angée, C and Hadjadj, D and Passet, B and David, P and Kostic, C and Dodé, E and Zanlonghi, X and Cagnard, N and Nedelec, B and Crippa, SV and Bole-Feysot, C and Zarhrate, M and Creuzet, S and Castille, J and Vilotte, JL and Calvas, P and Plaisancié, J and Chassaing, N and Kaplan, J and Rozet, JM and Taie, LF},
title = {Congenital microcoria deletion in mouse links Sox21 dysregulation to disease and suggests a role for TGFB2 in glaucoma and myopia.},
journal = {American journal of human genetics},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ajhg.2024.08.019},
pmid = {39293448},
issn = {1537-6605},
abstract = {Congenital microcoria (MCOR) is a rare hereditary developmental defect of the iris dilator muscle frequently associated with high axial myopia and high intraocular pressure (IOP) glaucoma. The condition is caused by submicroscopic rearrangements of chromosome 13q32.1. However, the mechanisms underlying the failure of iris development and the origin of associated features remain elusive. Here, we present a 3D architecture model of the 13q32.1 region, demonstrating that MCOR-related deletions consistently disrupt the boundary between two topologically associating domains (TADs). Deleting the critical MCOR-causing region in mice reveals ectopic Sox21 expression precisely aligning with Dct, each located in one of the two neighbor TADs. This observation is consistent with the TADs' boundary alteration and adoption of Dct regulatory elements by the Sox21 promoter. Additionally, we identify Tgfb2 as a target gene of SOX21 and show TGFΒ2 accumulation in the aqueous humor of an MCOR-affected subject. Accumulation of TGFB2 is recognized for its role in glaucoma and potential impact on axial myopia. Our results highlight the importance of SOX21-TGFB2 signaling in iris development and control of eye growth and IOP. Insights from MCOR studies may provide therapeutic avenues for this condition but also for glaucoma and high myopia conditions, affecting millions of people.},
}
@article {pmid39283464,
year = {2025},
author = {Wall, BPG and Nguyen, M and Harrell, JC and Dozmorov, MG},
title = {Machine and Deep Learning Methods for Predicting 3D Genome Organization.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {2856},
number = {},
pages = {357-400},
pmid = {39283464},
issn = {1940-6029},
mesh = {*Chromatin/genetics/metabolism ; *Deep Learning ; Humans ; Computational Biology/methods ; Machine Learning ; Genomics/methods ; Enhancer Elements, Genetic ; Promoter Regions, Genetic ; Binding Sites ; Genome ; Software ; },
abstract = {Three-dimensional (3D) chromatin interactions, such as enhancer-promoter interactions (EPIs), loops, topologically associating domains (TADs), and A/B compartments, play critical roles in a wide range of cellular processes by regulating gene expression. Recent development of chromatin conformation capture technologies has enabled genome-wide profiling of various 3D structures, even with single cells. However, current catalogs of 3D structures remain incomplete and unreliable due to differences in technology, tools, and low data resolution. Machine learning methods have emerged as an alternative to obtain missing 3D interactions and/or improve resolution. Such methods frequently use genome annotation data (ChIP-seq, DNAse-seq, etc.), DNA sequencing information (k-mers and transcription factor binding site (TFBS) motifs), and other genomic properties to learn the associations between genomic features and chromatin interactions. In this review, we discuss computational tools for predicting three types of 3D interactions (EPIs, chromatin interactions, and TAD boundaries) and analyze their pros and cons. We also point out obstacles to the computational prediction of 3D interactions and suggest future research directions.},
}
@article {pmid39283452,
year = {2025},
author = {Nakato, R},
title = {Exploring Contact Distance Distributions with Google Colaboratory.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {2856},
number = {},
pages = {179-196},
pmid = {39283452},
issn = {1940-6029},
mesh = {*Software ; *High-Throughput Nucleotide Sequencing/methods ; Computational Biology/methods ; Web Browser ; Workflow ; Humans ; Chromatin/genetics ; Genomics/methods ; },
abstract = {Hi-C and Micro-C are the three-dimensional (3D) genome assays that use high-throughput sequencing. In the analysis, the sequenced paired-end reads are mapped to a reference genome to generate a two-dimensional contact matrix for identifying topologically associating domains (TADs), chromatin loops, and chromosomal compartments. On the other hand, the distance distribution of the paired-end mapped reads also provides insight into the 3D genome structure by highlighting global contact frequency patterns at distances indicative of loops, TADs, and compartments. This chapter presents a basic workflow for visualizing and analyzing contact distance distributions from Hi-C data. The workflow can be run on Google Colaboratory, which provides a ready-to-use Python environment accessible through a web browser. The notebook that demonstrates the workflow is available in the GitHub repository at https://github.com/rnakato/Springer_contact_distance_plot.},
}
@article {pmid39283443,
year = {2025},
author = {Okabe, A},
title = {Methods for Genome-Wide Chromatin Interaction Analysis.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {2856},
number = {},
pages = {3-9},
pmid = {39283443},
issn = {1940-6029},
mesh = {*Chromatin/genetics/metabolism/chemistry ; Humans ; *High-Throughput Nucleotide Sequencing/methods ; Genomics/methods ; Genome-Wide Association Study/methods ; Animals ; },
abstract = {Recent analyses revealed the essential function of chromatin structure in maintaining and regulating genomic information. Advancements in microscopy, nuclear structure observation techniques, and the development of methods utilizing next-generation sequencers (NGSs) have significantly progressed these discoveries. Methods utilizing NGS enable genome-wide analysis, which is challenging with microscopy, and have elucidated concepts of important chromatin structures such as a loop structure, a domain structure called topologically associating domains (TADs), and compartments. In this chapter, I introduce chromatin interaction techniques using NGS and outline the principles and features of each method.},
}
@article {pmid39273012,
year = {2024},
author = {Viushkov, VS and Lomov, NA and Rubtsov, MA},
title = {A Comparison of Two Versions of the CRISPR-Sirius System for the Live-Cell Visualization of the Borders of Topologically Associating Domains.},
journal = {Cells},
volume = {13},
number = {17},
pages = {},
doi = {10.3390/cells13171440},
pmid = {39273012},
issn = {2073-4409},
support = {22-24-00251//Russian Science Foundation/ ; },
mesh = {Humans ; *CRISPR-Cas Systems/genetics ; Chromatin/metabolism/genetics ; HEK293 Cells ; RNA, Guide, CRISPR-Cas Systems/genetics ; Clustered Regularly Interspaced Short Palindromic Repeats/genetics ; },
abstract = {In recent years, various technologies have emerged for the imaging of chromatin loci in living cells via catalytically inactive Cas9 (dCas9). These technologies facilitate a deeper understanding of the mechanisms behind the chromatin dynamics and provide valuable kinetic data that could not have previously been obtained via FISH applied to fixed cells. However, such technologies are relatively complicated, as they involve the expression of several chimeric proteins as well as sgRNAs targeting the visualized loci, a process that entails many technical subtleties. Therefore, the effectiveness in visualizing a specific target locus may be quite low. In this study, we directly compared two versions of a previously published CRISPR-Sirius method based on the use of sgRNAs containing eight MS2 or PP7 stem loops and the expression of MCP or PCP fused to fluorescent proteins. We assessed the visualization efficiency for several unique genomic loci by comparing the two approaches in delivering sgRNA genes (transient transfection and lentiviral transduction), as well as two CRISPR-Sirius versions (with PCP and with MCP). The efficiency of visualization varied among the loci, and not all loci could be visualized. However, the MCP-sfGFP version provided more efficient visualization in terms of the number of cells with signals than PCP-sfGFP for all tested loci. We also showed that lentiviral transduction was more efficient in locus imaging than transient transfection for both CRISPR-Sirius systems. Most of the target loci in our study were located at the borders of topologically associating domains, and we defined a set of TAD borders that could be effectively visualized using the MCP-sfGFP version of the CRISPR-Sirius system. Altogether, our study validates the use of the CRISPR-Sirius technology for live-cell visualization and highlights various technical details that should be considered when using this method.},
}
@article {pmid39272130,
year = {2024},
author = {Daly, AF and Dunnington, LA and Rodriguez-Buritica, DF and Spiegel, E and Brancati, F and Mantovani, G and Rawal, VM and Faucz, FR and Hijazi, H and Caberg, JH and Nardone, AM and Bengala, M and Fortugno, P and Del Sindaco, G and Ragonese, M and Gould, H and Cannavò, S and Pétrossians, P and Lania, A and Lupski, JR and Beckers, A and Stratakis, CA and Levy, B and Trivellin, G and Franke, M},
title = {Chromatin conformation capture in the clinic: 4C-seq/HiC distinguishes pathogenic from neutral duplications at the GPR101 locus.},
journal = {Genome medicine},
volume = {16},
number = {1},
pages = {112},
pmid = {39272130},
issn = {1756-994X},
support = {GGP20130//Fondazione Telethon/ ; 2018/20//Centre Hospitalier Universitaire de Li&#xe8;ge/ ; Z1A HD008920//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; R35NS105078//National Institute of Health (NINDS)/ ; Ricerca Corrente"//Ministero della Salute/ ; T3-AN-14 "LifeMap"//Ministero della Salute/ ; PRIN PNRR 2022//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca/ ; PRIN 2022//Ministero dell'Istruzione, dell'Universit&#xe0; e della Ricerca/ ; 100010434//'la Caixa' Foundation/ ; fellowship code LCF/BQ/PR22/11920006//'la Caixa' Foundation/ ; },
mesh = {Humans ; *Receptors, G-Protein-Coupled/genetics ; *Chromatin/genetics/metabolism ; Female ; Male ; Gene Duplication ; Chromosome Duplication ; Chromosomes, Human, X/genetics ; Pedigree ; },
abstract = {BACKGROUND: X-linked acrogigantism (X-LAG; MIM: 300942) is a severe form of pituitary gigantism caused by chromosome Xq26.3 duplications involving GPR101. X-LAG-associated duplications disrupt the integrity of the topologically associating domain (TAD) containing GPR101 and lead to the formation of a neo-TAD that drives pituitary GPR101 misexpression and gigantism. As X-LAG is fully penetrant and heritable, duplications involving GPR101 identified on prenatal screening studies, like amniocentesis, can pose an interpretation challenge for medical geneticists and raise important concerns for patients and families. Therefore, providing robust information on the functional genomic impact of such duplications has important research and clinical value with respect to gene regulation and triplosensitivity traits.<br><br>METHODS: We employed 4C/HiC-seq as a clinical tool to determine the functional impact of incidentally discovered GPR101 duplications on TAD integrity in three families. After defining duplications and breakpoints around GPR101 by clinical-grade and high-density aCGH, we constructed 4C/HiC chromatin contact maps for our study population and compared them with normal and active (X-LAG) controls.<br><br>RESULTS: We showed that duplications involving GPR101 that preserved the centromeric invariant TAD boundary did not generate a pathogenic neo-TAD and that&#xa0;ectopic enhancers were not adopted. This allowed us to discount presumptive/suspected X-LAG diagnoses and GPR101 misexpression, obviating the need for intensive clinical follow-up.<br><br>CONCLUSIONS: This study highlights the importance of TAD boundaries and chromatin interactions in determining the functional impact of copy number variants and provides proof-of-concept for using 4C/HiC-seq as a clinical tool to acquire crucial information for genetic counseling and to support clinical decision-making in cases of suspected TADopathies.},
}
@article {pmid39257002,
year = {2024},
author = {Maroofian, R and Pagnamenta, AT and Navabazam, A and Schwessinger, R and Roberts, HE and Lopopolo, M and Dehghani, M and Vahidi Mehrjardi, MY and Haerian, A and Soltanianzadeh, M and Noori Kooshki, MH and Knight, SJ and Miller, KA and McGowan, SJ and Chatron, N and Timberlake, AT and Melo, US and Mundlos, S and Buck, D and Twigg, SR and Taylor, JC and Wilkie, AO and Calpena, E},
title = {Familial severe skeletal Class II malocclusion with gingival hyperplasia caused by a complex structural rearrangement at the KCNJ2-KCNJ16 locus.},
journal = {HGG advances},
volume = {},
number = {},
pages = {100352},
doi = {10.1016/j.xhgg.2024.100352},
pmid = {39257002},
issn = {2666-2477},
abstract = {The aim of this work was to identify the underlying genetic cause in a four-generation family segregating an unusual phenotype comprising a severe form of skeletal Class II malocclusion with gingival hyperplasia. SNP-array identified a copy number gain on chr1, however this chromosomal region did not segregate correctly in the extended family. Exome sequencing also failed to identify a candidate causative variant, but highlighted co-segregating genetic markers on chr17 and chr19. Short- and long-read genome sequencing allowed us to pinpoint and characterize at nucleotide-level resolution a chromothripsis-like complex rearrangement (CR) inserted into the chr17 co-segregating region at the KCNJ2-SOX9 locus. The CR involved the gain of five different regions from chr1 that are shuffled, chained and inserted as a single block (∼828 kb) at chr17q24.3. The inserted sequences contain craniofacial enhancers that are predicted to interact with KCNJ2/KCNJ16 through neo-topologically associating domain (TAD) formation to induce ectopic activation. Our findings suggest that the CR inserted at chr17q24.3 is the cause of the severe skeletal Class II malocclusion with gingival hyperplasia in this family and expands the panoply of phenotypes linked to variation at the KCNJ2-SOX9 locus. In addition, we highlight a previously overlooked potential role for misregulation of the KCNJ2/KCNJ16 genes in the pathomechanism of gingival hyperplasia associated with deletions and other rearrangements of the 17q24.2-q24.3 region (MIM 135400).},
}
@article {pmid39222712,
year = {2024},
author = {Liu, H and Ma, W},
title = {DiffGR: Detecting Differentially Interacting Genomic Regions from Hi-C Contact Maps.},
journal = {Genomics, proteomics &amp; bioinformatics},
volume = {22},
number = {2},
pages = {},
doi = {10.1093/gpbjnl/qzae028},
pmid = {39222712},
issn = {2210-3244},
mesh = {Humans ; Mice ; Animals ; *Chromatin/genetics/metabolism ; *Software ; Genomics/methods ; Chromosome Mapping/methods ; },
abstract = {Recent advances in high-throughput chromosome conformation capture (Hi-C) techniques have allowed us to map genome-wide chromatin interactions and uncover higher-order chromatin structures, thereby shedding light on the principles of genome architecture and functions. However, statistical methods for detecting changes in large-scale chromatin organization such as topologically associating domains (TADs) are still lacking. Here, we proposed a new statistical method, DiffGR, for detecting differentially interacting genomic regions at the TAD level between Hi-C contact maps. We utilized the stratum-adjusted correlation coefficient to measure similarity of local TAD regions. We then developed a nonparametric approach to identify statistically significant changes of genomic interacting regions. Through simulation studies, we demonstrated that DiffGR can robustly and effectively discover differential genomic regions under various conditions. Furthermore, we successfully revealed cell type-specific changes in genomic interacting regions in both human and mouse Hi-C datasets, and illustrated that DiffGR yielded consistent and advantageous results compared with state-of-the-art differential TAD detection methods. The DiffGR R package is published under the GNU General Public License (GPL) ≥ 2 license and is publicly available at https://github.com/wmalab/DiffGR.},
}
@article {pmid39198689,
year = {2024},
author = {Lu, B and Qiu, R and Wei, J and Wang, L and Zhang, Q and Li, M and Zhan, X and Chen, J and Hsieh, IY and Yang, C and Zhang, J and Sun, Z and Zhu, Y and Jiang, T and Zhu, H and Li, J and Zhao, W},
title = {Phase separation of phospho-HDAC6 drives aberrant chromatin architecture in triple-negative breast cancer.},
journal = {Nature cancer},
volume = {},
number = {},
pages = {},
pmid = {39198689},
issn = {2662-1347},
support = {81972651//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82172698//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82372857//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {How dysregulated liquid-liquid phase separation (LLPS) contributes to the oncogenesis of female triple-negative breast cancer (TNBC) remains unknown. Here we demonstrate that phosphorylated histone deacetylase 6 (phospho-HDAC6) forms LLPS condensates in the nuclei of TNBC cells that are essential for establishing aberrant chromatin architecture. The disordered N-terminal domain and phosphorylated residue of HDAC6 facilitate effective LLPS, whereas nuclear export regions exert a negative dominant effect. Through phase-separation-based screening, we identified Nexturastat A as a specific disruptor of phospho-HDAC6 condensates, which effectively suppresses tumor growth. Mechanistically, importin-β interacts with phospho-HDAC6, promoting its translocation to the nucleus, where 14-3-3θ mediates the condensate formation. Disruption of phospho-HDAC6 LLPS re-established chromatin compartments and topologically associating domain boundaries, leading to disturbed chromatin loops. The phospho-HDAC6-induced aberrant chromatin architecture affects chromatin accessibility, histone acetylation, RNA polymerase II elongation and transcriptional profiles in TNBC. This study demonstrates phospho-HDAC6 LLPS as an emerging mechanism underlying the dysregulation of chromatin architecture in TNBC.},
}
@article {pmid39190242,
year = {2024},
author = {Carballo-Pacoret, P and Carracedo, A and Rodriguez-Fontenla, C},
title = {Unraveling the three-dimensional (3D) genome architecture in Neurodevelopmental Disorders (NDDs).},
journal = {Neurogenetics},
volume = {},
number = {},
pages = {},
pmid = {39190242},
issn = {1364-6753},
support = {PI22/00208//Instituto de Salud Carlos III/ ; PI22/00208//Instituto de Salud Carlos III/ ; PI22/00208//Instituto de Salud Carlos III/ ; },
abstract = {The human genome, comprising millions of pairs of bases, serves as the blueprint of life, encoding instructions for cellular processes. However, genomes are not merely linear sequences; rather, the complex of DNA and histones, known as chromatin, exhibits complex organization across various levels, which profoundly influence gene expression and cellular function. Central to understanding genome organization is the emerging field of three-dimensional (3D) genome studies. Utilizing advanced techniques such as Hi-C, researchers have unveiled non-random dispositions of genomic elements, highlighting their importance in transcriptional regulation and disease mechanisms. Topologically Associating Domains (TADs), that demarcate regions of chromatin with preferential internal interactions, play crucial roles in gene regulation and are increasingly implicated in various diseases such as cancer and schizophrenia. However, their role in Neurodevelopmental Disorders (NDDs) remains poorly understood. Here, we focus on TADs and 3D conservation across the evolution and between cell types in NDDs. The investigation into genome organization and its impact on disease has led to significant breakthroughs in understanding NDDs etiology such ASD (Autism Spectrum Disorder). By elucidating the wide spectrum of ASD manifestations, researchers aim to uncover the underlying genetic and epigenetic factors contributing to its heterogeneity. Moreover, studies linking TAD disruption to NDDs underscore the importance of spatial genome organization in maintaining proper brain development and function. In summary, this review highlights the intricate interplay between genome organization, transcriptional control, and disease pathology, shedding light on fundamental biological processes and offering insights into the mechanisms underlying NDDs like ASD.},
}
@article {pmid39179577,
year = {2024},
author = {Ealo, T and Sanchez-Gaya, V and Respuela, P and Muñoz-San Martín, M and Martin-Batista, E and Haro, E and Rada-Iglesias, A},
title = {Cooperative insulation of regulatory domains by CTCF-dependent physical insulation and promoter competition.},
journal = {Nature communications},
volume = {15},
number = {1},
pages = {7258},
pmid = {39179577},
issn = {2041-1723},
support = {862022//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; H2020-MSCA-ITN-2019-860002//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 Marie Sk&#x142;odowska-Curie Actions (H2020 Excellent Science - Marie Sk&#x142;odowska-Curie Actions)/ ; MSCA-2021-DN-01-101073334//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 Marie Sk&#x142;odowska-Curie Actions (H2020 Excellent Science - Marie Sk&#x142;odowska-Curie Actions)/ ; PID2021-123030NB-I00//Ministry of Economy and Competitiveness | Agencia Estatal de Investigaci&#xf3;n (Spanish Agencia Estatal de Investigaci&#xf3;n)/ ; RED2022-134100-T//Ministry of Economy and Competitiveness | Agencia Estatal de Investigaci&#xf3;n (Spanish Agencia Estatal de Investigaci&#xf3;n)/ ; },
mesh = {Animals ; *CCCTC-Binding Factor/metabolism/genetics ; Mice ; *Promoter Regions, Genetic/genetics ; *Enhancer Elements, Genetic/genetics ; *Mouse Embryonic Stem Cells/metabolism ; Gene Expression Regulation, Developmental ; Insulator Elements/genetics ; },
abstract = {The specificity of gene expression during development requires the insulation of regulatory domains to avoid inappropriate enhancer-gene interactions. In vertebrates, this insulator function is mostly attributed to clusters of CTCF sites located at topologically associating domain (TAD) boundaries. However, TAD boundaries allow some physical crosstalk across regulatory domains, which is at odds with the specific and precise expression of developmental genes. Here we show that developmental genes and nearby clusters of CTCF sites cooperatively foster the robust insulation of regulatory domains. By genetically dissecting a couple of representative loci in mouse embryonic stem cells, we show that CTCF sites prevent undesirable enhancer-gene contacts (i.e. physical insulation), while developmental genes preferentially contribute to regulatory insulation through non-structural mechanisms involving promoter competition rather than enhancer blocking. Overall, our work provides important insights into the insulation of regulatory domains, which in turn might help interpreting the pathological consequences of certain structural variants.},
}
@article {pmid39169755,
year = {2024},
author = {Huang, H and Wu, Q},
title = {Pushing the TAD boundary: Decoding insulator codes of clustered CTCF sites in 3D genomes.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {},
number = {},
pages = {e2400121},
doi = {10.1002/bies.202400121},
pmid = {39169755},
issn = {1521-1878},
support = {32330016//National Natural Science Foundation of China/ ; 2022YFC3400200//National Key R&amp;D Program of China/ ; },
abstract = {Topologically associating domain (TAD) boundaries are the flanking edges of TADs, also known as insulated neighborhoods, within the 3D structure of genomes. A prominent feature of TAD boundaries in mammalian genomes is the enrichment of clustered CTCF sites often with mixed orientations, which can either block or facilitate enhancer-promoter (E-P) interactions within or across distinct TADs, respectively. We will discuss recent progress in the understanding of fundamental organizing principles of the clustered CTCF insulator codes at TAD boundaries. Specifically, both inward- and outward-oriented CTCF sites function as topological chromatin insulators by asymmetrically blocking improper TAD-boundary-crossing cohesin loop extrusion. In addition, boundary stacking and enhancer clustering facilitate long-distance E-P interactions across multiple TADs. Finally, we provide a unified mechanism for RNA-mediated TAD boundary function via R-loop formation for both insulation and facilitation. This mechanism of TAD boundary formation and insulation has interesting implications not only on how the 3D genome folds in the Euclidean nuclear space but also on how the specificity of E-P interactions is developmentally regulated.},
}
@article {pmid39152239,
year = {2024},
author = {Denaud, S and Bardou, M and Papadopoulos, GL and Grob, S and Di Stefano, M and Sabarís, G and Nollmann, M and Schuettengruber, B and Cavalli, G},
title = {A PRE loop at the dac locus acts as a topological chromatin structure that restricts and specifies enhancer-promoter communication.},
journal = {Nature structural &amp; molecular biology},
volume = {},
number = {},
pages = {},
pmid = {39152239},
issn = {1545-9985},
abstract = {Three-dimensional (3D) genome folding has a fundamental role in the regulation of developmental genes by facilitating or constraining chromatin interactions between cis-regulatory elements (CREs). Polycomb response elements (PREs) are a specific kind of CRE involved in the memory of transcriptional states in Drosophila melanogaster. PREs act as nucleation sites for Polycomb group (PcG) proteins, which deposit the repressive histone mark H3K27me3, leading to the formation of a class of topologically associating domain (TAD) called a Polycomb domain. PREs can establish looping contacts that stabilize the gene repression of key developmental genes during development. However, the mechanism by which PRE loops fine-tune gene expression is unknown. Using clustered regularly interspaced short palindromic repeats and Cas9 genome engineering, we specifically perturbed PRE contacts or enhancer function and used complementary approaches including 4C-seq, Hi-C and Hi-M to analyze how chromatin architecture perturbation affects gene expression. Our results suggest that the PRE loop at the dac gene locus acts as a constitutive 3D chromatin scaffold during Drosophila development that forms independently of gene expression states and has a versatile function; it restricts enhancer-promoter communication and contributes to enhancer specificity.},
}
@article {pmid39152238,
year = {2024},
author = {Yao, Q and Zhu, L and Shi, Z and Banerjee, S and Chen, C},
title = {Topoisomerase-modulated genome-wide DNA supercoiling domains colocalize with nuclear compartments and regulate human gene expression.},
journal = {Nature structural &amp; molecular biology},
volume = {},
number = {},
pages = {},
pmid = {39152238},
issn = {1545-9985},
abstract = {DNA supercoiling is a biophysical feature of the double helix with a pivotal role in biological processes. However, understanding of DNA supercoiling in the chromatin remains limited. Here, we developed azide-trimethylpsoralen sequencing (ATMP-seq), a DNA supercoiling assay offering quantitative accuracy while minimizing genomic bias and background noise. Using ATMP-seq, we directly visualized transcription-dependent negative and positive twin-supercoiled domains around genes and mapped kilobase-resolution DNA supercoiling throughout the human genome. Remarkably, we discovered megabase-scale supercoiling domains (SDs) across all chromosomes that are modulated mainly by topoisomerases I and IIβ. Transcription activities, but not the consequent supercoiling accumulation in the local region, contribute to SD formation, indicating the long-range propagation of transcription-generated supercoiling. Genome-wide SDs colocalize with A/B compartments in both human and Drosophila cells but are distinct from topologically associating domains (TADs), with negative supercoiling accumulation at TAD boundaries. Furthermore, genome-wide DNA supercoiling varies between cell states and types and regulates human gene expression, underscoring the importance of supercoiling dynamics in chromatin regulation and function.},
}
@article {pmid39149372,
year = {2024},
author = {Kearly, A and Saelee, P and Bard, J and Sinha, S and Satterthwaite, A and Garrett-Sinha, LA},
title = {Sequences within and upstream of the mouse Ets1 gene drive high level expression in B cells, but are not sufficient for consistent expression in T cells.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.08.02.606433},
pmid = {39149372},
issn = {2692-8205},
abstract = {The levels of transcription factor Ets1 are high in resting B and T cells, but are downregulated by signaling through antigen receptors and Toll-like receptors (TLRs). Loss of Ets1 in mice leads to excessive immune cell activation and development of an autoimmune syndrome and reduced Ets1 expression has been observed in human PBMCs in the context of autoimmune diseases. In B cells, Ets1 serves to prevent premature activation and differentiation to antibody-secreting cells. Given these important roles for Ets1 in the immune response, stringent control of Ets1 gene expression levels is required for homeostasis. However, the genetic regulatory elements that control expression of the Ets1 gene remain relatively unknown. Here we identify a topologically-associating domain (TAD) in the chromatin of B cells that includes the mouse Ets1 gene locus and describe an interaction hub that extends over 100 kb upstream and into the gene body. Additionally, we compile epigenetic datasets to find several putative regulatory elements within the interaction hub by identifying regions of high DNA accessibility and enrichment of active enhancer histone marks. Using reporter constructs, we determine that DNA sequences within this interaction hub are sufficient to direct reporter gene expression in lymphoid tissues of transgenic mice. Further analysis indicates that the reporter construct drives faithful expression of the reporter gene in mouse B cells, but variegated expression in T cells, suggesting the existence of T cell regulatory elements outside this region. To investigate how the downregulation of Ets1 transcription is associated with alterations in the epigenetic landscape of stimulated B cells, we performed ATAC-seq in resting and BCR-stimulated primary B cells and identified four regions within and upstream of the Ets1 locus that undergo changes in chromatin accessibility that correlate to Ets1 gene expression. Interestingly, functional analysis of several putative Ets1 regulatory elements using luciferase constructs suggested a high level of functional redundancy. Taken together our studies reveal a complex network of regulatory elements and transcription factors that coordinate the B cell-specific expression of Ets1 .},
}
@article {pmid39094522,
year = {2024},
author = {Na, J and Tai, C and Wang, Z and Yang, Z and Chen, X and Zhang, J and Zheng, L and Fan, Y},
title = {Stiff extracellular matrix drives the differentiation of mesenchymal stem cells toward osteogenesis by the multiscale 3D genome reorganization.},
journal = {Biomaterials},
volume = {312},
number = {},
pages = {122715},
doi = {10.1016/j.biomaterials.2024.122715},
pmid = {39094522},
issn = {1878-5905},
abstract = {Extracellular matrix (ECM) stiffness is a major driver of stem cell fate. However, the involvement of the three-dimensional (3D) genomic reorganization in response to ECM stiffness remains unclear. Here, we generated comprehensive 3D chromatin landscapes of mesenchymal stem cells (MSCs) exposed to various ECM stiffness. We found that there were more long-range chromatin interactions, but less compartment A in MSCs cultured on stiff ECM than those cultured on soft ECM. However, the switch from compartment B in MSCs cultured on soft ECM to compartment A in MSCs cultured on stiff ECM included genes encoding proteins primarily enriched in cytoskeleton organization. At the topologically associating domains (TADs) level, stiff ECM tends to have merged TADs on soft ECM. These merged TADs on stiff ECM include upregulated genes encoding proteins enriched in osteogenesis, such as SP1, ETS1, and DCHS1, which were validated by quantitative real-time polymerase chain reaction and found to be consistent with the increase of alkaline phosphatase staining. Knockdown of SP1 or ETS1 led to the downregulation of osteogenic marker genes, including COL1A1, RUNX2, ALP, and OCN in MSCs cultured on stiff ECM. Our study provides an important insight into the stiff ECM-mediated promotion of MSC differentiation towards osteogenesis, emphasizing the influence of mechanical cues on the reorganization of 3D genome architecture and stem cell fate.},
}
@article {pmid39093600,
year = {2024},
author = {Chang, LH and Noordermeer, D},
title = {Permeable TAD boundaries and their impact on genome-associated functions.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {},
number = {},
pages = {e2400137},
doi = {10.1002/bies.202400137},
pmid = {39093600},
issn = {1521-1878},
support = {ANR-21-CE12-0034//Agence Nationale de la Recherche/ ; ANR-21-CE12-0034//Agence Nationale de la Recherche/ ; ANR-22-CE12-0016//Agence Nationale de la Recherche/ ; ANR-22-CE14-0021//Agence Nationale de la Recherche/ ; //Blood and Transplant Research Unit in Precision Cellular Therapeutics/ ; },
abstract = {TAD boundaries are genomic elements that separate biological processes in neighboring domains by blocking DNA loops that are formed through Cohesin-mediated loop extrusion. Most TAD boundaries consist of arrays of binding sites for the CTCF protein, whose interaction with the Cohesin complex blocks loop extrusion. TAD boundaries are not fully impermeable though and allow a limited amount of inter-TAD loop formation. Based on the reanalysis of Nano-C data, a multicontact Chromosome Conformation Capture assay, we propose a model whereby clustered CTCF binding sites promote the successive stalling of Cohesin and subsequent dissociation from the chromatin. A fraction of Cohesin nonetheless achieves boundary read-through. Due to a constant rate of Cohesin dissociation elsewhere in the genome, the maximum length of inter-TAD loops is restricted though. We speculate that the DNA-encoded organization of stalling sites regulates TAD boundary permeability and discuss implications for enhancer-promoter loop formation and other genomic processes.},
}
@article {pmid39083950,
year = {2024},
author = {Oji, A and Choubani, L and Miura, H and Hiratani, I},
title = {Structure and dynamics of nuclear A/B compartments and subcompartments.},
journal = {Current opinion in cell biology},
volume = {90},
number = {},
pages = {102406},
doi = {10.1016/j.ceb.2024.102406},
pmid = {39083950},
issn = {1879-0410},
abstract = {Mammalian chromosomes form a hierarchical structure within the cell nucleus, from chromatin loops, megabase (Mb)-sized topologically associating domains (TADs) to larger-scale A/B compartments. The molecular basis of the structures of loops and TADs has been actively studied. However, the A and B compartments, which correspond to early-replicating euchromatin and late-replicating heterochromatin, respectively, are still relatively unexplored. In this review, we focus on the A/B compartments, discuss their close relationship to DNA replication timing (RT), and introduce recent findings on the features of subcompartments revealed by detailed classification of the A/B compartments. In doing so, we speculate on the structure, potential function, and developmental dynamics of A/B compartments and subcompartments in mammalian cells.},
}
@article {pmid39078102,
year = {2024},
author = {Dimartino, P and Zadorozhna, M and Yumiceba, V and Basile, A and Cani, I and Melo, US and Henck, J and Breur, M and Tonon, C and Lodi, R and Brusco, A and Pippucci, T and Koufi, FD and Boschetti, E and Ramazzotti, G and Manzoli, L and Ratti, S and Pinto E Vairo, F and Delatycki, MB and Vaula, G and Cortelli, P and Bugiani, M and Spielmann, M and Giorgio, E},
title = {Structural Variants at the LMNB1 Locus: Deciphering Pathomechanisms in Autosomal Dominant Adult-Onset Demyelinating Leukodystrophy.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.27038},
pmid = {39078102},
issn = {1531-8249},
support = {GR-2021-12373348//Ministero della Salute, Ricerca Finalizzata/ ; MNESYS (PE0000006)//Ministero dell'Universit&#xe0; e della Ricerca, National Recovery and Resilience Plan (NRRP)/ ; },
abstract = {OBJECTIVES: We aimed to elucidate the pathogenic mechanisms underlying autosomal dominant adult-onset demyelinating leukodystrophy (ADLD), and to understand the genotype/phenotype correlation of structural variants (SVs) in the LMNB1 locus.<br><br>BACKGROUND: Since the discovery of 3D genome architectures and topologically associating domains (TADs), new pathomechanisms have been postulated for SVs, regardless of gene dosage changes. ADLD is a rare genetic disease associated with duplications (classical ADLD) or noncoding deletions (atypical ADLD) in the LMNB1 locus.<br><br>METHODS: High-throughput chromosome conformation capture, RNA sequencing, histopathological analyses of postmortem brain tissues, and clinical and neuroradiological investigations were performed.<br><br>RESULTS: We collected data from >20 families worldwide carrying SVs in the LMNB1 locus and reported strong clinical variability, even among patients carrying duplications of the entire LMNB1 gene, ranging from classical and atypical ADLD to asymptomatic carriers. We showed that patients with classic ADLD always carried intra-TAD duplications, resulting in a simple gene dose gain. Atypical ADLD was caused by LMNB1 forebrain-specific misexpression due to inter-TAD deletions or duplications. The inter-TAD duplication, which extends centromerically and crosses the 2 TAD boundaries, did not cause ADLD. Our results provide evidence that astrocytes are key players in ADLD pathology.<br><br>INTERPRETATION: Our study sheds light on the 3D genome and TAD structural changes associated with SVs in the LMNB1 locus, and shows that a duplication encompassing LMNB1 is not sufficient per se to diagnose ADLD, thereby strongly affecting genetic counseling. Our study supports breaking TADs as an emerging pathogenic mechanism that should be considered when studying brain diseases. ANN NEUROL 2024.},
}
@article {pmid39061232,
year = {2024},
author = {Zhou, T and Nguyen, S and Wu, J and He, B and Feng, Q},
title = {LncRNA LOC730101 Promotes Darolutamide Resistance in Prostate Cancer by Suppressing miR-1-3p.},
journal = {Cancers},
volume = {16},
number = {14},
pages = {},
doi = {10.3390/cancers16142594},
pmid = {39061232},
issn = {2072-6694},
support = {1R33AI133697-03A1/NH/NIH HHS/United States ; 1R01CA211861-05A1/NH/NIH HHS/United States ; },
abstract = {Antiandrogen is part of the standard-of-care treatment option for metastatic prostate cancer. However, prostate cancers frequently relapse, and the underlying resistance mechanism remains incompletely understood. This study seeks to investigate whether long non-coding RNAs (lncRNAs) contribute to the resistance against the latest antiandrogen drug, darolutamide. Our RNA sequencing analysis revealed significant overexpression of LOC730101 in darolutamide-resistant cancer cells compared to the parental cells. Elevated LOC730101 levels were also observed in clinical samples of metastatic castration-resistant prostate cancer (CRPC) compared to primary prostate cancer samples. Silencing LOC730101 with siRNA significantly impaired the growth of darolutamide-resistant cells. Additional RNA sequencing analysis identified a set of genes regulated by LOC730101, including key players in the cell cycle regulatory pathway. We further demonstrated that LOC730101 promotes darolutamide resistance by competitively inhibiting microRNA miR-1-3p. Moreover, by Hi-C sequencing, we found that LOC730101 is located in a topologically associating domain (TAD) that undergoes specific gene induction in darolutamide-resistant cells. Collectively, our study demonstrates the crucial role of the lncRNA LOC730101 in darolutamide resistance and its potential as a target for overcoming antiandrogen resistance in CRPC.},
}
@article {pmid39047029,
year = {2024},
author = {Ling, Z and Zhang, YW and Li, SC},
title = {SuperTAD-Fast: Accelerating Topologically Associating Domains Detection Through Discretization.},
journal = {Journal of computational biology : a journal of computational molecular cell biology},
volume = {},
number = {},
pages = {},
doi = {10.1089/cmb.2024.0490},
pmid = {39047029},
issn = {1557-8666},
abstract = {High-throughput chromosome conformation capture (Hi-C) technology captures spatial interactions of DNA sequences into matrices, and software tools are developed to identify topologically associating domains (TADs) from the Hi-C matrices. With structural information theory, SuperTAD adopted a dynamic programming approach to find the TAD hierarchy with minimal structural entropy. However, the algorithm suffers from high time complexity. To accelerate this algorithm, we design and implement an approximation algorithm with a theoretical performance guarantee. We implemented a package, SuperTAD-Fast. Using Hi-C matrices and simulated data, we demonstrated that SuperTAD-Fast achieved great runtime improvement compared with SuperTAD. SuperTAD-Fast shows high consistency and significant enrichment of structural proteins from Hi-C data of human cell lines in comparison with the existing six hierarchical TADs detecting methods.},
}
@article {pmid39039278,
year = {2024},
author = {Das, M and Semple, JI and Haemmerli, A and Volodkina, V and Scotton, J and Gitchev, T and Annan, A and Campos, J and Statzer, C and Dakhovnik, A and Ewald, CY and Mozziconacci, J and Meister, P},
title = {Condensin I folds the Caenorhabditis elegans genome.},
journal = {Nature genetics},
volume = {},
number = {},
pages = {},
pmid = {39039278},
issn = {1546-1718},
support = {31003A_176226/PP00P3_159320//Schweizerischer Nationalfonds zur F&#xf6;rderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)/ ; 31003A_176226/PP00P3_159320//Schweizerischer Nationalfonds zur F&#xf6;rderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)/ ; 31003A_176226/PP00P3_159320//Schweizerischer Nationalfonds zur F&#xf6;rderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)/ ; 31003A_176226/PP00P3_159320//Schweizerischer Nationalfonds zur F&#xf6;rderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)/ ; 31003A_176226/PP00P3_159320//Schweizerischer Nationalfonds zur F&#xf6;rderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)/ ; 31003A_176226/PP00P3_159320//Schweizerischer Nationalfonds zur F&#xf6;rderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)/ ; 31003A_176226/PP00P3_159320//Schweizerischer Nationalfonds zur F&#xf6;rderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)/ ; },
abstract = {The structural maintenance of chromosome (SMC) complexes-cohesin and condensins-are crucial for chromosome separation and compaction during cell division. During the interphase, mammalian cohesins additionally fold the genome into loops and domains. Here we show that, in Caenorhabditis elegans, a species with holocentric chromosomes, condensin I is the primary, long-range loop extruder. The loss of condensin I and its X-specific variant, condensin I[DC], leads to genome-wide decompaction, chromosome mixing and disappearance of X-specific topologically associating domains, while reinforcing fine-scale epigenomic compartments. In addition, condensin I/I[DC] inactivation led to the upregulation of X-linked genes and unveiled nuclear bodies grouping together binding sites for the X-targeting loading complex of condensin I[DC]. C. elegans condensin I/I[DC] thus uniquely organizes holocentric interphase chromosomes, akin to cohesin in mammals, as well as regulates X-chromosome gene expression.},
}
@article {pmid39008525,
year = {2024},
author = {Maisuradze, L and King, MC and Surovtsev, IV and Mochrie, SGJ and Shattuck, MD and O'Hern, CS},
title = {Identifying topologically associating domains using differential kernels.},
journal = {PLoS computational biology},
volume = {20},
number = {7},
pages = {e1012221},
doi = {10.1371/journal.pcbi.1012221},
pmid = {39008525},
issn = {1553-7358},
mesh = {*Algorithms ; *Chromatin/chemistry/genetics/metabolism ; *Computational Biology/methods ; Humans ; Image Processing, Computer-Assisted/methods ; Animals ; },
abstract = {Chromatin is a polymer complex of DNA and proteins that regulates gene expression. The three-dimensional (3D) structure and organization of chromatin controls DNA transcription and replication. High-throughput chromatin conformation capture techniques generate Hi-C maps that can provide insight into the 3D structure of chromatin. Hi-C maps can be represented as a symmetric matrix [Formula: see text], where each element represents the average contact probability or number of contacts between chromatin loci i and j. Previous studies have detected topologically associating domains (TADs), or self-interacting regions in [Formula: see text] within which the contact probability is greater than that outside the region. Many algorithms have been developed to identify TADs within Hi-C maps. However, most TAD identification algorithms are unable to identify nested or overlapping TADs and for a given Hi-C map there is significant variation in the location and number of TADs identified by different methods. We develop a novel method to identify TADs, KerTAD, using a kernel-based technique from computer vision and image processing that is able to accurately identify nested and overlapping TADs. We benchmark this method against state-of-the-art TAD identification methods on both synthetic and experimental data sets. We find that the new method consistently has higher true positive rates (TPR) and lower false discovery rates (FDR) than all tested methods for both synthetic and manually annotated experimental Hi-C maps. The TPR for KerTAD is also largely insensitive to increasing noise and sparsity, in contrast to the other methods. We also find that KerTAD is consistent in the number and size of TADs identified across replicate experimental Hi-C maps for several organisms. Thus, KerTAD will improve automated TAD identification and enable researchers to better correlate changes in TADs to biological phenomena, such as enhancer-promoter interactions and disease states.},
}
@article {pmid38968127,
year = {2024},
author = {An, J and Brik Chaouche, R and Pereyra-Bistraín, LI and Zalzalé, H and Wang, Q and Huang, Y and He, X and Dias Lopes, C and Antunez-Sanchez, J and Bergounioux, C and Boulogne, C and Dupas, C and Gillet, C and Pérez-Pérez, JM and Mathieu, O and Bouché, N and Fragkostefanakis, S and Zhang, Y and Zheng, S and Crespi, M and Mahfouz, MM and Ariel, F and Gutierrez-Marcos, J and Raynaud, C and Latrasse, D and Benhamed, M},
title = {An atlas of the tomato epigenome reveals that KRYPTONITE shapes TAD-like boundaries through the control of H3K9ac distribution.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {121},
number = {28},
pages = {e2400737121},
doi = {10.1073/pnas.2400737121},
pmid = {38968127},
issn = {1091-6490},
support = {Project 101044399-3Dwheat//EC | European Research Council (ERC)/ ; ANR-21-CE20-0036-4D Heat Tomato//Agence Nationale de la Recherche (ANR)/ ; ANR-17-EUR-0007//Agence Nationale de la Recherche (ANR)/ ; 202108320109//China Scholarship Council (CSC)/ ; 202308620118//China Scholarship Council (CSC)/ ; },
mesh = {*Solanum lycopersicum/genetics/metabolism ; *Histones/metabolism/genetics ; *Epigenome ; Epigenesis, Genetic ; Genome, Plant ; Chromatin/metabolism/genetics ; Plant Proteins/genetics/metabolism ; Gene Expression Regulation, Plant ; Heterochromatin/metabolism/genetics ; Histone Code/genetics ; },
abstract = {In recent years, the exploration of genome three-dimensional (3D) conformation has yielded profound insights into the regulation of gene expression and cellular functions in both animals and plants. While animals exhibit a characteristic genome topology defined by topologically associating domains (TADs), plants display similar features with a more diverse conformation across species. Employing advanced high-throughput sequencing and microscopy techniques, we investigated the landscape of 26 histone modifications and RNA polymerase II distribution in tomato (Solanum lycopersicum). Our study unveiled a rich and nuanced epigenetic landscape, shedding light on distinct chromatin states associated with heterochromatin formation and gene silencing. Moreover, we elucidated the intricate interplay between these chromatin states and the overall topology of the genome. Employing a genetic approach, we delved into the role of the histone modification H3K9ac in genome topology. Notably, our investigation revealed that the ectopic deposition of this chromatin mark triggered a reorganization of the 3D chromatin structure, defining different TAD-like borders. Our work emphasizes the critical role of H3K9ac in shaping the topology of the tomato genome, providing valuable insights into the epigenetic landscape of this agriculturally significant crop species.},
}
@article {pmid38967009,
year = {2024},
author = {Mulero-Hernández, J and Mironov, V and Miñarro-Giménez, JA and Kuiper, M and Fernández-Breis, JT},
title = {Integration of chromosome locations and functional aspects of enhancers and topologically associating domains in knowledge graphs enables versatile queries about gene regulation.},
journal = {Nucleic acids research},
volume = {},
number = {},
pages = {},
doi = {10.1093/nar/gkae566},
pmid = {38967009},
issn = {1362-4962},
support = {FPU18/03264//Ministerio de Ciencia, Innovaci&#xf3;n y Universidades/ ; },
abstract = {Knowledge about transcription factor binding and regulation, target genes, cis-regulatory modules and topologically associating domains is not only defined by functional associations like biological processes or diseases but also has a determinative genome location aspect. Here, we exploit these location and functional aspects together to develop new strategies to enable advanced data querying. Many databases have been developed to provide information about enhancers, but a schema that allows the standardized representation of data, securing interoperability between resources, has been lacking. In this work, we use knowledge graphs for the standardized representation of enhancers and topologically associating domains, together with data about their target genes, transcription factors, location on the human genome, and functional data about diseases and gene ontology annotations. We used this schema to integrate twenty-five enhancer datasets and two domain datasets, creating the most powerful integrative resource in this field to date. The knowledge graphs have been implemented using the Resource Description Framework and integrated within the open-access BioGateway knowledge network, generating a resource that contains an interoperable set of knowledge graphs (enhancers, TADs, genes, proteins, diseases, GO terms, and interactions between domains). We show how advanced queries, which combine functional and location restrictions, can be used to develop new hypotheses about functional aspects of gene expression regulation.},
}
@article {pmid38940151,
year = {2024},
author = {Murtaza, G and Butaney, B and Wagner, J and Singh, R},
title = {scGrapHiC: deep learning-based graph deconvolution for Hi-C using single cell gene expression.},
journal = {Bioinformatics (Oxford, England)},
volume = {40},
number = {Supplement_1},
pages = {i490-i500},
doi = {10.1093/bioinformatics/btae223},
pmid = {38940151},
issn = {1367-4811},
support = {1R35HG011939-01/GF/NIH HHS/United States ; },
mesh = {*Deep Learning ; *Single-Cell Analysis/methods ; *Chromatin/metabolism/chemistry ; Humans ; },
abstract = {SUMMARY: Single-cell Hi-C (scHi-C) protocol helps identify cell-type-specific chromatin interactions and sheds light on cell differentiation and disease progression. Despite providing crucial insights, scHi-C data is often underutilized due to the high cost and the complexity of the experimental protocol. We present a deep learning framework, scGrapHiC, that predicts pseudo-bulk scHi-C contact maps using pseudo-bulk scRNA-seq data. Specifically, scGrapHiC performs graph deconvolution to extract genome-wide single-cell interactions from a bulk Hi-C contact map using scRNA-seq as a guiding signal. Our evaluations show that scGrapHiC, trained on seven cell-type co-assay datasets, outperforms typical sequence encoder approaches. For example, scGrapHiC achieves a substantial improvement of 23.2% in recovering cell-type-specific Topologically Associating Domains over the baselines. It also generalizes to unseen embryo and brain tissue samples. scGrapHiC is a novel method to generate cell-type-specific scHi-C contact maps using widely available genomic signals that enables the study of cell-type-specific chromatin interactions.<br><br>The GitHub link: https://github.com/rsinghlab/scGrapHiC contains the source code of scGrapHiC and associated scripts to preprocess publicly available datasets to produce the results and visualizations we have discuss in this manuscript.},
}
@article {pmid38935071,
year = {2024},
author = {Chen, B and Ren, C and Ouyang, Z and Xu, J and Xu, K and Li, Y and Guo, H and Bai, X and Tian, M and Xu, X and Wang, Y and Li, H and Bo, X and Chen, H},
title = {Stratifying TAD boundaries pinpoints focal genomic regions of regulation, damage, and repair.},
journal = {Briefings in bioinformatics},
volume = {25},
number = {4},
pages = {},
doi = {10.1093/bib/bbae306},
pmid = {38935071},
issn = {1477-4054},
support = {62173338//National Natural Science Foundation of China/ ; 20220484198//Beijing Nova Program of Science and Technology/ ; },
mesh = {*DNA Repair ; Humans ; *DNA Breaks, Double-Stranded ; *Chromatin/metabolism/genetics ; *Gene Expression Regulation ; Transcription Factors/metabolism/genetics ; Animals ; Genomics/methods ; Genomic Instability ; Chromatin Assembly and Disassembly ; },
abstract = {Advances in chromatin mapping have exposed the complex chromatin hierarchical organization in mammals, including topologically associating domains (TADs) and their substructures, yet the functional implications of this hierarchy in gene regulation and disease progression are not fully elucidated. Our study delves into the phenomenon of shared TAD boundaries, which are pivotal in maintaining the hierarchical chromatin structure and regulating gene activity. By integrating high-resolution Hi-C data, chromatin accessibility, and DNA double-strand breaks (DSBs) data from various cell lines, we systematically explore the complex regulatory landscape at high-level TAD boundaries. Our findings indicate that these boundaries are not only key architectural elements but also vibrant hubs, enriched with functionally crucial genes and complex transcription factor binding site-clustered regions. Moreover, they exhibit a pronounced enrichment of DSBs, suggesting a nuanced interplay between transcriptional regulation and genomic stability. Our research provides novel insights into the intricate relationship between the 3D genome structure, gene regulation, and DNA repair mechanisms, highlighting the role of shared TAD boundaries in maintaining genomic integrity and resilience against perturbations. The implications of our findings extend to understanding the complexities of genomic diseases and open new avenues for therapeutic interventions targeting the structural and functional integrity of TAD boundaries.},
}
@article {pmid38927609,
year = {2024},
author = {Zhu, H and Liu, T and Wang, Z},
title = {C2c: Predicting Micro-C from Hi-C.},
journal = {Genes},
volume = {15},
number = {6},
pages = {},
doi = {10.3390/genes15060673},
pmid = {38927609},
issn = {2073-4425},
support = {1R35GM137974/GM/NIGMS NIH HHS/United States ; },
mesh = {*Chromatin/genetics ; Humans ; Computational Biology/methods ; Neural Networks, Computer ; Micrococcal Nuclease/metabolism/genetics ; Nucleosomes/genetics ; Software ; },
abstract = {MOTIVATION: High-resolution Hi-C data, capable of detecting chromatin features below the level of Topologically Associating Domains (TADs), significantly enhance our understanding of gene regulation. Micro-C, a variant of Hi-C incorporating a micrococcal nuclease (MNase) digestion step to examine interactions between nucleosome pairs, has been developed to overcome the resolution limitations of Hi-C. However, Micro-C experiments pose greater technical challenges compared to Hi-C, owing to the need for precise MNase digestion control and higher-resolution sequencing. Therefore, developing computational methods to derive Micro-C data from existing Hi-C datasets could lead to better usage of a large amount of existing Hi-C data in the scientific community and cost savings.<br><br>RESULTS: We developed C2c ("high" or upper case C to "micro" or lower case c), a computational tool based on a residual neural network to learn the mapping between Hi-C and Micro-C contact matrices and then predict Micro-C contact matrices based on Hi-C contact matrices. Our evaluation results show that the predicted Micro-C contact matrices reveal more chromatin loops than the input Hi-C contact matrices, and more of the loops detected from predicted Micro-C match the promoter-enhancer interactions. Furthermore, we found that the mutual loops from real and predicted Micro-C better match the ChIA-PET data compared to Hi-C and real Micro-C loops, and the predicted Micro-C leads to more TAD-boundaries detected compared to the Hi-C data. The website URL of C2c can be found in the Data Availability Statement.},
}
@article {pmid38895201,
year = {2024},
author = {Wong, EWP and Sahin, M and Yang, R and Lee, U and Zhan, YA and Misra, R and Tomas, F and Alomran, N and Polyzos, A and Lee, CJ and Trieu, T and Fundichely, AM and Wiesner, T and Rosowicz, A and Cheng, S and Liu, C and Lallo, M and Merghoub, T and Hamard, PJ and Koche, R and Khurana, E and Apostolou, E and Zheng, D and Chen, Y and Leslie, CS and Chi, P},
title = {TAD hierarchy restricts poised LTR activation and loss of TAD hierarchy promotes LTR co-option in cancer.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.05.31.596845},
pmid = {38895201},
abstract = {Transposable elements (TEs) are abundant in the human genome, and they provide the sources for genetic and functional diversity. The regulation of TEs expression and their functional consequences in physiological conditions and cancer development remain to be fully elucidated. Previous studies suggested TEs are repressed by DNA methylation and chromatin modifications. The effect of 3D chromatin topology on TE regulation remains elusive. Here, by integrating transcriptome and 3D genome architecture studies, we showed that haploinsufficient loss of NIPBL selectively activates alternative promoters at the long terminal repeats (LTRs) of the TE subclasses. This activation occurs through the reorganization of topologically associating domain (TAD) hierarchical structures and recruitment of proximal enhancers. These observations indicate that TAD hierarchy restricts transcriptional activation of LTRs that already possess open chromatin features. In cancer, perturbation of the hierarchical chromatin topology can lead to co-option of LTRs as functional alternative promoters in a context-dependent manner and drive aberrant transcriptional activation of novel oncogenes and other divergent transcripts. These data uncovered a new layer of regulatory mechanism of TE expression beyond DNA and chromatin modification in human genome. They also posit the TAD hierarchy dysregulation as a novel mechanism for alternative promoter-mediated oncogene activation and transcriptional diversity in cancer, which may be exploited therapeutically.},
}
@article {pmid38871723,
year = {2024},
author = {Sun, W and Xiong, D and Ouyang, J and Xiao, X and Jiang, Y and Wang, Y and Li, S and Xie, Z and Wang, J and Tang, Z and Zhang, Q},
title = {Altered chromatin topologies caused by balanced chromosomal translocation lead to central iris hypoplasia.},
journal = {Nature communications},
volume = {15},
number = {1},
pages = {5048},
pmid = {38871723},
issn = {2041-1723},
support = {82171056//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
mesh = {Humans ; *Translocation, Genetic ; *Chromatin/metabolism/genetics ; *Iris/metabolism ; Male ; Female ; *Pedigree ; Chromosomes, Human, Pair 6/genetics ; Chromosomes, Human, Pair 18/genetics ; Induced Pluripotent Stem Cells/metabolism ; Adult ; Iris Diseases/genetics/metabolism/pathology ; Genetic Linkage ; },
abstract = {Despite the advent of genomic sequencing, molecular diagnosis remains unsolved in approximately half of patients with Mendelian disorders, largely due to unclarified functions of noncoding regions and the difficulty in identifying complex structural variations. In this study, we map a unique form of central iris hypoplasia in a large family to 6q15-q23.3 and 18p11.31-q12.1 using a genome-wide linkage scan. Long-read sequencing reveals a balanced translocation t(6;18)(q22.31;p11.22) with intergenic breakpoints. By performing Hi-C on induced pluripotent stem cells from a patient, we identify two chromatin topologically associating domains spanning across the breakpoints. These alterations lead the ectopic chromatin interactions between APCDD1 on chromosome 18 and enhancers on chromosome 6, resulting in upregulation of APCDD1. Notably, APCDD1 is specifically localized in the iris of human eyes. Our findings demonstrate that noncoding structural variations can lead to Mendelian diseases by disrupting the 3D genome structure and resulting in altered gene expression.},
}
@article {pmid38826443,
year = {2024},
author = {Aharonoff, A and Kim, J and Washington, A and Ercan, S},
title = {SMC-mediated dosage compensation in C. elegans evolved in the presence of an ancestral nematode mechanism.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.05.21.595224},
pmid = {38826443},
abstract = {UNLABELLED: Mechanisms of X chromosome dosage compensation have been studied extensively in a few model species representing clades of shared sex chromosome ancestry. However, the diversity within each clade as a function of sex chromosome evolution is largely unknown. Here, we anchor ourselves to the nematode Caenorhabditis elegans , for which a well-studied mechanism of dosage compensation occurs through a specialized structural maintenance of chromosomes (SMC) complex, and explore the diversity of dosage compensation in the surrounding phylogeny of nematodes. Through phylogenetic analysis of the C. elegan s dosage compensation complex and a survey of its epigenetic signatures, including X-specific topologically associating domains (TADs) and X-enrichment of H4K20me1, we found that the condensin-mediated mechanism evolved recently in the lineage leading to Caenorhabditis through an SMC-4 duplication. Intriguingly, an independent duplication of SMC-4 and the presence of X-specific TADs in Pristionchus pacificus suggest that condensin-mediated dosage compensation arose more than once. mRNA-seq analyses of gene expression in several nematode species indicate that dosage compensation itself is ancestral, as expected from the ancient XO sex determination system. Indicative of the ancestral mechanism, H4K20me1 is enriched on the X chromosomes in Oscheius tipulae , which does not contain X-specific TADs or SMC-4 paralogs. Together, our results indicate that the dosage compensation system in C. elegans is surprisingly new, and condensin may have been co-opted repeatedly in nematodes, suggesting that the process of evolving a chromosome-wide gene regulatory mechanism for dosage compensation is constrained.<br><br>SIGNIFICANCE STATEMENT: X chromosome dosage compensation mechanisms evolved in response to Y chromosome degeneration during sex chromosome evolution. However, establishment of dosage compensation is not an endpoint. As sex chromosomes change, dosage compensation strategies may have also changed. In this study, we performed phylogenetic and epigenomic analyses surrounding Caenorhabditis elegans and found that the condensin-mediated dosage compensation mechanism in C. elegans is surprisingly new, and has evolved in the presence of an ancestral mechanism. Intriguingly, condensin-based dosage compensation may have evolved more than once in the nematode lineage, the other time in Pristionchus . Together, our work highlights a previously unappreciated diversity of dosage compensation mechanisms within a clade, and suggests constraints in evolving new mechanisms in the presence of an existing one.},
}
@article {pmid38810546,
year = {2024},
author = {Bhattacharya, M and Lyda, SF and Lei, EP},
title = {Chromatin insulator mechanisms ensure accurate gene expression by controlling overall 3D genome organization.},
journal = {Current opinion in genetics &amp; development},
volume = {87},
number = {},
pages = {102208},
doi = {10.1016/j.gde.2024.102208},
pmid = {38810546},
issn = {1879-0380},
abstract = {Chromatin insulators are DNA-protein complexes that promote specificity of enhancer-promoter interactions and maintain distinct transcriptional states through control of 3D genome organization. In this review, we highlight recent work visualizing how mammalian CCCTC-binding factor acts as a boundary to dynamic DNA loop extrusion mediated by cohesin. We also discuss new studies in both mammals and Drosophila that elucidate biological redundancy of chromatin insulator function and interplay with transcription with respect to topologically associating domain formation. Finally, we present novel concepts in spatiotemporal regulation of chromatin insulator function during differentiation and development and possible consequences of disrupted insulator activity on cellular proliferation.},
}
@article {pmid38783373,
year = {2024},
author = {Zagirova, D and Kononkova, A and Vaulin, N and Khrameeva, E},
title = {From compartments to loops: understanding the unique chromatin organization in neuronal cells.},
journal = {Epigenetics &amp; chromatin},
volume = {17},
number = {1},
pages = {18},
pmid = {38783373},
issn = {1756-8935},
support = {21-74-10102//Russian Science Foundation/ ; },
abstract = {The three-dimensional organization of the genome plays a central role in the regulation of cellular functions, particularly in the human brain. This review explores the intricacies of chromatin organization, highlighting the distinct structural patterns observed between neuronal and non-neuronal brain cells. We integrate findings from recent studies to elucidate the characteristics of various levels of chromatin organization, from differential compartmentalization and topologically associating domains (TADs) to chromatin loop formation. By defining the unique chromatin landscapes of neuronal and non-neuronal brain cells, these distinct structures contribute to the regulation of gene expression specific to each cell type. In particular, we discuss potential functional implications of unique neuronal chromatin organization characteristics, such as weaker compartmentalization, neuron-specific TAD boundaries enriched with active histone marks, and an increased number of chromatin loops. Additionally, we explore the role of Polycomb group (PcG) proteins in shaping cell-type-specific chromatin patterns. This review further emphasizes the impact of variations in chromatin architecture between neuronal and non-neuronal cells on brain development and the onset of neurological disorders. It highlights the need for further research to elucidate the details of chromatin organization in the human brain in order to unravel the complexities of brain function and the genetic mechanisms underlying neurological disorders. This research will help bridge a significant gap in our comprehension of the interplay between chromatin structure and cell functions.},
}
@article {pmid38782890,
year = {2024},
author = {Xu, J and Xu, X and Huang, D and Luo, Y and Lin, L and Bai, X and Zheng, Y and Yang, Q and Cheng, Y and Huang, A and Shi, J and Bo, X and Gu, J and Chen, H},
title = {A comprehensive benchmarking with interpretation and operational guidance for the hierarchy of topologically associating domains.},
journal = {Nature communications},
volume = {15},
number = {1},
pages = {4376},
pmid = {38782890},
issn = {2041-1723},
support = {62173338//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82073223//National Natural Science Foundation of China (National Science Foundation of China)/ ; 62173338//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82073223//National Natural Science Foundation of China (National Science Foundation of China)/ ; 62173338//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82073223//National Natural Science Foundation of China (National Science Foundation of China)/ ; 20220484198//Beijing Nova Program/ ; 20220484198//Beijing Nova Program/ ; 20220484198//Beijing Nova Program/ ; },
mesh = {*Benchmarking ; *Chromatin/chemistry ; Humans ; Computational Biology/methods ; Software ; Chromatin Assembly and Disassembly ; },
abstract = {Topologically associating domains (TADs), megabase-scale features of chromatin spatial architecture, are organized in a domain-within-domain TAD hierarchy. Within TADs, the inner and smaller subTADs not only manifest cell-to-cell variability, but also precisely regulate transcription and differentiation. Although over 20 TAD callers are able to detect TAD, their usability in biomedicine is confined by a disagreement of outputs and a limit in understanding TAD hierarchy. We compare 13 computational tools across various conditions and develop a metric to evaluate the similarity of TAD hierarchy. Although outputs of TAD hierarchy at each level vary among callers, data resolutions, sequencing depths, and matrices normalization, they are more consistent when they have a higher similarity of larger TADs. We present comprehensive benchmarking of TAD hierarchy callers and operational guidance to researchers of life science researchers. Moreover, by simulating the mixing of different types of cells, we confirm that TAD hierarchy is generated not simply from stacking Hi-C heatmaps of heterogeneous cells. Finally, we propose an air conditioner model to decipher the role of TAD hierarchy in transcription.},
}
@article {pmid38778427,
year = {2024},
author = {Sui, P and Wang, Z and Zhang, P and Pan, F},
title = {Three-dimensional chromatin landscapes in MLLr AML.},
journal = {Experimental hematology &amp; oncology},
volume = {13},
number = {1},
pages = {56},
pmid = {38778427},
issn = {2162-3619},
abstract = {Rearrangements of the mixed lineage leukemia (MLLr) gene are frequently associated with aggressive acute myeloid leukemia (AML). However, the treatment options are limited due to the genomic complexity and dynamics of 3D structure, which regulate oncogene transcription and leukemia development. Here, we carried out an integrative analysis of 3D genome structure, chromatin accessibility, and gene expression in gene-edited MLL-AF9 AML samples. Our data revealed profound MLLr-specific alterations of chromatin accessibility, A/B compartments, topologically associating domains (TAD), and chromatin loops in AML. The local 3D configuration of the AML genome was rewired specifically at loci associated with AML-specific gene expression. Together, we demonstrate that MLL-AF9 fusion disrupts the 3D chromatin landscape, potentially contributing to the dramatic transcriptome remodeling in MLLr AML.},
}
@article {pmid38775198,
year = {2024},
author = {Moindrot, B and Imaizumi, Y and Feil, R},
title = {Differential 3D genome architecture and imprinted gene expression: cause or consequence?.},
journal = {Biochemical Society transactions},
volume = {},
number = {},
pages = {},
doi = {10.1042/BST20230143},
pmid = {38775198},
issn = {1470-8752},
abstract = {Imprinted genes provide an attractive paradigm to unravel links between transcription and genome architecture. The parental allele-specific expression of these essential genes - which are clustered in chromosomal domains - is mediated by parental methylation imprints at key regulatory DNA sequences. Recent chromatin conformation capture (3C)-based studies show differential organization of topologically associating domains between the parental chromosomes at imprinted domains, in embryonic stem and differentiated cells. At several imprinted domains, differentially methylated regions show allelic binding of the insulator protein CTCF, and linked focal retention of cohesin, at the non-methylated allele only. This generates differential patterns of chromatin looping between the parental chromosomes, already in the early embryo, and thereby facilitates the allelic gene expression. Recent research evokes also the opposite scenario, in which allelic transcription contributes to the differential genome organization, similarly as reported for imprinted X chromosome inactivation. This may occur through epigenetic effects on CTCF binding, through structural effects of RNA Polymerase II, or through imprinted long non-coding RNAs that have chromatin repressive functions. The emerging picture is that epigenetically-controlled differential genome architecture precedes and facilitates imprinted gene expression during development, and that at some domains, conversely, the mono-allelic gene expression also influences genome architecture.},
}
@article {pmid38766012,
year = {2024},
author = {Irastorza-Azcarate, I and Kukalev, A and Kempfer, R and Thieme, CJ and Mastrobuoni, G and Markowski, J and Loof, G and Sparks, TM and Brookes, E and Natarajan, KN and Sauer, S and Fisher, AG and Nicodemi, M and Ren, B and Schwarz, RF and Kempa, S and Pombo, A},
title = {Extensive folding variability between homologous chromosomes in mammalian cells.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.05.08.591087},
pmid = {38766012},
abstract = {Genetic variation and 3D chromatin structure have major roles in gene regulation. Due to challenges in mapping chromatin conformation with haplotype-specific resolution, the effects of genetic sequence variation on 3D genome structure and gene expression imbalance remain understudied. Here, we applied Genome Architecture Mapping (GAM) to a hybrid mouse embryonic stem cell (mESC) line with high density of single nucleotide polymorphisms (SNPs). GAM resolved haplotype-specific 3D genome structures with high sensitivity, revealing extensive allelic differences in chromatin compartments, topologically associating domains (TADs), long-range enhancer-promoter contacts, and CTCF loops. Architectural differences often coincide with allele-specific differences in gene expression, mediated by Polycomb repression. We show that histone genes are expressed with allelic imbalance in mESCs, are involved in haplotype-specific chromatin contact marked by H3K27me3, and are targets of Polycomb repression through conditional knockouts of Ezh2 or Ring1b. Our work reveals highly distinct 3D folding structures between homologous chromosomes, and highlights their intricate connections with allelic gene expression.},
}
@article {pmid38764013,
year = {2024},
author = {Zhang, B and Long, Y and Pei, L and Huang, X and Li, B and Han, B and Zhang, M and Lindsey, K and Zhang, X and Wang, M and Yang, X},
title = {Drought response revealed by chromatin organization variation and transcriptional regulation in cotton.},
journal = {BMC biology},
volume = {22},
number = {1},
pages = {114},
pmid = {38764013},
issn = {1741-7007},
mesh = {*Gossypium/genetics/physiology ; *Droughts ; *Gene Expression Regulation, Plant ; *Chromatin/metabolism ; Stress, Physiological/genetics ; Genes, Plant ; },
abstract = {BACKGROUND: Cotton is a major world cash crop and an important source of natural fiber, oil, and protein. Drought stress is becoming a restrictive factor affecting cotton production. To facilitate the development of drought-tolerant cotton varieties, it is necessary to study the molecular mechanism of drought stress response by exploring key drought-resistant genes and related regulatory factors.<br><br>RESULTS: In this study, two cotton varieties, ZY007 (drought-sensitive) and ZY168 (drought-tolerant), showing obvious phenotypic differences under drought stress, were selected. A total of 25,898 drought-induced genes were identified, exhibiting significant enrichment in pathways related to plant stress responses. Under drought induction, At subgenome expression bias was observed at the whole-genome level, which may be due to stronger inhibition of Dt subgenome expression. A gene co-expression module that was significantly associated with drought resistance was identified. About 90% of topologically associating domain (TAD) boundaries were stable, and 6613 TAD variation events were identified between the two varieties under drought. We identified 92 genes in ZY007 and 98 in ZY168 related to chromatin 3D structural variation and induced by drought stress. These genes are closely linked to the cotton response to drought stress through canonical hormone-responsive pathways, modulation of kinase and phosphatase activities, facilitation of calcium ion transport, and other related molecular mechanisms.<br><br>CONCLUSIONS: These results lay a foundation for elucidating the molecular mechanism of the cotton drought response and provide important regulatory locus and gene resources for the future molecular breeding of drought-resistant cotton varieties.},
}
@article {pmid38755928,
year = {2024},
author = {Yuan, T and Yan, H and Bailey, MLP and Williams, JF and Surovtsev, I and King, MC and Mochrie, SGJ},
title = {Effect of loops on the mean-square displacement of Rouse-model chromatin.},
journal = {Physical review. E},
volume = {109},
number = {4-1},
pages = {044502},
doi = {10.1103/PhysRevE.109.044502},
pmid = {38755928},
issn = {2470-0053},
mesh = {*Chromatin/metabolism/genetics/chemistry ; Models, Molecular ; },
abstract = {Chromatin polymer dynamics are commonly described using the classical Rouse model. The subsequent discovery, however, of intermediate-scale chromatin organization known as topologically associating domains (TADs) in experimental Hi-C contact maps for chromosomes across the tree of life, together with the success of loop extrusion factor (LEF) model in explaining TAD formation, motivates efforts to understand the effect of loops and loop extrusion on chromatin dynamics. This paper seeks to fulfill this need by combining LEF-model simulations with extended Rouse-model polymer simulations to investigate the dynamics of chromatin with loops and dynamic loop extrusion. We show that loops significantly suppress the averaged mean-square displacement (MSD) of a gene locus, consistent with recent experiments that track fluorescently labeled chromatin loci. We also find that loops reduce the MSD's stretching exponent from the classical Rouse-model value of 1/2 to a loop-density-dependent value in the 0.45-0.40 range. Remarkably, stretching exponent values in this range have also been observed in recent experiments [Weber et al., Phys. Rev. Lett. 104, 238102 (2010)0031-900710.1103/PhysRevLett.104.238102; Bailey et al., Mol. Biol. Cell 34, ar78 (2023)1059-152410.1091/mbc.E23-04-0119]. We also show that the dynamics of loop extrusion itself negligibly affects chromatin mobility. By studying static "rosette" loop configurations, we also demonstrate that chromatin MSDs and stretching exponents depend on the location of the locus in question relative to the position of the loops and on the local friction environment.},
}
@article {pmid38753319,
year = {2024},
author = {Barozzi, I and Slaven, N and Canale, E and Lopes, R and Amorim Monteiro Barbosa, I and Bleu, M and Ivanoiu, D and Pacini, C and Mensa, E and Chambers, A and Bravaccini, S and Ravaioli, S and Gyorffy, B and Dieci, MV and Pruneri, G and Galli, GG and Magnani, L},
title = {A functional survey of the regulatory landscape of estrogen-receptor-positive breast cancer evolution.},
journal = {Cancer discovery},
volume = {},
number = {},
pages = {},
doi = {10.1158/2159-8290.CD-23-1157},
pmid = {38753319},
issn = {2159-8290},
abstract = {Only a handful of somatic alterations have been linked to endocrine therapy resistance in hormone-dependent breast cancer (HDBC), potentially explaining ~40% of relapses. If other mechanisms underlie the evolution of HDBC under adjuvant therapy is currently unknown. In this work, we employ functional genomics to dissect the contribution of cis-regulatory elements (CREs) to cancer evolution by focusing on 12 megabases of non-coding DNA, including clonal enhancers, gene promoters, and boundaries of topologically associating domains. Parallel epigenetic perturbation (CRISPRi) in vitro reveals context-dependent roles for many of these CREs, with a specific impact on dormancy entrance and endocrine therapy resistance. Profiling of CRE somatic alterations in a unique, longitudinal cohort of patients treated with endocrine therapies identifies a limited set of non-coding changes potentially involved in therapy resistance. Overall, our data uncover how endocrine therapies triggers the emergence of transient features which could ultimately be exploited to hinder the adaptive process.},
}
@article {pmid38743310,
year = {2024},
author = {Semeigazin, A and Iida, S and Minami, K and Tamura, S and Ide, S and Higashi, K and Toyoda, A and Kurokawa, K and Maeshima, K},
title = {Behaviors of nucleosomes with mutant histone H4s in euchromatic domains of living human cells.},
journal = {Histochemistry and cell biology},
volume = {},
number = {},
pages = {},
pmid = {38743310},
issn = {1432-119X},
support = {JP23KJ0996//Japan Society for the Promotion of Science/ ; JP23KJ0998//Japan Society for the Promotion of Science/ ; JP22H05606//Japan Society for the Promotion of Science/ ; JP23K17398//Japan Society for the Promotion of Science/ ; JPMJSP2104//Japan Science and Technology Agency/ ; JPMJSP2104//Japan Science and Technology Agency/ ; },
abstract = {Since Robert Feulgen first stained DNA in the cell, visualizing genome chromatin has been a central issue in cell biology to uncover how chromatin is organized and behaves in the cell. To approach this issue, we have developed single-molecule imaging of nucleosomes, a basic unit of chromatin, to unveil local nucleosome behavior in living cells. In this study, we investigated behaviors of nucleosomes with various histone H4 mutants in living HeLa cells to address the role of H4 tail acetylation, including H4K16Ac and others, which are generally associated with more transcriptionally active chromatin regions. We ectopically expressed wild-type (wt) or mutated H4s (H4K16 point; H4K5,8,12,16 quadruple; and H4 tail deletion) fused with HaloTag in HeLa cells. Cells that expressed wtH4-Halo, H4K16-Halo mutants, and multiple H4-Halo mutants had euchromatin-concentrated distribution. Consistently, the genomic regions of the wtH4-Halo nucleosomes corresponded to Hi-C contact domains (or topologically associating domains, TADs) with active chromatin marks (A-compartment). Utilizing single-nucleosome imaging, we found that none of the H4 deacetylation or acetylation mimicked H4 mutants altered the overall local nucleosome motion. This finding suggests that H4 mutant nucleosomes embedded in the condensed euchromatic domains with excess endogenous H4 nucleosomes cannot cause an observable change in the local motion. Interestingly, H4 with four lysine-to-arginine mutations displayed a substantial freely diffusing fraction in the nucleoplasm, whereas H4 with a truncated N-terminal tail was incorporated in heterochromatic regions as well as euchromatin. Our study indicates the power of single-nucleosome imaging to understand individual histone/nucleosome behavior reflecting chromatin environments in living cells.},
}
@article {pmid38712032,
year = {2024},
author = {Loke, P and Zhao, M and Jankovic, D and Hornick, K and Link, V and Souza, COS and Belkaid, Y and Lack, J},
title = {Genetic variation in IL-4 activated tissue resident macrophages alters the epigenetic state to determine strain specific synergistic responses to LPS.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-3759654/v1},
pmid = {38712032},
abstract = {How macrophages in the tissue environment integrate multiple stimuli will depend on the genetic background of the host, but this is poorly understood. Here, we investigated C57BL/6 and BALB/c strain specific in vivo IL-4 activation of tissue-resident macrophages (TRMs) from the peritoneal cavity. C57BL/6 TRMs are more transcriptionally responsive to IL-4 stimulation, with a greater association of induced genes with super enhancers, induced enhancers, and topologically associating domains (TAD) boundaries. IL-4-directed epigenomic remodeling revealed BL/6 specific enrichment of NF-κB, IRF, and STAT motifs. Additionally, IL-4-activated BL/6 TRMs demonstrated an augmented synergistic response upon in vitro lipopolysaccharide (LPS) exposure compared to BALB/c TRMs, despite naïve BALB/c TRMs displaying a more robust transcriptional response to LPS than naïve BL/6 TRMs. Single-cell RNA sequencing (scRNA-seq) analysis of mixed bone marrow chimeric mice indicated that transcriptional differences between BL/6 and BALB/c TRMs, and synergy between IL-4 and LPS, are cell intrinsic within the same tissue environment. Hence, genetic variation alters IL-4-induced cell intrinsic epigenetic reprogramming resulting in strain specific synergistic responses to LPS exposure.},
}
@article {pmid38705995,
year = {2024},
author = {Afanasyev, AY and Kim, Y and Tolokh, IS and Sharakhov, IV and Onufriev, AV},
title = {The probability of chromatin to be at the nuclear lamina has no systematic effect on its transcription level in fruit flies.},
journal = {Epigenetics &amp; chromatin},
volume = {17},
number = {1},
pages = {13},
pmid = {38705995},
issn = {1756-8935},
support = {MCB-1715207//Directorate for Biological Sciences/ ; GM14459//Office of Extramural Research, National Institutes of Health/ ; },
mesh = {Animals ; *Nuclear Lamina/metabolism ; *Drosophila melanogaster/metabolism ; *Chromatin/metabolism ; *Transcription, Genetic ; },
abstract = {BACKGROUND: Multiple studies have demonstrated a negative correlation between gene expression and positioning of genes at the nuclear envelope (NE) lined by nuclear lamina, but the exact relationship remains unclear, especially in light of the highly stochastic, transient nature of the gene association with the NE.<br><br>RESULTS: In this paper, we ask whether there is a causal, systematic, genome-wide relationship between the expression levels of the groups of genes in topologically associating domains (TADs) of Drosophila nuclei and the probabilities of TADs to be found at the NE. To investigate the nature of this possible relationship, we combine a coarse-grained dynamic model of the entire Drosophila nucleus with genome-wide gene expression data; we analyze the TAD averaged transcription levels of genes against the probabilities of individual TADs to be in contact with the NE in the control and lamins-depleted nuclei. Our findings demonstrate that, within the statistical error margin, the stochastic positioning of Drosophila melanogaster TADs at the NE does not, by itself, systematically affect the mean level of gene expression in these TADs, while the expected negative correlation is confirmed. The correlation is weak and disappears completely for TADs not containing lamina-associated domains (LADs) or TADs containing LADs, considered separately. Verifiable hypotheses regarding the underlying mechanism for the presence of the correlation without causality are discussed. These&#xa0;include the possibility&#xa0;that the epigenetic marks and affinity to the NE of a TAD are determined by various non-mutually exclusive mechanisms and remain relatively stable during interphase.<br><br>CONCLUSIONS: At the level of TADs, the probability of chromatin being in contact with the nuclear envelope has no systematic, causal effect on the transcription level in Drosophila. The conclusion is reached by combining model-derived time-evolution of TAD locations within the nucleus with their experimental gene expression levels.},
}
@article {pmid38697116,
year = {2024},
author = {Liu, C and Nagashima, H and Fernando, N and Bass, V and Gopalakrishnan, J and Signorella, S and Montgomery, W and Lim, AI and Harrison, O and Reich, L and Yao, C and Sun, HW and Brooks, SR and Jiang, K and Nagarajan, V and Zhao, Y and Jung, S and Phillips, R and Mikami, Y and Lareau, CA and Kanno, Y and Jankovic, D and Aryee, MJ and Pękowska, A and Belkaid, Y and O'Shea, J and Shih, HY},
title = {A CTCF-binding site in the Mdm1-Il22-Ifng locus shapes cytokine expression profiles and plays a critical role in early Th1 cell fate specification.},
journal = {Immunity},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.immuni.2024.04.007},
pmid = {38697116},
issn = {1097-4180},
abstract = {Cytokine expression during T cell differentiation is a highly regulated process that involves long-range promoter-enhancer and CTCF-CTCF contacts at cytokine loci. Here, we investigated the impact of dynamic chromatin loop formation within the topologically associating domain (TAD) in regulating the expression of interferon gamma (IFN-γ) and interleukin-22 (IL-22); these cytokine loci are closely located in the genome and are associated with complex enhancer landscapes, which are selectively active in type 1 and type 3 lymphocytes. In situ Hi-C analyses revealed inducible TADs that insulated Ifng and Il22 enhancers during Th1 cell differentiation. Targeted deletion of a 17 bp boundary motif of these TADs imbalanced Th1- and Th17-associated immunity, both in vitro and in vivo, upon Toxoplasma gondii infection. In contrast, this boundary element was dispensable for cytokine regulation in natural killer cells. Our findings suggest that precise cytokine regulation relies on lineage- and developmental stage-specific interactions of 3D chromatin architectures and enhancer landscapes.},
}
@article {pmid38696651,
year = {2024},
author = {Daly, AF and Beckers, A},
title = {The Genetic Pathophysiology and Clinical Management of the TADopathy, X-Linked Acrogigantism.},
journal = {Endocrine reviews},
volume = {},
number = {},
pages = {},
doi = {10.1210/endrev/bnae014},
pmid = {38696651},
issn = {1945-7189},
abstract = {Pituitary gigantism is a rare manifestation of chronic growth hormone (GH) excess that begins before closure of the growth plates. Nearly half of pituitary gigantism patients have an identifiable genetic cause. X-linked acrogigantism (X-LAG; 10% of pituitary gigantism) typically begins during infancy and can lead to the tallest individuals described. In the 10 years since its discovery, about 40 patients have been identified. Patients with X-LAG usually develop mixed GH and prolactin macroadenomas with occasional hyperplasia that secrete copious amounts of GH, and frequently prolactin. Circulating GH releasing hormone (GHRH) is also elevated in a proportion of patients. X-LAG is caused by constitutive or sporadic mosaic duplications at chromosome Xq26.3 that disrupt the normal chromatin architecture of a topologically associating domain (TAD) around the orphan G protein coupled receptor (GPCR), GPR101. This leads to the formation of a neoTAD in which GPR101 over-expression is driven by ectopic enhancers ("TADopathy"). X-LAG has been seen in three families due to transmission of the duplication from affected mothers to sons. GPR101 is a constitutively active receptor with an unknown natural ligand that signals via multiple G proteins and protein kinases A and C to promote GH/prolactin hypersecretion. Treatment of X-LAG is challenging due to the young patient population and resistance to somatostatin analogs; the GH receptor antagonist pegvisomant is often an effective option. GH, insulin-like growth factor 1 (IGF-1) and prolactin hypersecretion and physical overgrowth can be controlled before definitive adult gigantism occurs, often at the cost of permanent hypopituitarism.},
}
@article {pmid38685685,
year = {2024},
author = {Liu, H and Pan, Z and Lin, X and Chen, L and Yang, Q and Zhang, W and Dai, L and Zhang, Y and Li, W and Chen, Y and Peng, K and Wanggou, S and Zeng, F and Li, X},
title = {A potassium-chloride co-transporter with altered genome architecture functions as a suppressor in glioma.},
journal = {Journal of cellular and molecular medicine},
volume = {28},
number = {9},
pages = {e18352},
doi = {10.1111/jcmm.18352},
pmid = {38685685},
issn = {1582-4934},
support = {82270825//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Glioma/genetics/pathology/metabolism ; *Gene Expression Regulation, Neoplastic ; *Cell Proliferation/genetics ; Cell Line, Tumor ; *Brain Neoplasms/genetics/pathology/metabolism ; *Symporters/genetics/metabolism ; Cell Movement/genetics ; Prognosis ; Receptors, GABA-A/metabolism/genetics ; *K Cl- Cotransporters ; },
abstract = {Gliomas, the most lethal tumours in brain, have a poor prognosis despite accepting standard treatment. Limited benefits from current therapies can be attributed to genetic, epigenetic and microenvironmental cues that affect cell programming and drive tumour heterogeneity. Through the analysis of Hi-C data, we identified a potassium-chloride co-transporter SLC12A5 associated with disrupted topologically associating domain which was downregulated in tumour tissues. Multiple independent glioma cohorts were included to analyse the characterization of SLC12A5 and found it was significantly associated with pathological features, prognostic value, genomic alterations, transcriptional landscape and drug response. We constructed two SLC12A5 overexpression cell lines to verify the function of SLC12A5 that suppressed tumour cell proliferation and migration in vitro. In addition, SLC12A5 was also positively associated with GABAA receptor activity and negatively associated with pro-tumour immune signatures and immunotherapy response. Collectively, our study provides a comprehensive characterization of SLC12A5 in glioma and supports SLC12A5 as a potential suppressor of disease progression.},
}
@article {pmid38669773,
year = {2024},
author = {Wang, X and Yue, F},
title = {Hijacked enhancer-promoter and silencer-promoter loops in cancer.},
journal = {Current opinion in genetics &amp; development},
volume = {86},
number = {},
pages = {102199},
doi = {10.1016/j.gde.2024.102199},
pmid = {38669773},
issn = {1879-0380},
abstract = {Recent work has shown that besides inducing fusion genes, structural variations (SVs) can also contribute to oncogenesis by disrupting the three-dimensional genome organization and dysregulating gene expression. At the chromatin-loop level, SVs can relocate enhancers or silencers from their original genomic loci to activate oncogenes or repress tumor suppressor genes. On a larger scale, different types of alterations in topologically associating domains (TADs) have been reported in cancer, such as TAD expansion, shuffling, and SV-induced neo-TADs. Furthermore, the transformation from normal cells to cancerous cells is usually coupled with active or repressive compartmental switches, and cancer-specific compartments have been proposed. This review discusses the sites, and the other latest advances in studying how SVs disrupt higher-order genome structure in cancer, which in turn leads to oncogene dysregulation. We also highlight the clinical implications of these changes and the challenges ahead in this field.},
}
@article {pmid38669177,
year = {2024},
author = {Kuffler, L and Skelly, DA and Czechanski, A and Fortin, HJ and Munger, SC and Baker, CL and Reinholdt, LG and Carter, GW},
title = {Imputation of 3D genome structure by genetic-epigenetic interaction modeling in mice.},
journal = {eLife},
volume = {12},
number = {},
pages = {},
doi = {10.7554/eLife.88222},
pmid = {38669177},
issn = {2050-084X},
support = {R01GM115518/GM/NIGMS NIH HHS/United States ; R35GM133724/GM/NIGMS NIH HHS/United States ; P40OD011102/NH/NIH HHS/United States ; },
mesh = {Animals ; Mice ; *Epigenesis, Genetic ; *Chromatin/metabolism/genetics ; *Genome ; Genetic Variation ; Embryonic Stem Cells/metabolism ; },
abstract = {Gene expression is known to be affected by interactions between local genetic variation and DNA accessibility, with the latter organized into three-dimensional chromatin structures. Analyses of these interactions have previously been limited, obscuring their regulatory context, and the extent to which they occur throughout the genome. Here, we undertake a genome-scale analysis of these interactions in a genetically diverse population to systematically identify global genetic-epigenetic interaction, and reveal constraints imposed by chromatin structure. We establish the extent and structure of genotype-by-epigenotype interaction using embryonic stem cells derived from Diversity Outbred mice. This mouse population segregates millions of variants from eight inbred founders, enabling precision genetic mapping with extensive genotypic and phenotypic diversity. With 176 samples profiled for genotype, gene expression, and open chromatin, we used regression modeling to infer genetic-epigenetic interactions on a genome-wide scale. Our results demonstrate that statistical interactions between genetic variants and chromatin accessibility are common throughout the genome. We found that these interactions occur within the local area of the affected gene, and that this locality corresponds to topologically associated domains (TADs). The likelihood of interaction was most strongly defined by the three-dimensional (3D) domain structure rather than linear DNA sequence. We show that stable 3D genome structure is an effective tool to guide searches for regulatory elements and, conversely, that regulatory elements in genetically diverse populations provide a means to infer 3D genome structure. We confirmed this finding with CTCF ChIP-seq that revealed strain-specific binding in the inbred founder mice. In stem cells, open chromatin participating in the most significant regression models demonstrated an enrichment for developmental genes and the TAD-forming CTCF-binding complex, providing an opportunity for statistical inference of shifting TAD boundaries operating during early development. These findings provide evidence that genetic and epigenetic factors operate within the context of 3D chromatin structure.},
}
@article {pmid38663040,
year = {2024},
author = {Martitz, A and Schulz, EG},
title = {Spatial orchestration of the genome: topological reorganisation during X-chromosome inactivation.},
journal = {Current opinion in genetics &amp; development},
volume = {86},
number = {},
pages = {102198},
doi = {10.1016/j.gde.2024.102198},
pmid = {38663040},
issn = {1879-0380},
abstract = {Genomes are organised through hierarchical structures, ranging from local kilobase-scale cis-regulatory contacts to large chromosome territories. Most notably, (sub)-compartments partition chromosomes according to transcriptional activity, while topologically associating domains (TADs) define cis-regulatory landscapes. The inactive X chromosome in mammals has provided unique insights into the regulation and function of the three-dimensional (3D) genome. Concurrent with silencing of the majority of genes and major alterations of its chromatin state, the X chromosome undergoes profound spatial rearrangements at multiple scales. These include the emergence of megadomains, alterations of the compartment structure and loss of the majority of TADs. Moreover, the Xist locus, which orchestrates X-chromosome inactivation, has provided key insights into regulation and function of regulatory domains. This review provides an overview of recent insights into the control of these structural rearrangements and contextualises them within a broader understanding of 3D genome organisation.},
}
@article {pmid38410476,
year = {2024},
author = {Martins, F and Machado, AL and Ribeiro, A and Oliveira, SM and Carvalho, J and Matthiesen, R and Backman, V and Velho, S},
title = {KRAS silencing alters chromatin physical organization and transcriptional activity in colorectal cancer cells.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-3752760/v2},
pmid = {38410476},
support = {R01 CA228272/CA/NCI NIH HHS/United States ; U54 CA261694/CA/NCI NIH HHS/United States ; U54 CA268084/CA/NCI NIH HHS/United States ; },
abstract = {Clinical data revealed that KRAS mutant tumors, while initially sensitive to treatment, rapidly bypass KRAS dependence to acquire a drug-tolerant phenotype. However, the mechanisms underlying the transition from a drug-sensitive to a drug-tolerant state still elude us. Here, we show that global chromatin reorganization is a recurrent and specific feature of KRAS-dependent cells that tolerated KRAS silencing. We show that KRAS-dependent cells undergo G0/G1 cell cycle arrest after KRAS silencing, presenting a transcriptomic signature of quiescence. Proteomic analysis showed upregulated chromatin-associated proteins and transcription-associated biological processes. Accordingly, these cells shifted euchromatin/heterochromatin states, gained topologically associating domains, and altered the nanoscale physical organization of chromatin, more precisely by downregulating chromatin packing domains, a feature associated with the induction of quiescence. In addition, they also accumulated transcriptional alterations over time leading to a diversification of biological processes, linking chromatin alterations to transcriptional performance. Overall, our observations pinpoint a novel molecular mechanism of tolerance to KRAS oncogenic loss driven not by specific gene alterations but by global reorganization of genomic information, in which cells transition chromatin domain structure towards a more quiescent state and gain transcriptional reprogramming capacity.},
}
@article {pmid38654598,
year = {2024},
author = {Banerjee, A and Zhang, S and Bahar, I},
title = {Genome structural dynamics: insights from Gaussian network analysis of Hi-C data.},
journal = {Briefings in functional genomics},
volume = {},
number = {},
pages = {},
doi = {10.1093/bfgp/elae014},
pmid = {38654598},
issn = {2041-2657},
support = {R01 GM139297/GF/NIH HHS/United States ; },
abstract = {Characterization of the spatiotemporal properties of the chromatin is essential to gaining insights into the physical bases of gene co-expression, transcriptional regulation and epigenetic modifications. The Gaussian network model (GNM) has proven in recent work to serve as a useful tool for modeling chromatin structural dynamics, using as input high-throughput chromosome conformation capture data. We focus here on the exploration of the collective dynamics of chromosomal structures at hierarchical levels of resolution, from single gene loci to topologically associating domains or entire chromosomes. The GNM permits us to identify long-range interactions between gene loci, shedding light on the role of cross-correlations between distal regions of the chromosomes in regulating gene expression. Notably, GNM analysis performed across diverse cell lines highlights the conservation of the global/cooperative movements of the chromatin across different types of cells. Variations driven by localized couplings between genomic loci, on the other hand, underlie cell differentiation, underscoring the significance of the four-dimensional properties of the genome in defining cellular identity. Finally, we demonstrate the close relation between the cell type-dependent mobility profiles of gene loci and their gene expression patterns, providing a clear demonstration of the role of chromosomal 4D features in defining cell-specific differential expression of genes.},
}
@article {pmid38643172,
year = {2024},
author = {Baudic, M and Murata, H and Bosada, FM and Melo, US and Aizawa, T and Lindenbaum, P and van der Maarel, LE and Guedon, A and Baron, E and Fremy, E and Foucal, A and Ishikawa, T and Ushinohama, H and Jurgens, SJ and Choi, SH and Kyndt, F and Le Scouarnec, S and Wakker, V and Thollet, A and Rajalu, A and Takaki, T and Ohno, S and Shimizu, W and Horie, M and Kimura, T and Ellinor, PT and Petit, F and Dulac, Y and Bru, P and Boland, A and Deleuze, JF and Redon, R and Le Marec, H and Le Tourneau, T and Gourraud, JB and Yoshida, Y and Makita, N and Vieyres, C and Makiyama, T and Mundlos, S and Christoffels, VM and Probst, V and Schott, JJ and Barc, J},
title = {TAD boundary deletion causes PITX2-related cardiac electrical and structural defects.},
journal = {Nature communications},
volume = {15},
number = {1},
pages = {3380},
pmid = {38643172},
issn = {2041-1723},
support = {R21006NN, RPV21014NNA//Agence Nationale de la Recherche (French National Research Agency)/ ; },
abstract = {While 3D chromatin organization in topologically associating domains (TADs) and loops mediating regulatory element-promoter interactions is crucial for tissue-specific gene regulation, the extent of their involvement in human Mendelian disease is largely unknown. Here, we identify 7 families presenting a new cardiac entity associated with a heterozygous deletion of 2 CTCF binding sites on 4q25, inducing TAD fusion and chromatin conformation remodeling. The CTCF binding sites are located in a gene desert at 1 Mb from the Paired-like homeodomain transcription factor 2 gene (PITX2). By introducing the ortholog of the human deletion in the mouse genome, we recapitulate the patient phenotype and characterize an opposite dysregulation of PITX2 expression in the sinoatrial node (ectopic activation) and ventricle (reduction), respectively. Chromatin conformation assay performed in human induced pluripotent stem cell-derived cardiomyocytes harboring the minimal deletion identified in family#1 reveals a conformation remodeling and fusion of TADs. We conclude that TAD remodeling mediated by deletion of CTCF binding sites causes a new autosomal dominant Mendelian cardiac disorder.},
}
@article {pmid38613389,
year = {2024},
author = {Farhadova, S and Ghousein, A and Charon, F and Surcis, C and Gomez-Velazques, M and Roidor, C and Di Michele, F and Borensztein, M and De Sario, A and Esnault, C and Noordermeer, D and Moindrot, B and Feil, R},
title = {The long non-coding RNA Meg3 mediates imprinted gene expression during stem cell differentiation.},
journal = {Nucleic acids research},
volume = {},
number = {},
pages = {},
doi = {10.1093/nar/gkae247},
pmid = {38613389},
issn = {1362-4962},
support = {ANR-18-CE12-0022-02//Agence National de Recherche/ ; ANR-10-LABX-12-01//LabEx EPIGENMED-an ANR 'Investissement d'avenir' programme/ ; EQU202103012763//Fondation pour la Recherche M&#xe9;dicale/ ; 19CS145-00//PlanCancer/ ; //CNRS-INSERM ATIP-Avenir Programme/ ; //Azerbaijan National Academy of Sciences/ ; //Ministry of Education/ ; //University of Montpellier/ ; //La Ligue Nationale Contre le Cancer/ ; },
abstract = {The imprinted Dlk1-Dio3 domain comprises the developmental genes Dlk1 and Rtl1, which are silenced on the maternal chromosome in different cell types. On this parental chromosome, the domain's imprinting control region activates a polycistron that produces the lncRNA Meg3 and many miRNAs (Mirg) and C/D-box snoRNAs (Rian). Although Meg3 lncRNA is nuclear and associates with the maternal chromosome, it is unknown whether it controls gene repression in cis. We created mouse embryonic stem cells (mESCs) that carry an ectopic poly(A) signal, reducing RNA levels along the polycistron, and generated Rian-/- mESCs as well. Upon ESC differentiation, we found that Meg3 lncRNA (but not Rian) is required for Dlk1 repression on the maternal chromosome. Biallelic Meg3 expression acquired through CRISPR-mediated demethylation of the paternal Meg3 promoter led to biallelic Dlk1 repression, and to loss of Rtl1 expression. lncRNA expression also correlated with DNA hypomethylation and CTCF binding at the 5'-side of Meg3. Using Capture Hi-C, we found that this creates a Topologically Associating Domain (TAD) organization that brings Meg3 close to Dlk1 on the maternal chromosome. The requirement of Meg3 for gene repression and TAD structure may explain how aberrant MEG3 expression at the human DLK1-DIO3 locus associates with imprinting disorders.},
}
@article {pmid38589516,
year = {2024},
author = {Xiong, K and Zhang, R and Ma, J},
title = {scGHOST: identifying single-cell 3D genome subcompartments.},
journal = {Nature methods},
volume = {},
number = {},
pages = {},
pmid = {38589516},
issn = {1548-7105},
support = {UM1HG011593//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; R01HG012303//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; },
abstract = {Single-cell Hi-C (scHi-C) technologies allow for probing of genome-wide cell-to-cell variability in three-dimensional (3D) genome organization from individual cells. Computational methods have been developed to reveal single-cell 3D genome features based on scHi-C, including A/B compartments, topologically associating domains and chromatin loops. However, no method exists for annotating single-cell subcompartments, which is important for understanding chromosome spatial localization in single cells. Here we present scGHOST, a single-cell subcompartment annotation method using graph embedding with constrained random walk sampling. Applications of scGHOST to scHi-C data and contact maps derived from single-cell 3D genome imaging demonstrate reliable identification of single-cell subcompartments, offering insights into cell-to-cell variability of nuclear subcompartments. Using scHi-C data from complex tissues, scGHOST identifies cell-type-specific or allele-specific subcompartments linked to gene transcription across various cell types and developmental stages, suggesting functional implications of single-cell subcompartments. scGHOST is an effective method for annotating single-cell 3D genome subcompartments in a broad range of biological contexts.},
}
@article {pmid38567720,
year = {2024},
author = {Funaya, S and Takahashi, Y and Suzuki, MG and Suzuki, Y and Aoki, F},
title = {H3.1/3.2 regulate the initial progression of the gene expression program.},
journal = {Nucleic acids research},
volume = {},
number = {},
pages = {},
doi = {10.1093/nar/gkae214},
pmid = {38567720},
issn = {1362-4962},
support = {19H05752//Ministry of Education, Culture, Sports, Science and Technology/ ; },
abstract = {In mice, transcription from the zygotic genome is initiated at the mid-one-cell stage, and occurs promiscuously in many areas of the genome, including intergenic regions. Regulated transcription from selected genes is established during the two-cell stage. This dramatic change in the gene expression pattern marks the initiation of the gene expression program and is essential for early development. We investigated the involvement of the histone variants H3.1/3.2 in the regulation of changes in gene expression pattern during the two-cell stage. Immunocytochemistry analysis showed low nuclear deposition of H3.1/3.2 in the one-cell stage, followed by a rapid increase in the late two-cell stage. Where chromatin structure is normally closed between the one- and two-cell stages, it remained open until the late two-cell stage when H3.1/3.2 were knocked down by small interfering RNA. Hi-C analysis showed that the formation of the topologically associating domain was disrupted in H3.1/3.2 knockdown (KD) embryos. Promiscuous transcription was also maintained in the late two-cell stage in H3.1/3.2 KD embryos. These results demonstrate that H3.1/3.2 are involved in the initial process of the gene expression program after fertilization, through the formation of a closed chromatin structure to execute regulated gene expression during the two-cell stage.},
}
@article {pmid38565950,
year = {2024},
author = {Ramírez-Cuéllar, J and Ferrari, R and Sanz, RT and Valverde-Santiago, M and García-García, J and Nacht, AS and Castillo, D and Le Dily, F and Neguembor, MV and Malatesta, M and Bonnin, S and Marti-Renom, MA and Beato, M and Vicent, GP},
title = {LATS1 controls CTCF chromatin occupancy and hormonal response of 3D-grown breast cancer cells.},
journal = {The EMBO journal},
volume = {},
number = {},
pages = {},
pmid = {38565950},
issn = {1460-2075},
support = {PID2019-105173RB-I00//Ministerio de Ciencia e Innovaci&#xf3;n (MCIN)/ ; PID2022-137045OB-I00//Ministerio de Ciencia e Innovaci&#xf3;n (MCIN)/ ; PID2020-115696RB-I00//Ministerio de Ciencia e Innovaci&#xf3;n (MCIN)/ ; 4DGenome" nr: 609989//EC | European Research Council (ERC)/ ; 201820I131//MEC | Consejo Superior de Investigaciones Cient&#xed;ficas (CSIC)/ ; MIUR: 2018-2022 MUR:2023-2027//Italian Ministry for University and Research/ ; 2013-2017//Centro de Excelencia Severo Ochoa/ ; },
abstract = {The cancer epigenome has been studied in cells cultured in two-dimensional (2D) monolayers, but recent studies highlight the impact of the extracellular matrix and the three-dimensional (3D) environment on multiple cellular functions. Here, we report the physical, biochemical, and genomic differences between T47D breast cancer cells cultured in 2D and as 3D spheroids. Cells within 3D spheroids exhibit a rounder nucleus with less accessible, more compacted chromatin, as well as altered expression of ~2000 genes, the majority of which become repressed. Hi-C analysis reveals that cells in 3D are enriched for regions belonging to the B compartment, have decreased chromatin-bound CTCF and increased fusion of topologically associating domains (TADs). Upregulation of the Hippo pathway in 3D spheroids results in the activation of the LATS1 kinase, which promotes phosphorylation and displacement of CTCF from DNA, thereby likely causing the observed TAD fusions. 3D cells show higher chromatin binding of progesterone receptor (PR), leading to an increase in the number of hormone-regulated genes. This effect is in part mediated by LATS1 activation, which favors cytoplasmic retention of YAP and CTCF removal.},
}
@article {pmid38561401,
year = {2024},
author = {Serra, F and Nieto-Aliseda, A and Fanlo-Escudero, L and Rovirosa, L and Cabrera-Pasadas, M and Lazarenkov, A and Urmeneta, B and Alcalde-Merino, A and Nola, EM and Okorokov, AL and Fraser, P and Graupera, M and Castillo, SD and Sardina, JL and Valencia, A and Javierre, BM},
title = {p53 rapidly restructures 3D chromatin organization to trigger a transcriptional response.},
journal = {Nature communications},
volume = {15},
number = {1},
pages = {2821},
pmid = {38561401},
issn = {2041-1723},
support = {CP22/00127//Ministry of Economy and Competitiveness | Instituto de Salud Carlos III (Institute of Health Carlos III)/ ; 4823998//European Hematology Association (EHA)/ ; PID2021-125277OB-I00//Ministry of Economy and Competitiveness | Agencia Estatal de Investigaci&#xf3;n (Spanish Agencia Estatal de Investigaci&#xf3;n)/ ; },
abstract = {Activation of the p53 tumor suppressor triggers a transcriptional program to control cellular response to stress. However, the molecular mechanisms by which p53 controls gene transcription are not completely understood. Here, we uncover the critical role of spatio-temporal genome architecture in this process. We demonstrate that p53 drives direct and indirect changes in genome compartments, topologically associating domains, and DNA loops prior to one hour of its activation, which escort the p53 transcriptional program. Focusing on p53-bound enhancers, we report 340 genes directly regulated by p53 over a median distance of 116 kb, with 74% of these genes not previously identified. Finally, we showcase that p53 controls transcription of distal genes through newly formed and pre-existing enhancer-promoter loops in a cohesin dependent manner. Collectively, our findings demonstrate a previously unappreciated architectural role of p53 as regulator at distinct topological layers and provide a reliable set of new p53 direct target genes that may help designs of cancer therapies.},
}
@article {pmid38553796,
year = {2024},
author = {Li, M and Yang, J and Xiao, R and Liu, Y and Hu, J and Li, T and Wu, P and Zhang, M and Huang, Y and Sun, Y and Li, C},
title = {The effect of trisomic chromosomes on spatial genome organization and global transcription in embryonic stem cells.},
journal = {Cell proliferation},
volume = {},
number = {},
pages = {e13639},
doi = {10.1111/cpr.13639},
pmid = {38553796},
issn = {1365-2184},
support = {2016YFA0100103//National Key Research and Development Program of China/ ; 2021YFA1100300//National Key Research and Development Program of China/ ; 2021-I2M-1-019//CAMS Innovation Fund for Medical Sciences/ ; 2016-I2M-3-002//CAMS Innovation Fund for Medical Sciences/ ; 32288102//National Natural Science Foundation of China/ ; 32025006//National Natural Science Foundation of China/ ; },
abstract = {Aneuploidy frequently occurs in cancer and developmental diseases such as Down syndrome, with its functional consequences implicated in dosage effects on gene expression and global perturbation of stress response and cell proliferation pathways. However, how aneuploidy affects spatial genome organization remains less understood. In this study, we addressed this question by utilizing the previously established isogenic wild-type (WT) and trisomic mouse embryonic stem cells (mESCs). We employed a combination of Hi-C, RNA-seq, chromosome painting and nascent RNA imaging technologies to compare the spatial genome structures and gene transcription among these cells. We found that trisomy has little effect on spatial genome organization at the level of A/B compartment or topologically associating domain (TAD). Inter-chromosomal interactions are associated with chromosome regions with high gene density, active histone modifications and high transcription levels, which are confirmed by imaging. Imaging also revealed contracted chromosome volume and weakened transcriptional activity for trisomic chromosomes, suggesting potential implications for the transcriptional output of these chromosomes. Our data resources and findings may contribute to a better understanding of the consequences of aneuploidy from the angle of spatial genome organization.},
}
@article {pmid38502563,
year = {2024},
author = {Jeong, D and Shi, G and Li, X and Thirumalai, D},
title = {Structural basis for the preservation of a subset of topologically associating domains in interphase chromosomes upon cohesin depletion.},
journal = {eLife},
volume = {12},
number = {},
pages = {},
doi = {10.7554/eLife.88564},
pmid = {38502563},
issn = {2050-084X},
support = {CHE 2320256//National Science Foundation/ ; F-0019//Welch Foundation/ ; },
abstract = {Compartment formation in interphase chromosomes is a result of spatial segregation between euchromatin and heterochromatin on a few megabase pairs (Mbp) scale. On the sub-Mbp scales, topologically associating domains (TADs) appear as interacting domains along the diagonal in the ensemble averaged Hi-C contact map. Hi-C experiments showed that most of the TADs vanish upon deleting cohesin, while the compartment structure is maintained, and perhaps even enhanced. However, closer inspection of the data reveals that a non-negligible fraction of TADs is preserved (P-TADs) after cohesin loss. Imaging experiments show that, at the single-cell level, TAD-like structures are present even without cohesin. To provide a structural basis for these findings, we first used polymer simulations to show that certain TADs with epigenetic switches across their boundaries survive after depletion of loops. More importantly, the three-dimensional structures show that many of the P-TADs have sharp physical boundaries. Informed by the simulations, we analyzed the Hi-C maps (with and without cohesin) in mouse liver and human colorectal carcinoma cell lines, which affirmed that epigenetic switches and physical boundaries (calculated using the predicted 3D structures using the data-driven HIPPS method that uses Hi-C as the input) explain the origin of the P-TADs. Single-cell structures display TAD-like features in the absence of cohesin that are remarkably similar to the findings in imaging experiments. Some P-TADs, with physical boundaries, are relevant to the retention of enhancer-promoter/promoter-promoter interactions. Overall, our study shows that preservation of a subset of TADs upon removing cohesin is a robust phenomenon that is valid across multiple cell lines.},
}
@article {pmid38495565,
year = {2024},
author = {Wall, BPG and Nguyen, M and Harrell, JC and Dozmorov, MG},
title = {Machine and deep learning methods for predicting 3D genome organization.},
journal = {ArXiv},
volume = {},
number = {},
pages = {},
pmid = {38495565},
issn = {2331-8422},
abstract = {Three-Dimensional (3D) chromatin interactions, such as enhancer-promoter interactions (EPIs), loops, Topologically Associating Domains (TADs), and A/B compartments play critical roles in a wide range of cellular processes by regulating gene expression. Recent development of chromatin conformation capture technologies has enabled genome-wide profiling of various 3D structures, even with single cells. However, current catalogs of 3D structures remain incomplete and unreliable due to differences in technology, tools, and low data resolution. Machine learning methods have emerged as an alternative to obtain missing 3D interactions and/or improve resolution. Such methods frequently use genome annotation data (ChIP-seq, DNAse-seq, etc.), DNA sequencing information (k-mers, Transcription Factor Binding Site (TFBS) motifs), and other genomic properties to learn the associations between genomic features and chromatin interactions. In this review, we discuss computational tools for predicting three types of 3D interactions (EPIs, chromatin interactions, TAD boundaries) and analyze their pros and cons. We also point out obstacles of computational prediction of 3D interactions and suggest future research directions.},
}
@article {pmid38490101,
year = {2024},
author = {Mizokami, H and Okabe, A and Choudhary, R and Mima, M and Saeda, K and Fukuyo, M and Rahmutulla, B and Seki, M and Goh, BC and Kondo, S and Dochi, H and Moriyama-Kita, M and Misawa, K and Hanazawa, T and Tan, P and Yoshizaki, T and Fullwood, MJ and Kaneda, A},
title = {Enhancer infestation drives tumorigenic activation of inactive B compartment in Epstein-Barr virus-positive nasopharyngeal carcinoma.},
journal = {EBioMedicine},
volume = {102},
number = {},
pages = {105057},
doi = {10.1016/j.ebiom.2024.105057},
pmid = {38490101},
issn = {2352-3964},
abstract = {BACKGROUND: Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated malignant epithelial tumor endemic to Southern China and Southeast Asia. While previous studies have revealed a low frequency of gene mutations in NPC, its epigenomic aberrations are not fully elucidated apart from DNA hypermethylation. Epigenomic rewiring and enhancer dysregulation, such as enhancer hijacking due to genomic structural changes or extrachromosomal DNA, drive cancer progression.<br><br>METHODS: We conducted Hi-C, 4C-seq, ChIP-seq, and RNA-seq analyses to comprehensively elucidate the epigenome and interactome of NPC using C666-1 EBV(+)-NPC cell lines, NP69T immortalized nasopharyngeal epithelial cells, clinical NPC biopsy samples, and in&#xa0;vitro EBV infection in HK1 and NPC-TW01 EBV(-) cell lines.<br><br>FINDINGS: In C666-1, the EBV genome significantly interacted with inactive B compartments of host cells; the significant association of EBV-interacting regions (EBVIRs) with B compartment was confirmed using clinical NPC and in&#xa0;vitro EBV infection model. EBVIRs in C666-1 showed significantly higher levels of active histone modifications compared with NP69T. Aberrant activation of EBVIRs after EBV infection was validated using in&#xa0;vitro EBV infection models. Within the EBVIR-overlapping topologically associating domains, 14 H3K4me3(+) genes were significantly upregulated in C666-1. Target genes of EBVIRs including PLA2G4A, PTGS2 and CITED2, interacted with the enhancers activated in EBVIRs and were highly expressed in NPC, and their knockdown significantly reduced cell proliferation.<br><br>INTERPRETATION: The EBV genome contributes to NPC tumorigenesis through "enhancer infestation" by interacting with the inactive B compartments of the host genome and aberrantly activating enhancers.<br><br>FUNDING: The funds are listed in the Acknowledgements section.},
}
@article {pmid38481440,
year = {2024},
author = {Caruso, M and Mazzatenta, D and Asioli, S and Costanza, G and Trivellin, G and Franke, M and Abboud, D and Hanson, J and Raverot, V and Pétrossians, P and Beckers, A and Cappa, M and Daly, AF},
title = {Case report: Management of pediatric gigantism caused by the TADopathy, X-linked acrogigantism.},
journal = {Frontiers in endocrinology},
volume = {15},
number = {},
pages = {1345363},
pmid = {38481440},
issn = {1664-2392},
abstract = {X-linked acrogigantism (X-LAG) is a rare form of pituitary gigantism that is associated with growth hormone (GH) and prolactin-secreting pituitary adenomas/pituitary neuroendocrine tumors (PitNETs) that develop in infancy. It is caused by a duplication on chromosome Xq26.3 that leads to the misexpression of the gene GPR101, a constitutively active stimulator of pituitary GH and prolactin secretion. GPR101 normally exists within its own topologically associating domain (TAD) and is insulated from surrounding regulatory elements. X-LAG is a TADopathy in which the duplication disrupts a conserved TAD border, leading to a neo-TAD in which ectopic enhancers drive GPR101 over-expression, thus causing gigantism. Here we trace the full diagnostic and therapeutic pathway of a female patient with X-LAG from 4C-seq studies demonstrating the neo-TAD through medical and surgical interventions and detailed tumor histopathology. The complex nature of treating young children with X-LAG is illustrated, including the achievement of hormonal control using a combination of neurosurgery and adult doses of first-generation somatostatin analogs.},
}
@article {pmid38473917,
year = {2024},
author = {Plaisancié, J and Chesneau, B and Fares-Taie, L and Rozet, JM and Pechmeja, J and Noero, J and Gaston, V and Bailleul-Forestier, I and Calvas, P and Chassaing, N},
title = {Structural Variant Disrupting the Expression of the Remote FOXC1 Gene in a Patient with Syndromic Complex Microphthalmia.},
journal = {International journal of molecular sciences},
volume = {25},
number = {5},
pages = {},
doi = {10.3390/ijms25052669},
pmid = {38473917},
issn = {1422-0067},
abstract = {Ocular malformations (OMs) arise from early defects during embryonic eye development. Despite the identification of over 100 genes linked to this heterogeneous group of disorders, the genetic cause remains unknown for half of the individuals following Whole-Exome Sequencing. Diagnosis procedures are further hampered by the difficulty of studying samples from clinically relevant tissue, which is one of the main obstacles in OMs. Whole-Genome Sequencing (WGS) to screen for non-coding regions and structural variants may unveil new diagnoses for OM individuals. In this study, we report a patient exhibiting a syndromic OM with a de novo 3.15 Mb inversion in the 6p25 region identified by WGS. This balanced structural variant was located 100 kb away from the FOXC1 gene, previously associated with ocular defects in the literature. We hypothesized that the inversion disrupts the topologically associating domain of FOXC1 and impairs the expression of the gene. Using a new type of samples to study transcripts, we were able to show that the patient presented monoallelic expression of FOXC1 in conjunctival cells, consistent with the abolition of the expression of the inverted allele. This report underscores the importance of investigating structural variants, even in non-coding regions, in individuals affected by ocular malformations.},
}
@article {pmid38455359,
year = {2023},
author = {Pathak, RU and Phanindhar, K and Mishra, RK},
title = {Transposable elements as scaffold/matrix attachment regions: shaping organization and functions in genomes.},
journal = {Frontiers in molecular biosciences},
volume = {10},
number = {},
pages = {1326933},
doi = {10.3389/fmolb.2023.1326933},
pmid = {38455359},
issn = {2296-889X},
abstract = {The hierarchical structure of eukaryotic genomes has regulatory layers, one of them being epigenetic "indexing" of the genome that leads to cell-type-specific patterns of gene expression. By establishing loops and defining chromatin domains, cells can achieve coordinated control over multi-locus segments of the genome. This is thought to be achieved using scaffold/matrix attachment regions (S/MARs) that establish structural and functional loops and topologically associating domains (TADs) that define a self-interacting region of the genome. Large-scale genome-wide mapping of S/MARs has begun to uncover these aspects of genome organization. A recent genome-wide study showed the association of transposable elements (TEs) with a significant fraction of S/MARs, suggesting that the multitude of TE-derived repeats constitute a class of anchorage sites of chromatin loops to nuclear architecture. In this study, we provide an insight that TE-driven dispersal of S/MARs has the potential to restructure the chromosomes by creating novel loops and domains. The combination of TEs and S/MARs, as elements that can hop through the genome along with regulatory capabilities, may provide an active mechanism of genome evolution leading to the emergence of novel features in biological systems. The significance is that a genome-wide study mapping developmental S/MARs reveals an intriguing link between these elements and TEs. This article highlights the potential of the TE-S/MAR combination to drive evolution by restructuring and shaping the genome.},
}
@article {pmid38452764,
year = {2024},
author = {Kim, KL and Rahme, GJ and Goel, VY and El Farran, CA and Hansen, AS and Bernstein, BE},
title = {Dissection of a CTCF topological boundary uncovers principles of enhancer-oncogene regulation.},
journal = {Molecular cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.molcel.2024.02.007},
pmid = {38452764},
issn = {1097-4164},
abstract = {Enhancer-gene communication is dependent on topologically associating domains (TADs) and boundaries enforced by the CCCTC-binding factor (CTCF) insulator, but the underlying structures and mechanisms remain controversial. Here, we investigate a boundary that typically insulates fibroblast growth factor (FGF) oncogenes but is disrupted by DNA hypermethylation in gastrointestinal stromal tumors (GISTs). The boundary contains an array of CTCF sites that enforce adjacent TADs, one containing FGF genes and the other containing ANO1 and its putative enhancers, which are specifically active in GIST and its likely cell of origin. We show that coordinate disruption of four CTCF motifs in the boundary fuses the adjacent TADs, allows the ANO1 enhancer to contact FGF3, and causes its robust induction. High-resolution micro-C maps reveal specific contact between transcription initiation sites in the ANO1 enhancer and FGF3 promoter that quantitatively scales with FGF3 induction such that modest changes in contact frequency result in strong changes in expression, consistent with a causal relationship.},
}
@article {pmid38449288,
year = {2024},
author = {Liu, E and Lyu, H and Liu, Y and Fu, L and Cheng, X and Yin, X},
title = {Identifying TAD-like domains on single-cell Hi-C data by graph embedding and changepoint detection.},
journal = {Bioinformatics (Oxford, England)},
volume = {},
number = {},
pages = {},
doi = {10.1093/bioinformatics/btae138},
pmid = {38449288},
issn = {1367-4811},
abstract = {MOTIVATION: Topologically associating domains (TADs) are fundamental building blocks of three-dimensional genome. TAD-like domains in single cells are regarded as the underlying genesis of TADs discovered in bulk cells. Understanding the organization of TAD-like domains helps to get deeper insights into their regulatory functions. Unfortunately, it remains a challenge to identify TAD-like domains on single-cell Hi-C data due to its ultra-sparsity.<br><br>RESULTS: We propose scKTLD, an in silico tool for the identification of TAD-like domains on single-cell Hi-C data. It takes Hi-C contact matrix as the adjacency matrix for a graph, embeds the graph structures into a low-dimensional space with the help of sparse matrix factorization followed by spectral propagation, and the TAD-like domains can be identified using a kernel-based changepoint detection in the embedding space. The results tell that our scKTLD is superior to the other methods on the sparse contact matrices, including downsampled bulk Hi-C data as well as simulated and experimental single-cell Hi-C data. Besides, we demonstrated the conservation of TAD-like domain boundaries at single-cell level apart from heterogeneity within and across cell types, and found that the boundaries with higher frequency across single cells are more enriched for architectural proteins and chromatin marks, and they preferentially occur at TAD boundaries in bulk cells, especially at those with higher hierarchical levels.<br><br>AVAILABILITY: scKTLD is freely available at https://github.com/lhqxinghun/scKTLD.<br><br>SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},
}
@article {pmid38448979,
year = {2024},
author = {Liu, Y and Zheng, Z and Wang, C and Wang, Y and Sun, X and Ren, Z and Yang, X and Yang, X},
title = {Reorganization of 3D genome architecture provides insights into pathogenesis of early fatty liver disease in laying hens.},
journal = {Journal of animal science and biotechnology},
volume = {15},
number = {1},
pages = {40},
pmid = {38448979},
issn = {1674-9782},
support = {32372910 and 32102567//the National Science Foundation of China/ ; 2022KJXX-13, 2023-YBNY-144 and K3031223077//Program for Shaanxi Science and Technology/ ; 2022GD-TSLD-46-0302//Program for Shaanxi Science and Technology/ ; },
abstract = {BACKGROUND: Fatty liver disease causes huge economic losses in the poultry industry due to its high occurrence and lethality rate. Three-dimensional (3D) chromatin architecture takes part in disease processing by regulating transcriptional reprogramming. The study is carried out to investigate the alterations of hepatic 3D genome and H3K27ac profiling in early fatty liver (FLS) and reveal their effect on hepatic transcriptional reprogramming in laying hens.<br><br>RESULTS: Results show that FLS model is constructed with obvious phenotypes including hepatic visible lipid deposition as well as higher total triglyceride and cholesterol in serum. A/B compartment switching, topologically associating domain (TAD) and chromatin loop changes are identified by high-throughput/resolution chromosome conformation capture (HiC) technology. Targeted genes of these alternations in hepatic 3D genome organization significantly enrich pathways related to lipid metabolism and hepatic damage. H3K27ac differential peaks and differential expression genes (DEGs) identified through RNA-seq analysis are also enriched in these pathways. Notably, certain DEGs are found to correspond with changes in 3D chromatin structure and H3K27ac binding in their promoters. DNA motif analysis reveals that candidate transcription factors are implicated in regulating transcriptional reprogramming. Furthermore, disturbed folate metabolism is observed, as evidenced by lower folate levels and altered enzyme expression.<br><br>CONCLUSION: Our findings establish a link between transcriptional reprogramming changes and 3D chromatin structure variations during early FLS formation, which provides candidate transcription factors and folate as targets for FLS prevention or treatment.},
}
@article {pmid38432398,
year = {2024},
author = {Fraile, A and Cebrián, J and Thuissard-Vasallo, I and Pérez-Martín, S and Casado, R and Gil-Fournier, B and Alonso-Martín, J and Tamargo, J and Caballero, R and Delpón, E and Cosío, FG},
title = {Coexistent HCN4 and GATA5 rare variants and Atrial Fibrillation in a large Spanish Family.},
journal = {The Canadian journal of cardiology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cjca.2024.02.024},
pmid = {38432398},
issn = {1916-7075},
abstract = {BACKGROUND: Familial association of atrial fibrillation (AF) can involve single gene variants related to known arrhythmogenic mechanisms; however, genome-wide association studies often disclose complex genetic variants in familial and non-familial AF, making it difficult to relate to known pathogenetic mechanisms.<br><br>METHODS: The finding of 4 siblings with AF led to studying 47 members of a family. Long-term Holter monitoring (298 hours average) ruled out silent AFWhole-exome sequencing was performed and variants shared by the index cases were filtered and prioritized according to current recommendations. HCN4 currents (IHCN4) were recorded in Chinese hamster ovary cells expressing human p.P1163H and/or native Hcn4 channels using the patch-clamp technique and topologically associated domain analysis of GATA5 variant carriers were performed.<br><br>RESULTS: The clinical study diagnosed 2 more AF cases. Five family members carried the heterozygous p.P1163H, HCN4 variant, 14 the intronic 20,61040536,G,A GATA5 rare variant, and 9 carried both variants (HCN4+GATA5). Five of the 6 AF cases (onset age ranging 33-70 years) carried both variants and one the GATA5 variant alone. Multivariate analysis showed that the presence of HCN4+GATA5 variants significantly and independently increased AF risk [OR=32.740 (1.812-591.408)] and not age, hypertension or overweight. Functional testing showed that IHcn4 generated by heterozygous p.P1163H were normal. Topologically associating domain analysis suggested that GATA5 could affect the expression of many genes, including those encoding microRNA-1.<br><br>CONCLUSION: The coincidence of two rare gene variants was independently associated with AF, but functional studies do not allow the postulation of the arrhythmogenic mechanism(s) involved.},
}
@article {pmid38402218,
year = {2024},
author = {Torres, DE and Kramer, HM and Tracanna, V and Fiorin, GL and Cook, DE and Seidl, MF and Thomma, BPHJ},
title = {Implications of the three-dimensional chromatin organization for genome evolution in a fungal plant pathogen.},
journal = {Nature communications},
volume = {15},
number = {1},
pages = {1701},
pmid = {38402218},
issn = {2041-1723},
support = {project 831.15.002//Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Netherlands Organisation for Scientific Research)/ ; LT000627/2014-L//Human Frontier Science Program (HFSP)/ ; 2018-67013-28492//United States Department of Agriculture | National Institute of Food and Agriculture (NIFA)/ ; },
abstract = {The spatial organization of eukaryotic genomes is linked to their biological functions, although it is not clear how this impacts the overall evolution of a genome. Here, we uncover the three-dimensional (3D) genome organization of the phytopathogen Verticillium dahliae, known to possess distinct genomic regions, designated adaptive genomic regions (AGRs), enriched in transposable elements and genes that mediate host infection. Short-range DNA interactions form clear topologically associating domains (TADs) with gene-rich boundaries that show reduced levels of gene expression and reduced genomic variation. Intriguingly, TADs are less clearly insulated in AGRs than in the core genome. At a global scale, the genome contains bipartite long-range interactions, particularly enriched for AGRs and more generally containing segmental duplications. Notably, the patterns observed for V. dahliae are also present in other Verticillium species. Thus, our analysis links 3D genome organization to evolutionary features conserved throughout the Verticillium genus.},
}
@article {pmid38355805,
year = {2024},
author = {Patta, I and Zand, M and Lee, L and Mishra, S and Bortnick, A and Lu, H and Prusty, A and McArdle, S and Mikulski, Z and Wang, HY and Cheng, CS and Fisch, KM and Hu, M and Murre, C},
title = {Nuclear morphology is shaped by loop-extrusion programs.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {38355805},
issn = {1476-4687},
abstract = {It is well established that neutrophils adopt malleable polymorphonuclear shapes to migrate through narrow interstitial tissue spaces[1-3]. However, how polymorphonuclear structures are assembled remains unknown[4]. Here we show that in neutrophil progenitors, halting loop extrusion-a motor-powered process that generates DNA loops by pulling in chromatin[5]-leads to the assembly of polymorphonuclear genomes. Specifically, we found that in mononuclear neutrophil progenitors, acute depletion of the loop-extrusion loading factor nipped-B-like protein (NIPBL) induced the assembly of horseshoe, banded, ringed and hypersegmented nuclear structures and led to a reduction in nuclear volume, mirroring what is observed during the differentiation of neutrophils. Depletion of NIPBL also induced cell-cycle arrest, activated a neutrophil-specific gene program and conditioned a loss of interactions across topologically associating domains to generate a chromatin architecture that resembled that of differentiated neutrophils. Removing NIPBL resulted in enrichment for mega-loops and interchromosomal hubs that contain genes associated with neutrophil-specific enhancer repertoires and an inflammatory gene program. On the basis of these observations, we propose that in neutrophil progenitors, loop-extrusion programs produce lineage-specific chromatin architectures that permit the packing of chromosomes into geometrically confined lobular structures. Our data also provide a blueprint for the assembly of polymorphonuclear structures, and point to the possibility of engineering de novo nuclear shapes to facilitate the migration of effector cells in densely populated tumorigenic environments.},
}
@article {pmid38346246,
year = {2024},
author = {Liu, S and Athreya, A and Lao, Z and Zhang, B},
title = {From Nucleosomes to Compartments: Physicochemical Interactions Underlying Chromatin Organization.},
journal = {Annual review of biophysics},
volume = {},
number = {},
pages = {},
doi = {10.1146/annurev-biophys-030822-032650},
pmid = {38346246},
issn = {1936-1238},
abstract = {Chromatin organization plays a critical role in cellular function by regulating access to genetic information. However, understanding chromatin folding is challenging due to its complex, multiscale nature. Significant progress has been made in studying in vitro systems, uncovering the structure of individual nucleosomes and their arrays, and elucidating the role of physicochemical forces in stabilizing these structures. Additionally, remarkable advancements have been achieved in characterizing chromatin organization in vivo, particularly at the whole-chromosome level, revealing important features such as chromatin loops, topologically associating domains, and nuclear compartments. However, bridging the gap between in vitro and in vivo studies remains challenging. The resemblance between in vitro and in vivo chromatin conformations and the relevance of internucleosomal interactions for chromatin folding in vivo are subjects of debate. This article reviews experimental and computational studies conducted at various length scales, highlighting the significance of intrinsic interactions between nucleosomes and their roles in chromatin folding in vivo. Expected final online publication date for the Annual Review of Biophysics, Volume 53 is May 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.},
}
@article {pmid38280381,
year = {2024},
author = {Nakamura, T and Ueda, J and Mizuno, S and Honda, K and Kazuno, AA and Yamamoto, H and Hara, T and Takata, A},
title = {Topologically associating domains define the impact of de novo promoter variants on autism spectrum disorder risk.},
journal = {Cell genomics},
volume = {},
number = {},
pages = {100488},
doi = {10.1016/j.xgen.2024.100488},
pmid = {38280381},
issn = {2666-979X},
abstract = {Whole-genome sequencing (WGS) studies of autism spectrum disorder (ASD) have demonstrated the roles of rare promoter de novo variants (DNVs). However, most promoter DNVs in ASD are not located immediately upstream of known ASD genes. In this study analyzing WGS data of 5,044 ASD probands, 4,095 unaffected siblings, and their parents, we show that promoter DNVs within topologically associating domains (TADs) containing ASD genes are significantly and specifically associated with ASD. An analysis considering TADs as functional units identified specific TADs enriched for promoter DNVs in ASD and indicated that common variants in these regions also confer ASD heritability. Experimental validation using human induced pluripotent stem cells (iPSCs) showed that likely deleterious promoter DNVs in ASD can influence multiple genes within the same TAD, resulting in overall dysregulation of ASD-associated genes. These results highlight the importance of TADs and gene-regulatory mechanisms in better understanding the genetic architecture of ASD.},
}
@article {pmid38254945,
year = {2023},
author = {Murtaza, G and Jain, A and Hughes, M and Wagner, J and Singh, R},
title = {A Comprehensive Evaluation of Generalizability of Deep Learning-Based Hi-C Resolution Improvement Methods.},
journal = {Genes},
volume = {15},
number = {1},
pages = {},
doi = {10.3390/genes15010054},
pmid = {38254945},
issn = {2073-4425},
support = {1R35HG011939-01/NH/NIH HHS/United States ; GR5245041/NIST/NIST DOC/United States ; },
abstract = {Hi-C is a widely used technique to study the 3D organization of the genome. Due to its high sequencing cost, most of the generated datasets are of a coarse resolution, which makes it impractical to study finer chromatin features such as Topologically Associating Domains (TADs) and chromatin loops. Multiple deep learning-based methods have recently been proposed to increase the resolution of these datasets by imputing Hi-C reads (typically called upscaling). However, the existing works evaluate these methods on either synthetically downsampled datasets, or a small subset of experimentally generated sparse Hi-C datasets, making it hard to establish their generalizability in the real-world use case. We present our framework-Hi-CY-that compares existing Hi-C resolution upscaling methods on seven experimentally generated low-resolution Hi-C datasets belonging to various levels of read sparsities originating from three cell lines on a comprehensive set of evaluation metrics. Hi-CY also includes four downstream analysis tasks, such as TAD and chromatin loops recall, to provide a thorough report on the generalizability of these methods. We observe that existing deep learning methods fail to generalize to experimentally generated sparse Hi-C datasets, showing a performance reduction of up to 57%. As a potential solution, we find that retraining deep learning-based methods with experimentally generated Hi-C datasets improves performance by up to 31%. More importantly, Hi-CY shows that even with retraining, the existing deep learning-based methods struggle to recover biological features such as chromatin loops and TADs when provided with sparse Hi-C datasets. Our study, through the Hi-CY framework, highlights the need for rigorous evaluation in the future. We identify specific avenues for improvements in the current deep learning-based Hi-C upscaling methods, including but not limited to using experimentally generated datasets for training.},
}
@article {pmid38244545,
year = {2024},
author = {Wahl, N and Espeso-Gil, S and Chietera, P and Nagel, A and Laighneach, A and Morris, DW and Rajarajan, P and Akbarian, S and Dechant, G and Apostolova, G},
title = {SATB2 organizes the 3D genome architecture of cognition in cortical neurons.},
journal = {Molecular cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.molcel.2023.12.024},
pmid = {38244545},
issn = {1097-4164},
abstract = {The DNA-binding protein SATB2 is genetically linked to human intelligence. We studied its influence on the three-dimensional (3D) epigenome by mapping chromatin interactions and accessibility in control versus SATB2-deficient cortical neurons. We find that SATB2 affects the chromatin looping between enhancers and promoters of neuronal-activity-regulated genes, thus influencing their expression. It also alters A/B compartments, topologically associating domains, and frequently interacting regions. Genes linked to SATB2-dependent 3D genome changes are implicated in highly specialized neuronal functions and contribute to cognitive ability and risk for neuropsychiatric and neurodevelopmental disorders. Non-coding DNA regions with a SATB2-dependent structure are enriched for common variants associated with educational attainment, intelligence, and schizophrenia. Our data establish SATB2 as a cell-type-specific 3D genome modulator, which operates both independently and in cooperation with CCCTC-binding factor (CTCF) to set up the chromatin landscape of pyramidal neurons for cognitive processes.},
}
@article {pmid38238628,
year = {2024},
author = {Hung, TC and Kingsley, DM and Boettiger, AN},
title = {Boundary stacking interactions enable cross-TAD enhancer-promoter communication during limb development.},
journal = {Nature genetics},
volume = {},
number = {},
pages = {},
pmid = {38238628},
issn = {1546-1718},
support = {DP2GM132935A//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; U01DK127419//U.S. Department of Health &amp; Human Services | National Institutes of Health (NIH)/ ; },
abstract = {Although promoters and their enhancers are frequently contained within a topologically associating domain (TAD), some developmentally important genes have their promoter and enhancers within different TADs. Hypotheses about molecular mechanisms enabling cross-TAD interactions remain to be assessed. To test these hypotheses, we used optical reconstruction of chromatin architecture to characterize the conformations of the Pitx1 locus on single chromosomes in developing mouse limbs. Our data support a model in which neighboring boundaries are stacked as a result of loop extrusion, bringing boundary-proximal cis-elements into contact. This stacking interaction also contributes to the appearance of architectural stripes in the population average maps. Through molecular dynamics simulations, we found that increasing boundary strengths facilitates the formation of the stacked boundary conformation, counter-intuitively facilitating border bypass. This work provides a revised view of the TAD borders' function, both facilitating and preventing cis-regulatory interactions, and introduces a framework to distinguish border-crossing from border-respecting enhancer-promoter pairs.},
}
@article {pmid38218905,
year = {2024},
author = {Hua, D and Gu, M and Zhang, X and Du, Y and Xie, H and Qi, L and Du, X and Bai, Z and Zhu, X and Tian, D},
title = {DiffDomain enables identification of structurally reorganized topologically associating domains.},
journal = {Nature communications},
volume = {15},
number = {1},
pages = {502},
pmid = {38218905},
issn = {2041-1723},
support = {2022A1515010043//Guangdong Science and Technology Department (Science and Technology Department, Guangdong Province)/ ; KCXFZ20211020172545006//Shenzhen Science and Technology Innovation Commission/ ; 12171198//National Natural Science Foundation of China (National Science Foundation of China)/ ; 20210101147JC//Department of Science and Technology of Jilin Province (Jilin Province Science and Technology Department)/ ; },
abstract = {Topologically associating domains (TADs) are critical structural units in three-dimensional genome organization of mammalian genome. Dynamic reorganizations of TADs between health and disease states are associated with essential genome functions. However, computational methods for identifying reorganized TADs are still in the early stages of development. Here, we present DiffDomain, an algorithm leveraging high-dimensional random matrix theory to identify structurally reorganized TADs using high-throughput chromosome conformation capture (Hi-C) contact maps. Method comparison using multiple real Hi-C datasets reveals that DiffDomain outperforms alternative methods for false positive rates, true positive rates, and identifying a new subtype of reorganized TADs. Applying DiffDomain to Hi-C data from different cell types and disease states demonstrates its biological relevance. Identified reorganized TADs are associated with structural variations and epigenomic changes such as changes in CTCF binding sites. By applying to a single-cell Hi-C data from mouse neuronal development, DiffDomain can identify reorganized TADs between cell types with reasonable reproducibility using pseudo-bulk Hi-C data from as few as 100 cells per condition. Moreover, DiffDomain reveals differential cell-to-population variability and heterogeneous cell-to-cell variability in TADs. Therefore, DiffDomain is a statistically sound method for better comparative analysis of TADs using both Hi-C and single-cell Hi-C data.},
}
@article {pmid38213897,
year = {2023},
author = {Rosen, J and Lee, L and Abnousi, A and Chen, J and Wen, J and Hu, M and Li, Y},
title = {HPTAD: A computational method to identify topologically associating domains from HiChIP and PLAC-seq datasets.},
journal = {Computational and structural biotechnology journal},
volume = {21},
number = {},
pages = {931-939},
pmid = {38213897},
issn = {2001-0370},
abstract = {High-throughput chromatin conformation capture technologies, such as Hi-C and Micro-C, have enabled genome-wide view of chromatin spatial organization. Most recently, Hi-C-derived enrichment-based technologies, including HiChIP and PLAC-seq, offer attractive alternatives due to their high signal-to-noise ratio and low cost. While a series of computational tools have been developed for Hi-C data, methods tailored for HiChIP and PLAC-seq data are still under development. Here we present HPTAD, a computational method to identify topologically associating domains (TADs) from HiChIP and PLAC-seq data. We performed comprehensive benchmark analysis to demonstrate its superior performance over existing TAD callers designed for Hi-C data. HPTAD is freely available at https://github.com/yunliUNC/HPTAD.},
}
@article {pmid38206813,
year = {2024},
author = {Zhang, M and Huang, H and Li, J and Wu, Q},
title = {ZNF143 deletion alters enhancer/promoter looping and CTCF/cohesin geometry.},
journal = {Cell reports},
volume = {43},
number = {1},
pages = {113663},
doi = {10.1016/j.celrep.2023.113663},
pmid = {38206813},
issn = {2211-1247},
abstract = {The transcription factor ZNF143 contains a central domain of seven zinc fingers in a tandem array and is involved in 3D genome construction. However, the mechanism by which ZNF143 functions in chromatin looping remains unclear. Here, we show that ZNF143 directionally recognizes a diverse range of genomic sites directly within enhancers and promoters and is required for chromatin looping between these sites. In addition, ZNF143 is located between CTCF and cohesin at numerous CTCF sites, and ZNF143 removal narrows the space between CTCF and cohesin. Moreover, genetic deletion of ZNF143, in conjunction with acute CTCF degradation, reveals that ZNF143 and CTCF collaborate to regulate higher-order topological chromatin organization. Finally, CTCF depletion enlarges direct ZNF143 chromatin looping. Thus, ZNF143 is recruited by CTCF to the CTCF sites to regulate CTCF/cohesin configuration and TAD (topologically associating domain) formation, whereas directional recognition of genomic DNA motifs directly by ZNF143 itself regulates promoter activity via chromatin looping.},
}
@article {pmid37748139,
year = {2024},
author = {Tang, B and Wang, X and He, H and Chen, R and Qiao, G and Yang, Y and Xu, Z and Wang, L and Dong, Q and Yu, J and Zhang, MQ and Shi, M and Wang, J},
title = {Aging-disturbed FUS phase transition impairs hematopoietic stem cells by altering chromatin structure.},
journal = {Blood},
volume = {143},
number = {2},
pages = {124-138},
doi = {10.1182/blood.2023020539},
pmid = {37748139},
issn = {1528-0020},
abstract = {Aged hematopoietic stem cells (HSCs) exhibit compromised reconstitution capacity. The molecular mechanisms behind this phenomenon are not fully understood. Here, we observed that the expression of FUS is increased in aged HSCs, and enforced FUS recapitulates the phenotype of aged HSCs through arginine-glycine-glycine-mediated aberrant FUS phase transition. By using Fus-gfp mice, we observed that FUShigh HSCs exhibit compromised FUS mobility and resemble aged HSCs both functionally and transcriptionally. The percentage of FUShigh HSCs is increased upon physiological aging and replication stress, and FUSlow HSCs of aged mice exhibit youthful function. Mechanistically, FUShigh HSCs exhibit a different global chromatin organization compared with FUSlow HSCs, which is observed in aged HSCs. Many topologically associating domains (TADs) are merged in aged HSCs because of the compromised binding of CCCTC-binding factor with chromatin, which is invoked by aberrant FUS condensates. It is notable that the transcriptional alteration between FUShigh and FUSlow HSCs originates from the merged TADs and is enriched in HSC aging-related genes. Collectively, this study reveals for the first time that aberrant FUS mobility promotes HSC aging by altering chromatin structure.},
}
@article {pmid38168424,
year = {2023},
author = {Li, Y and Xiao, P and Boadu, F and Goldkamp, AK and Nirgude, S and Cheng, J and Hagen, DE and Kalish, JM and Rivera, RM},
title = {The counterpart congenital overgrowth syndromes Beckwith-Wiedemann Syndrome in human and large offspring syndrome in bovine involve alterations in DNA methylation, transcription, and chromatin configuration.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2023.12.14.23299981},
pmid = {38168424},
abstract = {Beckwith-Wiedemann Syndrome (BWS, OMIM #130650) is a congenital epigenetic disorder in humans which affects approximately 1 in 10,340 children. The incidence is likely an underestimation as the condition is usually recognized based on observable phenotypes at birth. BWS children have up to a 28% risk of developing tumors and currently, only 80% of patients can be corroborated molecularly (epimutations/variants). It is unknown how the subtypes of this condition are molecularly similar/dissimilar globally, therefore there is a need to deeply characterize the syndrome at the molecular level. Here we characterize the methylome, transcriptome and chromatin configuration of 18 BWS individuals together with the animal model of the condition, the bovine large offspring syndrome (LOS). Sex specific comparisons are performed for a subset of the BWS patients and LOS. Given that this epigenetic overgrowth syndrome has been characterized as a loss-of-imprinting condition, parental allele-specific comparisons were performed using the bovine animal model. In general, the differentially methylated regions (DMRs) detected in BWS and LOS showed significant enrichment for CTCF binding sites. Altered chromosome compartments in BWS and LOS were positively correlated with gene expression changes, and the promoters of differentially expressed genes showed significant enrichment for DMRs, differential topologically associating domains, and differential A/B compartments in some comparisons of BWS subtypes and LOS. We show shared regions of dysregulation between BWS and LOS, including several HOX gene clusters, and also demonstrate that altered DNA methylation differs between the clinically epigenetically identified BWS patients and those identified as having DNA variants (i.e. CDKN1C microdeletion). Lastly, we highlight additional genes and genomic regions that have the potential to serve as targets for biomarker development to improve current molecular methodologies. In summary, our results suggest that genome-wide alternation of chromosome architecture, which is partially caused by DNA methylation changes, also contribute to the development of BWS and LOS.},
}
@article {pmid38167349,
year = {2024},
author = {Sun, L and Zhou, J and Xu, X and Liu, Y and Ma, N and Liu, Y and Nie, W and Zou, L and Deng, XW and He, H},
title = {Mapping nucleosome-resolution chromatin organization and enhancer-promoter loops in plants using Micro-C-XL.},
journal = {Nature communications},
volume = {15},
number = {1},
pages = {35},
pmid = {38167349},
issn = {2041-1723},
abstract = {Although chromatin organizations in plants have been dissected at the scales of compartments and topologically associating domain (TAD)-like domains, there remains a gap in resolving fine-scale structures. Here, we use Micro-C-XL, a high-throughput chromosome conformation capture (Hi-C)-based technology that involves micrococcal nuclease (instead of restriction enzymes) and long cross-linkers, to dissect single nucleosome-resolution chromatin organization in Arabidopsis. Insulation analysis reveals more than 14,000 boundaries, which mostly include chromatin accessibility, epigenetic modifications, and transcription factors. Micro-C-XL reveals associations between RNA Pols and local chromatin organizations, suggesting that gene transcription substantially contributes to the establishment of local chromatin domains. By perturbing Pol II both genetically and chemically at the gene level, we confirm its function in regulating chromatin organization. Visible loops and stripes are assigned to super-enhancers and their targeted genes, thus providing direct insights for the identification and mechanistic analysis of distal CREs and their working modes in plants. We further investigate possible factors regulating these chromatin loops. Subsequently, we expand Micro-C-XL to soybean and rice. In summary, we use Micro-C-XL for analyses of plants, which reveal fine-scale chromatin organization and enhancer-promoter loops and provide insights regarding three-dimensional genomes in plants.},
}
@article {pmid38134876,
year = {2023},
author = {Malachowski, T and Chandradoss, KR and Boya, R and Zhou, L and Cook, AL and Su, C and Pham, K and Haws, SA and Kim, JH and Ryu, HS and Ge, C and Luppino, JM and Nguyen, SC and Titus, KR and Gong, W and Wallace, O and Joyce, EF and Wu, H and Rojas, LA and Phillips-Cremins, JE},
title = {Spatially coordinated heterochromatinization of long synaptic genes in fragile X syndrome.},
journal = {Cell},
volume = {186},
number = {26},
pages = {5840-5858.e36},
doi = {10.1016/j.cell.2023.11.019},
pmid = {38134876},
issn = {1097-4172},
abstract = {Short tandem repeat (STR) instability causes transcriptional silencing in several repeat expansion disorders. In fragile X syndrome (FXS), mutation-length expansion of a CGG STR represses FMR1 via local DNA methylation. Here, we find megabase-scale H3K9me3 domains on autosomes and encompassing FMR1 on the X chromosome in FXS patient-derived iPSCs, iPSC-derived neural progenitors, EBV-transformed lymphoblasts, and brain tissue with mutation-length CGG expansion. H3K9me3 domains connect via inter-chromosomal interactions and demarcate severe misfolding of TADs and loops. They harbor long synaptic genes replicating at the end of S phase, replication-stress-induced double-strand breaks, and STRs prone to stepwise somatic instability. CRISPR engineering of the mutation-length CGG to premutation length reverses H3K9me3 on the X chromosome and multiple autosomes, refolds TADs, and restores gene expression. H3K9me3 domains can also arise in normal-length iPSCs created with perturbations linked to genome instability, suggesting their relevance beyond FXS. Our results reveal Mb-scale heterochromatinization and trans interactions among loci susceptible to instability.},
}
@article {pmid38129077,
year = {2023},
author = {Jessberger, G and Várnai, C and Stocsits, RR and Tang, W and Stary, G and Peters, JM},
title = {Cohesin and CTCF do not assemble TADs in Xenopus sperm and male pronuclei.},
journal = {Genome research},
volume = {},
number = {},
pages = {},
doi = {10.1101/gr.277865.123},
pmid = {38129077},
issn = {1549-5469},
abstract = {Paternal genomes are compacted during spermiogenesis and decompacted following fertilization. These processes are fundamental for inheritance but incompletely understood. We analyzed these processes in the frog Xenopus laevis, whose sperm can be assembled into functional pronuclei in egg extracts in vitro. In such extracts, cohesin extrudes DNA into loops, but in vivo cohesin only assembles topologically associating domains (TADs) at the mid-blastula transition (MBT). Why cohesin assembles TADs only at this stage is unknown. We first analyzed genome architecture in frog sperm and compared it to human and mouse. Our results indicate that sperm genome organization is conserved between frogs and humans and occurs without formation of TADs. TADs can be detected in mouse sperm samples, as reported, but these structures might originate from somatic chromatin contaminations. We therefore discuss the possibility that the absence of TADs might be a general feature of vertebrate sperm. To analyze sperm genome remodeling upon fertilization, we reconstituted male pronuclei in Xenopus egg extracts. In pronuclei, chromatin compartmentalization increases, but cohesin does not accumulate at CTCF sites and assemble TADs. However, if pronuclei are formed in the presence of exogenous CTCF, CTCF binds to its consensus sites, and cohesin accumulates at these and forms short-range chromatin loops, which are preferentially anchored at CTCF's N terminus. These results indicate that TADs are only assembled at MBT because before this stage CTCF sites are not occupied and cohesin only forms short-range chromatin loops.},
}
@article {pmid38102116,
year = {2023},
author = {Xiao, M and Kondo, S and Nomura, M and Kato, S and Nishimura, K and Zang, W and Zhang, Y and Akashi, T and Viny, A and Shigehiro, T and Ikawa, T and Yamazaki, H and Fukumoto, M and Tanaka, A and Hayashi, Y and Koike, Y and Aoyama, Y and Ito, H and Nishikawa, H and Kitamura, T and Kanai, A and Yokoyama, A and Fujiwara, T and Goyama, S and Noguchi, H and Lee, SC and Toyoda, A and Hinohara, K and Abdel-Wahab, O and Inoue, D},
title = {BRD9 determines the cell fate of hematopoietic stem cells by regulating chromatin state.},
journal = {Nature communications},
volume = {14},
number = {1},
pages = {8372},
pmid = {38102116},
issn = {2041-1723},
support = {21ck0106697h0001//Japan Agency for Medical Research and Development (AMED)/ ; JP20H00537//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; JP20H03717//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; 16H06279//MEXT | Japan Society for the Promotion of Science (JSPS)/ ; },
abstract = {ATP-dependent chromatin remodeling SWI/SNF complexes exist in three subcomplexes: canonical BAF (cBAF), polybromo BAF (PBAF), and a newly described non-canonical BAF (ncBAF). While cBAF and PBAF regulate fates of multiple cell types, roles for ncBAF in hematopoietic stem cells (HSCs) have not been investigated. Motivated by recent discovery of disrupted expression of BRD9, an essential component of ncBAF, in multiple cancers, including clonal hematopoietic disorders, we evaluate here the role of BRD9 in normal and malignant HSCs. BRD9 loss enhances chromatin accessibility, promoting myeloid lineage skewing while impairing B cell development. BRD9 significantly colocalizes with CTCF, whose chromatin recruitment is augmented by BRD9 loss, leading to altered chromatin state and expression of myeloid-related genes within intact topologically associating domains. These data uncover ncBAF as critical for cell fate specification in HSCs via three-dimensional regulation of gene expression and illuminate roles for ncBAF in normal and malignant hematopoiesis.},
}
@article {pmid38092881,
year = {2023},
author = {Fok, ET and Moorlag, SJCFM and Negishi, Y and Groh, LA and Dos Santos, JC and Gräwe, C and Monge, VV and Craenmehr, DDD and van Roosmalen, M and da Cunha Jolvino, DP and Migliorini, LB and Neto, AS and Severino, P and Vermeulen, M and Joosten, LAB and Netea, MG and Fanucchi, S and Mhlanga, MM},
title = {A chromatin-regulated biphasic circuit coordinates IL-1β-mediated inflammation.},
journal = {Nature genetics},
volume = {},
number = {},
pages = {},
pmid = {38092881},
issn = {1546-1718},
abstract = {Inflammation is characterized by a biphasic cycle consisting initially of a proinflammatory phase that is subsequently resolved by anti-inflammatory processes. Interleukin-1β (IL-1β) is a master regulator of proinflammation and is encoded within the same topologically associating domain (TAD) as IL-37, which is an anti-inflammatory cytokine that opposes the function of IL-1β. Within this TAD, we identified a long noncoding RNA called AMANZI, which negatively regulates IL-1β expression and trained immunity through the induction of IL37 transcription. We found that the activation of IL37 occurs through the formation of a dynamic long-range chromatin contact that leads to the temporal delay of anti-inflammatory responses. The common variant rs16944 present in AMANZI augments this regulatory circuit, predisposing individuals to enhanced proinflammation or immunosuppression. Our work illuminates a chromatin-mediated biphasic circuit coordinating expression of IL-1β and IL-37, thereby regulating two functionally opposed states of inflammation from within a single TAD.},
}
@article {pmid38084924,
year = {2023},
author = {Balasubramanian, D and Borges Pinto, P and Grasso, A and Vincent, S and Tarayre, H and Lajoignie, D and Ghavi-Helm, Y},
title = {Enhancer-promoter interactions can form independently of genomic distance and be functional across TAD boundaries.},
journal = {Nucleic acids research},
volume = {},
number = {},
pages = {},
doi = {10.1093/nar/gkad1183},
pmid = {38084924},
issn = {1362-4962},
support = {Enhancer3D 759708/ERC_/European Research Council/International ; },
abstract = {Topologically Associating Domains (TADs) have been suggested to facilitate and constrain enhancer-promoter interactions. However, the role of TAD boundaries in effectively restricting these interactions remains unclear. Here, we show that a significant proportion of enhancer-promoter interactions are established across TAD boundaries in Drosophila embryos, but that developmental genes are strikingly enriched in intra- but not inter-TAD interactions. We pursued this observation using the twist locus, a master regulator of mesoderm development, and systematically relocated one of its enhancers to various genomic locations. While this developmental gene can establish inter-TAD interactions with its enhancer, the functionality of these interactions remains limited, highlighting the existence of topological constraints. Furthermore, contrary to intra-TAD interactions, the formation of inter-TAD enhancer-promoter interactions is not solely driven by genomic distance, with distal interactions sometimes favored over proximal ones. These observations suggest that other general mechanisms must exist to establish and maintain specific enhancer-promoter interactions across large distances.},
}
@article {pmid38076897,
year = {2023},
author = {Rossini, R and Oshaghi, M and Nekrasov, M and Bellanger, A and Domaschenz, R and Dijkwel, Y and Abdelhalim, M and Collas, P and Tremethick, D and Paulsen, J},
title = {Multi-level 3D genome organization deteriorates during breast cancer progression.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2023.11.26.568711},
pmid = {38076897},
abstract = {Breast cancer entails intricate alterations in genome organization and expression. However, how three-dimensional (3D) chromatin structure changes in the progression from a normal to a breast cancer malignant state remains unknown. To address this, we conducted an analysis combining Hi-C data with lamina-associated domains (LADs), epigenomic marks, and gene expression in an in vitro model of breast cancer progression. Our results reveal that while the fundamental properties of topologically associating domains (TADs) remain largely stable, significant changes occur in the organization of compartments and subcompartments. These changes are closely correlated with alterations in the expression of oncogenic genes. We also observe a restructuring of TAD-TAD interactions, coinciding with a loss of spatial compartmentalization and radial positioning of the 3D genome. Notably, we identify a previously unrecognized interchromosomal insertion event, wherein a locus on chromosome 8 housing the MYC oncogene is inserted into a highly active subcompartment on chromosome 10. This insertion leads to the formation of de novo enhancer contacts and activation of the oncogene, illustrating how structural variants can interact with the 3D genome to drive oncogenic states. In summary, our findings provide evidence for the degradation of genome organization at multiple scales during breast cancer progression revealing novel relationships between genome 3D structure and oncogenic processes.},
}
@article {pmid38061928,
year = {2023},
author = {Long, Y and Wendel, JF and Zhang, X and Wang, M},
title = {Evolutionary insights into the organization of chromatin structure and landscape of transcriptional regulation in plants.},
journal = {Trends in plant science},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tplants.2023.11.009},
pmid = {38061928},
issn = {1878-4372},
abstract = {Development of complex traits necessitates the functioning and coordination of intricate regulatory networks involving multiple genes. Understanding 3D chromatin structure can facilitate insight into the regulation of gene expression by regulatory elements. This potential, of visualizing the role of chromatin organization in the evolution and function of regulatory elements, remains largely unexplored. Here, we describe new perspectives that arise from the dual considerations of sequence variation of regulatory elements and chromatin structure, with a special focus on whole-genome doubling or polyploidy. We underscore the significance of hierarchical chromatin organization in gene regulation during evolution. In addition, we describe strategies for exploring chromatin organization in future investigations of regulatory evolution in plants, enabling insights into the evolutionary influence of regulatory elements on gene expression and, hence, phenotypes.},
}
@article {pmid38049665,
year = {2023},
author = {Leeman-Neill, RJ and Song, D and Bizarro, J and Wacheul, L and Rothschild, G and Singh, S and Yang, Y and Sarode, AY and Gollapalli, K and Wu, L and Zhang, W and Chen, Y and Lauring, MC and Whisenant, DE and Bhavsar, S and Lim, J and Swerdlow, SH and Bhagat, G and Zhao, Q and Berchowitz, LE and Lafontaine, DLJ and Wang, J and Basu, U},
title = {Noncoding mutations cause super-enhancer retargeting resulting in protein synthesis dysregulation during B cell lymphoma progression.},
journal = {Nature genetics},
volume = {},
number = {},
pages = {},
pmid = {38049665},
issn = {1546-1718},
support = {R01AI134988//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; RO1AI143897//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; R01AI099195//U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ ; DOD W81XWH-18-1-0394//U.S. Department of Defense (United States Department of Defense)/ ; GM124633//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; T32CA265828//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; },
abstract = {Whole-genome sequencing of longitudinal tumor pairs representing transformation of follicular lymphoma to high-grade B cell lymphoma with MYC and BCL2 rearrangements (double-hit lymphoma) identified coding and noncoding genomic alterations acquired during lymphoma progression. Many of these transformation-associated alterations recurrently and focally occur at topologically associating domain resident regulatory DNA elements, including H3K4me3 promoter marks located within H3K27ac super-enhancer clusters in B cell non-Hodgkin lymphoma. One region found to undergo recurrent alteration upon transformation overlaps a super-enhancer affecting the expression of the PAX5/ZCCHC7 gene pair. ZCCHC7 encodes a subunit of the Trf4/5-Air1/2-Mtr4 polyadenylation-like complex and demonstrated copy number gain, chromosomal translocation and enhancer retargeting-mediated transcriptional upregulation upon lymphoma transformation. Consequently, lymphoma cells demonstrate nucleolar dysregulation via altered noncoding 5.8S ribosomal RNA processing. We find that a noncoding mutation acquired during lymphoma progression affects noncoding rRNA processing, thereby rewiring protein synthesis leading to oncogenic changes in the lymphoma proteome.},
}
@article {pmid38017545,
year = {2023},
author = {Llinàs-Arias, P and Ensenyat-Mendez, M and Íñiguez-Muñoz, S and Orozco, JIJ and Valdez, B and Salomon, MP and Matsuba, C and Solivellas-Pieras, M and Bedoya-López, AF and Sesé, B and Mezger, A and Ormestad, M and Unzueta, F and Strand, SH and Boiko, AD and Hwang, ES and Cortés, J and DiNome, ML and Esteller, M and Lupien, M and Marzese, DM},
title = {Chromatin insulation orchestrates matrix metalloproteinase gene cluster expression reprogramming in aggressive breast cancer tumors.},
journal = {Molecular cancer},
volume = {22},
number = {1},
pages = {190},
pmid = {38017545},
issn = {1476-4598},
support = {CD22/00026//Instituto de Salud Carlos III/ ; CPII22/00004//Instituto de Salud Carlos III/ ; IMP21/10//IDISBA - Impetus Call/ ; Margalida Comas//Govern de les Illes Balears/ ; },
abstract = {BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype that exhibits a high incidence of distant metastases and lacks targeted therapeutic options. Here we explored how the epigenome contributes to matrix metalloprotease (MMP) dysregulation impacting tumor invasion, which is the first step of the metastatic process.<br><br>METHODS: We combined RNA expression and chromatin interaction data to identify insulator elements potentially associated with MMP gene expression and invasion. We employed CRISPR/Cas9 to disrupt the CCCTC-Binding Factor (CTCF) binding site on an insulator element downstream of the MMP8 gene (IE8) in two TNBC cellular models. We characterized these models by combining Hi-C, ATAC-seq, and RNA-seq with functional experiments to determine invasive ability. The potential of our findings to predict the progression of ductal carcinoma in situ (DCIS), was tested in data from clinical specimens.<br><br>RESULTS: We explored the clinical relevance of an insulator element located within the Chr11q22.2 locus, downstream of the MMP8 gene (IE8). This regulatory element resulted in a topologically associating domain (TAD) boundary that isolated nine MMP genes into two anti-correlated expression clusters. This expression pattern was associated with worse relapse-free (HR&#x2009;=&#x2009;1.57 [1.06&#x2009;-&#x2009;2.33]; p&#x2009;=&#x2009;0.023) and overall (HR&#x2009;=&#x2009;2.65 [1.31&#x2009;-&#x2009;5.37], p&#x2009;=&#x2009;0.005) survival of TNBC patients. After CRISPR/Cas9-mediated disruption of IE8, cancer cells showed a switch in the MMP expression signature, specifically downregulating the pro-invasive MMP1 gene and upregulating the antitumorigenic MMP8 gene, resulting in reduced invasive ability and collagen degradation. We observed that the MMP expression pattern predicts DCIS that eventually progresses into invasive ductal carcinomas (AUC&#x2009;=&#x2009;0.77, p&#x2009;<&#x2009;0.01).<br><br>CONCLUSION: Our study demonstrates how the activation of an IE near the MMP8 gene determines the regional transcriptional regulation of MMP genes with opposing functional activity, ultimately influencing the invasive properties of aggressive forms of breast cancer.},
}
@article {pmid38017297,
year = {2023},
author = {Jehangir, M and Ahmad, SF and Singchat, W and Panthum, T and Thong, T and Aramsirirujiwet, P and Lisachov, A and Muangmai, N and Han, K and Koga, A and Duengkae, P and Srikulnath, K},
title = {Hi-C sequencing unravels dynamic three-dimensional chromatin interactions in muntjac lineage: insights from chromosome fusions in Fea's muntjac genome.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {31},
number = {4},
pages = {34},
pmid = {38017297},
issn = {1573-6849},
support = {P-20-52605//National Science and Technology Development Agency (NSTDA)/ ; },
abstract = {Eukaryotes have varying numbers and structures of characteristic chromosomes across lineages or species. The evolutionary trajectory of species may have been affected by spontaneous genome rearrangements. Chromosome fusion drastically alters karyotypes. However, the mechanisms and consequences of chromosome fusions, particularly in muntjac species, are poorly understood. Recent research-based advancements in three-dimensional (3D) genomics, particularly high-throughput chromatin conformation capture (Hi-C) sequencing, have allowed for the identification of chromosome fusions and provided mechanistic insights into three muntjac species: Muntiacus muntjak, M. reevesi, and M. crinifrons. This study aimed to uncover potential genome rearrangement patterns in the threatened species Fea's muntjac (Muntiacus feae), which have not been previously examined for such characteristics. Deep Hi-C sequencing (31.42 × coverage) was performed to reveal the 3D chromatin architecture of the Fea's muntjac genome. Patterns of repeated chromosome fusions that were potentially mediated by high-abundance transposable elements were identified. Comparative Hi-C maps demonstrated linkage homology between the sex chromosomes in Fea's muntjac and autosomes in M. reevesi, indicating that fusions may have played a crucial role in the evolution of the sex chromosomes of the lineage. The species-level dynamics of topologically associated domains (TADs) suggest that TAD organization could be altered by differential chromosome interactions owing to repeated chromosome fusions. However, research on the effect of TADs on muntjac genome evolution is insufficient. This study generated Hi-C data for the Fea's muntjac, providing a genomic resource for future investigations of the evolutionary patterns of chromatin conformation at the chromosomal level.},
}
@article {pmid38014261,
year = {2023},
author = {Zhao, H and Lin, Y and Lin, E and Liu, F and Shu, L and Jing, D and Wang, B and Wang, M and Shan, F and Zhang, L and Lam, JC and Midla, SC and Giardine, BM and Keller, CA and Hardison, RC and Blobel, GA and Zhang, H},
title = {Genome folding principles revealed in condensin-depleted mitotic chromosomes.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2023.11.09.566494},
pmid = {38014261},
abstract = {During mitosis, condensin activity interferes with interphase chromatin structures. Here, we generated condensin-free mitotic chromosomes to investigate genome folding principles. Co- depletion of condensin I and II, but neither alone, triggered mitotic chromosome compartmentalization in ways that differ from interphase. Two distinct euchromatic compartments, indistinguishable in interphase, rapidly emerged upon condensin loss with different interaction preferences and dependence on H3K27ac. Constitutive heterochromatin gradually self-aggregated and co-compartmentalized with the facultative heterochromatin, contrasting with their separation during interphase. While topologically associating domains (TADs) and CTCF/cohesin mediated structural loops remained undetectable, cis-regulatory element contacts became apparent, providing an explanation for their quick re-establishment during mitotic exit. HP1 proteins, which are thought to partition constitutive heterochromatin, were absent from mitotic chromosomes, suggesting, surprisingly, that constitutive heterochromatin can self-aggregate without HP1. Indeed, in cells traversing from M- to G1-phase in the combined absence of HP1α, HP1Π and HP1γ, re-established constitutive heterochromatin compartments normally. In sum, "clean-slate" condensin-deficient mitotic chromosomes illuminate mechanisms of genome compartmentalization not revealed in interphase cells.},
}
@article {pmid38013620,
year = {2023},
author = {Singh, AK and Walavalkar, K and Tavernari, D and Ciriello, G and Notani, D and Sabarinathan, R},
title = {Cis-regulatory effect of HPV integration is constrained by host chromatin architecture in cervical cancers.},
journal = {Molecular oncology},
volume = {},
number = {},
pages = {},
doi = {10.1002/1878-0261.13559},
pmid = {38013620},
issn = {1878-0261},
abstract = {HPV infections are the primary drivers of cervical cancers, and often HPV DNA gets integrated into the host genome. Although the oncogenic impact of HPV encoded genes is relatively well known, the cis-regulatory effect of integrated HPV DNA on host chromatin structure and gene regulation remains less understood. We investigated genome-wide patterns of HPV integrations and associated host gene expression changes in the context of host chromatin states and TADs. HPV integrations were significantly enriched in active chromatin regions and depleted in inactive ones. Interestingly, regardless of chromatin state, genomic regions flanking HPV integrations showed transcriptional upregulation. Nevertheless, upregulation (both local and long-range) was mostly confined to TADs with integration, but not affecting adjacent TADs. Few TADs showed recurrent integrations associated with overexpression of oncogenes within them (e.g. MYC, PVT1, TP63 and ERBB2) regardless of proximity. Hi-C and 4C-seq analyses in cervical cancer cell line (HeLa) demonstrated chromatin looping interactions between integrated HPV and MYC/PVT1 regions (~500kb apart), leading to allele-specific overexpression. Based on these, we propose HPV integrations can trigger multimodal oncogenic activation to promote cancer progression.},
}
@article {pmid37976174,
year = {2023},
author = {Siqueira, E and Kim, BH and Reser, L and Chow, R and Delaney, K and Esteller, M and Ross, MM and Shabanowitz, J and Hunt, DF and Guil, S and Ausiö, J},
title = {Analysis of the interplay between MeCP2 and histone H1 during in vitro differentiation of human ReNCell neural progenitor cells.},
journal = {Epigenetics},
volume = {18},
number = {1},
pages = {2276425},
doi = {10.1080/15592294.2023.2276425},
pmid = {37976174},
issn = {1559-2308},
abstract = {An immortalized neural cell line derived from the human ventral mesencephalon, called ReNCell, and its MeCP2 knock out were used. With it, we characterized the chromatin compositional transitions undergone during differentiation, with special emphasis on linker histones. While the WT cells displayed the development of dendrites and axons the KO cells did not, despite undergoing differentiation as monitored by NeuN. ReNCell expressed minimal amounts of histone H1.0 and their linker histone complement consisted mainly of histone H1.2, H1.4 and H1.5. The overall level of histone H1 exhibited a trend to increase during the differentiation of MeCP2 KO cells. The phosphorylation levels of histone H1 proteins decreased dramatically during ReNCell's cell differentiation independently of the presence of MeCP2. Immunofluorescence analysis showed that MeCP2 exhibits an extensive co-localization with linker histones. Interestingly, the average size of the nucleus decreased during differentiation but in the MeCP2 KO cells, the smaller size of the nuclei at the start of differentiation increased by almost 40% after differentiation by 8 days (8 DIV). In summary, our data provide a compelling perspective on the dynamic changes of H1 histones during neural differentiation, coupled with the intricate interplay between H1 variants and MeCP2.Abbreviations: ACN, acetonitrile; A230, absorbance at 230 nm; bFGF, basic fibroblast growth factor; CM, chicken erythrocyte histone marker; CNS, central nervous system; CRISPR, clustered regulated interspaced short palindromic repeatsDAPI, 4,'6-diaminidino-2-phenylindole; DIV, days in vitro (days after differentiation is induced); DMEM, Dulbecco's modified Eagle medium; EGF, epidermal growth factor; ESC, embryonic stem cell; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GFAP, glial fibrillary acidic proteinHPLC, high-performance liquid chromatography; IF, immunofluorescence; iPSCs, induced pluripotent stem cells; MAP2, microtubule-associated protein 2; MBD, methyl-binding domain; MeCP2, methyl-CpG binding protein 2; MS, mass spectrometry; NCP, nucleosome core particle; NeuN, neuron nuclear antigen; NPC, neural progenitor cellPAGE, polyacrylamide gel electrophoresis; PBS, phosphate buffered saline; PFA, paraformaldehyde; PTM, posttranslational modification; RP-HPLC, reversed phase HPLC; ReNCells, ReNCells VM; RPLP0, ribosomal protein lateral stalk subunit P0; RT-qPCR, reverse transcription quantitative polymerase-chain reaction; RTT, Rett Syndrome; SDS, sodium dodecyl sulphate; TAD, topologically associating domain; Triple KO, triple knockout.},
}
@article {pmid37963468,
year = {2023},
author = {He, J and Yan, A and Chen, B and Huang, J and Kee, K},
title = {3D genome remodeling and homologous pairing during meiotic prophase of mouse oogenesis and spermatogenesis.},
journal = {Developmental cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.devcel.2023.10.009},
pmid = {37963468},
issn = {1878-1551},
abstract = {During meiosis, the chromatin and transcriptome undergo prominent switches. Although recent studies have explored the genome reorganization during spermatogenesis, the chromatin remodeling in oogenesis and characteristics of homologous pairing remain largely elusive. We comprehensively compared chromatin structures and transcriptomes at successive substages of meiotic prophase in both female and male mice using low-input high-through chromosome conformation capture (Hi-C) and RNA sequencing (RNA-seq). Compartments and topologically associating domains (TADs) gradually disappeared and slowly recovered in both sexes. We found that homologs adopted different sex-conserved pairing strategies prior to and after the leptotene-to-zygotene transition, changing from long interspersed nuclear element (LINE)-enriched compartments B to short interspersed nuclear element (SINE)-enriched compartments A. We complemented marker genes and predicted the sex-specific meiotic sterile genes for each substage. This study provides valuable insights into the similarities and distinctions between sexes in chromosome architecture, homologous pairing, and transcriptome during meiotic prophase of both oogenesis and spermatogenesis.},
}
@article {pmid37922325,
year = {2023},
author = {Zhu, Y and Rosenfeld, MG and Suh, Y},
title = {Ultrafine mapping of chromosome conformation at hundred basepair resolution reveals regulatory genome architecture.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {120},
number = {45},
pages = {e2313285120},
doi = {10.1073/pnas.2313285120},
pmid = {37922325},
issn = {1091-6490},
abstract = {The resolution limit of chromatin conformation capture methodologies (3Cs) has restrained their application in detection of fine-level chromatin structure mediated by cis-regulatory elements (CREs). Here, we report two 3C-derived methods, Tri-4C and Tri-HiC, which utilize multirestriction enzyme digestions for ultrafine mapping of targeted and genome-wide chromatin interaction, respectively, at up to one hundred basepair resolution. Tri-4C identified CRE loop interaction networks and quantitatively revealed their alterations underlying dynamic gene control. Tri-HiC uncovered global fine-gauge regulatory interaction networks, identifying >20-fold more enhancer:promoter (E:P) loops than in situ Hi-C. In addition to vastly improved identification of subkilobase-sized E:P loops, Tri-HiC also uncovered interaction stripes and contact domain insulation from promoters and enhancers, revealing their loop extrusion behaviors resembling the topologically associating domain boundaries. Tri-4C and Tri-HiC provide robust approaches to achieve the high-resolution interactome maps required for characterizing fine-gauge regulatory chromatin interactions in analysis of development, homeostasis, and disease.},
}
@article {pmid37907089,
year = {2023},
author = {Chu, X and Wang, J},
title = {Quantifying the large-scale chromosome structural dynamics during the mitosis-to-G1 phase transition of cell cycle.},
journal = {Open biology},
volume = {13},
number = {11},
pages = {230175},
doi = {10.1098/rsob.230175},
pmid = {37907089},
issn = {2046-2441},
abstract = {Cell cycle is known to be regulated by the underlying gene network. Chromosomes, which serve as the scaffold for gene expressions, undergo significant structural reorganizations during mitosis. Understanding the mechanism of the cell cycle from the chromosome structural perspective remains a grand challenge. In this study, we applied an integrated theoretical approach to investigate large-scale chromosome structural dynamics during the mitosis-to-G1 phase transition. We observed that the chromosome structural expansion and adaptation of the structural asphericity do not occur synchronously and attributed this behaviour to the unique unloading sequence of the two types of condensins. Furthermore, we observed that the coherent motions between the chromosomal loci are primarily enhanced within the topologically associating domains (TADs) as cells progress to the G1 phase, suggesting that TADs can be considered as both structural and dynamical units for organizing the three-dimensional chromosome. Our analysis also reveals that the quantified pathways of chromosome structural reorganization during the mitosis-to-G1 phase transition exhibit high stochasticity at the single-cell level and show nonlinear behaviours in changing TADs and contacts formed at the long-range regions. Our findings offer valuable insights into large-scale chromosome structural dynamics after mitosis.},
}
@article {pmid37898735,
year = {2023},
author = {Gao, GF and Li, P and Leonard, WJ},
title = {Co-localization of clusters of TCR-regulated genes with TAD rearrangements.},
journal = {BMC genomics},
volume = {24},
number = {1},
pages = {650},
pmid = {37898735},
issn = {1471-2164},
support = {Z99HL999999/HL/NHLBI NIH HHS/United States ; },
abstract = {BACKGROUND: Gene expression has long been known to be influenced by the relative proximity of DNA regulatory elements. Topologically associating domains (TADs) are self-interacting genomic regions involved in regulating gene expression by controlling the proximity of these elements. Prior studies of TADs and their biological roles have revealed correlations between TAD changes and cellular differentiation. Here, we used Hi-C and RNA-seq data to correlate TCR-induced changes in TAD structure and gene expression in human CD4[+] T cells.<br><br>RESULTS: We developed a pipeline, Differentially Expressed Gene Enrichment Finder (DEGEF), that identifies regions of differentially expressed gene enrichment. Using DEGEF, we found that TCR-regulated genes cluster non-uniformly across the genome and that these clusters preferentially localized in regions of TAD rearrangement. Interestingly, clusters of upregulated genes preferentially formed new Hi-C contacts compared to downregulated clusters, suggesting that TCR-activated CD4[+] T cells may regulate genes by changing stimulatory contacts rather than inhibitory contacts.<br><br>CONCLUSIONS: Our observations support a significant relationship between TAD rearrangements and changes in local gene expression. These findings indicate potentially important roles for TAD rearrangements in shaping their local regulatory environments and thus driving differential expression of nearby genes during CD4[+] T cell activation. Moreover, they provide new insights into global mechanisms that regulate gene expression.},
}
@article {pmid37889077,
year = {2023},
author = {Song, C and Zhang, G and Mu, X and Feng, C and Zhang, Q and Song, S and Zhang, Y and Yin, M and Zhang, H and Tang, H and Li, C},
title = {eRNAbase: a comprehensive database for decoding the regulatory eRNAs in human and mouse.},
journal = {Nucleic acids research},
volume = {},
number = {},
pages = {},
doi = {10.1093/nar/gkad925},
pmid = {37889077},
issn = {1362-4962},
support = {62171166//National Natural Science Foundation of China/ ; 20210002-1005 USCAT-2021-01//Affiliated Hospital of University of South China for Advanced Talents/ ; 2019M661311//China Postdoctoral Science Foundation/ ; 2023JJ30547//Natural Science Foundation of Hunan Province/ ; 20201920//Scientific Research Fund Project of Hunan Provincial Health Commission/ ; 2020SK4008//Construction of Innovative Provinces in Hunan/ ; 20214310NHYCG03//University of South China/ ; },
abstract = {Enhancer RNAs (eRNAs) transcribed from distal active enhancers serve as key regulators in gene transcriptional regulation. The accumulation of eRNAs from multiple sequencing assays has led to an urgent need to comprehensively collect and process these data to illustrate the regulatory landscape of eRNAs. To address this need, we developed the eRNAbase (http://bio.liclab.net/eRNAbase/index.php) to store the massive available resources of human and mouse eRNAs and provide comprehensive annotation and analyses for eRNAs. The current version of eRNAbase cataloged 10 399 928 eRNAs from 1012 samples, including 858 human samples and 154 mouse samples. These eRNAs were first identified and uniformly processed from 14 eRNA-related experiment types manually collected from GEO/SRA and ENCODE. Importantly, the eRNAbase provides detailed and abundant (epi)genetic annotations in eRNA regions, such as super enhancers, enhancers, common single nucleotide polymorphisms, expression quantitative trait loci, transcription factor binding sites, CRISPR/Cas9 target sites, DNase I hypersensitivity sites, chromatin accessibility regions, methylation sites, chromatin interactions regions, topologically associating domains and RNA spatial interactions. Furthermore, the eRNAbase provides users with three novel analyses including eRNA-mediated pathway regulatory analysis, eRNA-based variation interpretation analysis and eRNA-mediated TF-target gene analysis. Hence, eRNAbase is a powerful platform to query, browse and visualize regulatory cues associated with eRNAs.},
}
@article {pmid37886958,
year = {2023},
author = {Fischer, EF and Pilarczyk, G and Hausmann, M},
title = {Microscopic Analysis of Heterochromatin, Euchromatin and Cohesin in Cancer Cell Models and under Anti-Cancer Treatment.},
journal = {Current issues in molecular biology},
volume = {45},
number = {10},
pages = {8152-8172},
doi = {10.3390/cimb45100515},
pmid = {37886958},
issn = {1467-3045},
support = {02 NUK 058A//Federal Ministry of Education and Research/ ; },
abstract = {The spatial organization of euchromatin (EC) and heterochromatin (HC) appears as a cell-type specific network, which seems to have an impact on gene regulation and cell fate. The spatial organization of cohesin should thus also be characteristic for a cell type since it is involved in a TAD (topologically associating domain) formation, and thus in gene regulation or DNA repair processes. Based on the previous hypotheses and results on the general importance of heterochromatin organization on genome functions in particular, the configurations of these organizational units (EC represented by H3K4me3-positive regions, HC represented by H3K9me3-positive regions, cohesins) are investigated in the cell nuclei of different cancer and non-cancerous cell types and under different anti-cancer treatments. Confocal microscopic images of the model cell systems were used and analyzed using analytical processes of quantification created in Fiji, an imaging tool box well established in different fields of science. Human fibroblasts, breast cancer and glioblastoma cells as well as murine embryonal terato-carcinoma cells were used as these cell models and compared according to the different parameters of spatial arrangements. In addition, proliferating, quiescent and from the quiescent state reactivated fibroblasts were analyzed. In some selected cases, the cells were treated with X-rays or azacitidine. Heterogeneous results were obtained by the analyses of the configurations of the three different organizational units: granulation and a loss of H3K4me3-positive regions (EC) occurred after irradiation with 4 Gy or azacitidine treatment. While fibroblasts responded to irradiation with an increase in cohesin and granulation, in breast cancer cells, it resulted in decreases in cohesin and changes in granulation. H3K9me3-positive regions (HC) in fibroblasts experienced increased granulation, whereas in breast cancer cells, the amount of such regions increased. After azacitidine treatment, murine stem cells showed losses of cohesin and granulation and an increase in the granulation of H3K9me3-positive regions. Fibroblasts that were irradiated with 2 Gy only showed irregularities in structural amounts and granulation. Quiescent fibroblasts contained less euchromatin-related H3K4me3-positive signals and cohesin levels as well as higher heterochromatin-related H3K9me3-positive signals than non-quiescent ones. In general, fibroblasts responded more intensely to X-ray irradiation than breast cancer cells. The results indicate the usefulness of model cell systems and show that, in general, characteristic differences initially existing in chromatin and cohesin organizations result in specific responses to anti-cancer treatment.},
}
@article {pmid37884483,
year = {2023},
author = {Lee, H and Seo, PJ},
title = {Accessible gene borders establish a core structural unit for chromatin architecture in Arabidopsis.},
journal = {Nucleic acids research},
volume = {51},
number = {19},
pages = {10261-10277},
doi = {10.1093/nar/gkad710},
pmid = {37884483},
issn = {1362-4962},
support = {NRF-2022R1A2B5B02001266//Basic Science Research/ ; NRF-2022R1A4A3024451//Basic Research Laboratory/ ; //National Research Foundation of Korea/ ; },
abstract = {Three-dimensional (3D) chromatin structure is linked to transcriptional regulation in multicellular eukaryotes including plants. Taking advantage of high-resolution Hi-C (high-throughput chromatin conformation capture), we detected a small structural unit with 3D chromatin architecture in the Arabidopsis genome, which lacks topologically associating domains, and also in the genomes of tomato, maize, and Marchantia polymorpha. The 3D folding domain unit was usually established around an individual gene and was dependent on chromatin accessibility at the transcription start site (TSS) and transcription end site (TES). We also observed larger contact domains containing two or more neighboring genes, which were dependent on accessible border regions. Binding of transcription factors to accessible TSS/TES regions formed these gene domains. We successfully simulated these Hi-C contact maps via computational modeling using chromatin accessibility as input. Our results demonstrate that gene domains establish basic 3D chromatin architecture units that likely contribute to higher-order 3D genome folding in plants.},
}
@article {pmid37882064,
year = {2023},
author = {Sreenivas, P and Wang, L and Wang, M and Challa, A and Modi, P and Hensch, NR and Gryder, B and Chou, HC and Zhao, XR and Sunkel, B and Moreno-Campos, R and Khan, J and Stanton, BZ and Ignatius, MS},
title = {A SNAI2/CTCF Interaction is Required for NOTCH1 Expression in Rhabdomyosarcoma.},
journal = {Molecular and cellular biology},
volume = {},
number = {},
pages = {1-19},
doi = {10.1080/10985549.2023.2256640},
pmid = {37882064},
issn = {1098-5549},
abstract = {Rhabdomyosarcoma (RMS) is a pediatric malignancy of the muscle with characteristics of cells blocked in differentiation. NOTCH1 is an oncogene that promotes self-renewal and blocks differentiation in the fusion negative-RMS sub-type. However, how NOTCH1 expression is transcriptionally maintained in tumors is unknown. Analyses of SNAI2 and CTCF chromatin binding and HiC analyses revealed a conserved SNAI2/CTCF overlapping peak downstream of the NOTCH1 locus marking a sub-topologically associating domain (TAD) boundary. Deletion of the SNAI2-CTCF peak showed that it is essential for NOTCH1 expression and viability of FN-RMS cells. Reintroducing constitutively activated NOTCH1-ΔE in cells with the SNAI2-CTCF peak deleted restored cell-viability. Ablation of SNAI2 using CRISPR/Cas9 reagents resulted in the loss of majority of RD and SMS-CTR FN-RMS cells. However, the few surviving clones that repopulate cultures have recovered NOTCH1. Cells that re-establish NOTCH1 expression after SNAI2 ablation are unable to differentiate robustly as SNAI2 shRNA knockdown cells; yet, SNAI2-ablated cells continued to be exquisitely sensitive to ionizing radiation. Thus, we have uncovered a novel mechanism by which SNAI2 and CTCF maintenance of a sub-TAD boundary promotes rather than represses NOTCH1 expression. Further, we demonstrate that SNAI2 suppression of apoptosis post-radiation is independent of SNAI2/NOTCH1 effects on self-renewal and differentiation.},
}
@article {pmid37865700,
year = {2023},
author = {Messina, O and Raynal, F and Gurgo, J and Fiche, JB and Pancaldi, V and Nollmann, M},
title = {3D chromatin interactions involving Drosophila insulators are infrequent but preferential and arise before TADs and transcription.},
journal = {Nature communications},
volume = {14},
number = {1},
pages = {6678},
pmid = {37865700},
issn = {2041-1723},
support = {episcope//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; },
abstract = {In mammals, insulators contribute to the regulation of loop extrusion to organize chromatin into topologically associating domains. In Drosophila the role of insulators in 3D genome organization is, however, under current debate. Here, we addressed this question by combining bioinformatics analysis and multiplexed chromatin imaging. We describe a class of Drosophila insulators enriched at regions forming preferential chromatin interactions genome-wide. Notably, most of these 3D interactions do not involve TAD borders. Multiplexed imaging shows that these interactions occur infrequently, and only rarely involve multiple genomic regions coalescing together in space in single cells. Finally, we show that non-border preferential 3D interactions enriched in this class of insulators are present before TADs and transcription during Drosophila development. Our results are inconsistent with insulators forming stable hubs in single cells, and instead suggest that they fine-tune existing 3D chromatin interactions, providing an additional regulatory layer for transcriptional regulation.},
}
@article {pmid37853125,
year = {2023},
author = {Arnould, C and Rocher, V and Saur, F and Bader, AS and Muzzopappa, F and Collins, S and Lesage, E and Le Bozec, B and Puget, N and Clouaire, T and Mangeat, T and Mourad, R and Ahituv, N and Noordermeer, D and Erdel, F and Bushell, M and Marnef, A and Legube, G},
title = {Chromatin compartmentalization regulates the response to DNA damage.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {37853125},
issn = {1476-4687},
abstract = {The DNA damage response is essential to safeguard genome integrity. Although the contribution of chromatin in DNA repair has been investigated[1,2], the contribution of chromosome folding to these processes remains unclear[3]. Here we report that, after the production of double-stranded breaks (DSBs) in mammalian cells, ATM drives the formation of a new chromatin compartment (D compartment) through the clustering of damaged topologically associating domains, decorated with γH2AX and 53BP1. This compartment forms by a mechanism that is consistent with polymer-polymer phase separation rather than liquid-liquid phase separation. The D compartment arises mostly in G1 phase, is independent of cohesin and is enhanced after pharmacological inhibition of DNA-dependent protein kinase (DNA-PK) or R-loop accumulation. Importantly, R-loop-enriched DNA-damage-responsive genes physically localize to the D compartment, and this contributes to their optimal activation, providing a function for DSB clustering in the DNA damage response. However, DSB-induced chromosome reorganization comes at the expense of an increased rate of translocations, also observed in cancer genomes. Overall, we characterize how DSB-induced compartmentalization orchestrates the DNA damage response and highlight the critical impact of chromosome architecture in genomic instability.},
}
@article {pmid37845234,
year = {2023},
author = {Calandrelli, R and Wen, X and Charles Richard, JL and Luo, Z and Nguyen, TC and Chen, CJ and Qi, Z and Xue, S and Chen, W and Yan, Z and Wu, W and Zaleta-Rivera, K and Hu, R and Yu, M and Wang, Y and Li, W and Ma, J and Ren, B and Zhong, S},
title = {Genome-wide analysis of the interplay between chromatin-associated RNA and 3D genome organization in human cells.},
journal = {Nature communications},
volume = {14},
number = {1},
pages = {6519},
pmid = {37845234},
issn = {2041-1723},
support = {DP1DK126138//U.S. Department of Health &amp; Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes &amp; Digestive &amp; Kidney Diseases)/ ; U54DK107977//U.S. Department of Health &amp; Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes &amp; Digestive &amp; Kidney Diseases)/ ; R01GM138852//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01GM136922//U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; R01HD107206//U.S. Department of Health &amp; Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)/ ; DP1HD087990//U.S. Department of Health &amp; Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)/ ; U01CA200147//U.S. Department of Health &amp; Human Services | NIH | National Cancer Institute (NCI)/ ; UM1HG011593//U.S. Department of Health &amp; Human Services | NIH | National Human Genome Research Institute (NHGRI)/ ; UM1HG011585//U.S. Department of Health &amp; Human Services | NIH | National Human Genome Research Institute (NHGRI)/ ; U01HL156059//U.S. Department of Health &amp; Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; },
abstract = {The interphase genome is dynamically organized in the nucleus and decorated with chromatin-associated RNA (caRNA). It remains unclear whether the genome architecture modulates the spatial distribution of caRNA and vice versa. Here, we generate a resource of genome-wide RNA-DNA and DNA-DNA contact maps in human cells. These maps reveal the chromosomal domains demarcated by locally transcribed RNA, hereafter termed RNA-defined chromosomal domains. Further, the spreading of caRNA is constrained by the boundaries of topologically associating domains (TADs), demonstrating the role of the 3D genome structure in modulating the spatial distribution of RNA. Conversely, stopping transcription or acute depletion of RNA induces thousands of chromatin loops genome-wide. Activation or suppression of the transcription of specific genes suppresses or creates chromatin loops straddling these genes. Deletion of a specific caRNA-producing genomic sequence promotes chromatin loops that straddle the interchromosomal target sequences of this caRNA. These data suggest a feedback loop where the 3D genome modulates the spatial distribution of RNA, which in turn affects the dynamic 3D genome organization.},
}
@article {pmid37811140,
year = {2023},
author = {Bonaglia, MC and Salvo, E and Sironi, M and Bertuzzo, S and Errichiello, E and Mattina, T and Zuffardi, O},
title = {Case Report: Decrypting an interchromosomal insertion associated with Marfan's syndrome: how optical genome mapping emphasizes the morbid burden of copy-neutral variants.},
journal = {Frontiers in genetics},
volume = {14},
number = {},
pages = {1244983},
pmid = {37811140},
issn = {1664-8021},
abstract = {Optical genome mapping (OGM), which allows analysis of ultra-high molecular weight (UHMW) DNA molecules, represents a response to the restriction created by short-read next-generation-sequencing, even in cases where the causative variant is a neutral copy-number-variant insensitive to quantitative investigations. This study aimed to provide a molecular diagnosis to a boy with Marfan syndrome (MFS) and intellectual disability (ID) carrying a de novo translocation involving chromosomes 3, 4, and 13 and a 1.7 Mb deletion at the breakpoint of chromosome 3. No FBN1 alteration explaining his Marfan phenotype was highlighted. UHMW gDNA was isolated from both the patient and his parents and processed using OGM. Genome assembly was followed by variant calling and annotation. Multiple strategies confirmed the results. The 3p deletion, which disrupted ROBO2, (MIM*602431) included three copy-neutral insertions. Two came from chromosome 13; the third contained 15q21.1, including the FBN1 from intron-45 onwards, thus explaining the MFS phenotype. We could not attribute the ID to a specific gene variant nor to the reshuffling of topologically associating domains (TADs). Our patient did not have vesicular reflux-2, as reported by missense alterations of ROBO2 (VUR2, MIM#610878), implying that reduced expression of all or some isoforms has a different effect than some of the point mutations. Indeed, the ROBO2 expression pattern and its role as an axon-guide suggests that its partial deletion is responsible for the patient's neurological phenotype. Conclusion: OGM testing 1) highlights copy-neutral variants that could remain invisible if no loss of heterozygosity is observed and 2) is mandatory before other molecular studies in the presence of any chromosomal rearrangement for an accurate genotype-phenotype relationship.},
}
@article {pmid37790381,
year = {2023},
author = {Hristov, BH and Noble, WS and Bertero, A},
title = {Systematic identification of inter-chromosomal interaction networks supports the existence of RNA factories.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2023.09.21.558852},
pmid = {37790381},
abstract = {Most studies of genome organization have focused on intra-chromosomal (cis) contacts because they harbor key features such as DNA loops and topologically associating domains. Inter-chromosomal (trans) contacts have received much less attention, and tools for interrogating potential biologically relevant trans structures are lacking. Here, we develop a computational framework to identify sets of loci that jointly interact in trans from Hi-C data. This method, trans-C, initiates probabilistic random walks with restarts from a set of seed loci to traverse an input Hi-C contact network, thereby identifying sets of trans -contacting loci. We validate trans-C in three increasingly complex models of established trans contacts: the Plasmodium falciparum var genes, the mouse olfactory receptor "Greek islands", and the human RBM20 cardiac splicing factory. We then apply trans-C to systematically test the hypothesis that genes co-regulated by the same trans -acting element (i.e., a transcription or splicing factor) co-localize in three dimensions to form "RNA factories" that maximize the efficiency and accuracy of RNA biogenesis. We find that many loci with multiple binding sites of the same transcription factor interact with one another in trans , especially those bound by transcription factors with intrinsically disordered domains. Similarly, clustered binding of a subset of RNA binding proteins correlates with trans interaction of the encoding loci. These findings support the existence of trans interacting chromatin domains (TIDs) driven by RNA biogenesis. Trans-C provides an efficient computational framework for studying these and other types of trans interactions, empowering studies of a poorly understood aspect of genome architecture.},
}
@article {pmid37787451,
year = {2023},
author = {Parodi, L and Comeau, ME and Georgakis, MK and Mayerhofer, E and Chung, J and Falcone, GJ and Malik, R and Demel, SL and Worrall, BB and Koch, S and Testai, FD and Kittner, SJ and McCauley, JL and Hall, CE and Mayson, DJ and Elkind, MS and James, ML and Woo, D and Rosand, J and Langefeld, CD and Anderson, CD},
title = {Deep resequencing of the 1q22 locus in non-lobar intracerebral hemorrhage.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.26814},
pmid = {37787451},
issn = {1531-8249},
abstract = {OBJECTIVE: Genome-wide association studies have identified 1q22 as a susceptibility locus for cerebral small vessel diseases (CSVDs), including non-lobar intracerebral hemorrhage (ICH) and lacunar stroke. In the present study we performed targeted high-depth sequencing of 1q22 in ICH cases and controls to further characterize this locus and prioritize potential causal mechanisms, which remain unknown.<br><br>METHODS: 95,000 base pairs spanning 1q22, including SEMA4A, SLC25A44 and PMF1/PMF1-BGLAP were sequenced in 1,055 spontaneous ICH cases (534 lobar and 521 non-lobar) and 1,078 controls. Firth regression and RIFT analysis were used to analyze common and rare variants, respectively. Chromatin interaction analyses were performed using Hi-C, ChIP-Seq and ChIA-PET databases. Multivariable Mendelian randomization (MVMR) assessed whether alterations in gene-specific expression relative to regionally co-expressed genes at 1q22 could be causally related to ICH risk.<br><br>RESULTS: Common and rare variant analyses prioritized variants in SEMA4A 5'-UTR and PMF1 intronic regions, overlapping with active promoter and enhancer regions based on ENCODE annotation. Hi-C data analysis determined that 1q22 is spatially organized in a single chromatin loop and that the genes therein belong to the same Topologically Associating Domain. ChIP-Seq and ChIA-PET data analysis highlighted the presence of long-range interactions between the SEMA4A-promoter and PMF1-enhancer regions prioritized by association testing. MVMR analyses demonstrated that PMF1 overexpression could be causally related to non-lobar ICH risk.<br><br>INTERPRETATION: Altered promoter-enhancer interactions leading to PMF1 overexpression, potentially dysregulating polyamine catabolism, could explain demonstrated associations with non-lobar ICH risk at 1q22, offering a potential new target for prevention of ICH and CSVD. This article is protected by copyright. All rights reserved.},
}
@article {pmid37774974,
year = {2023},
author = {Kaur, P and Lu, X and Xu, Q and Irvin, EM and Pappas, C and Zhang, H and Finkelstein, IJ and Shi, Z and Tao, YJ and Yu, H and Wang, H},
title = {High-speed AFM imaging reveals DNA capture and loop extrusion dynamics by cohesin-NIPBL.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {105296},
doi = {10.1016/j.jbc.2023.105296},
pmid = {37774974},
issn = {1083-351X},
abstract = {3D chromatin organization plays a critical role in regulating gene expression, DNA replication, recombination, and repair. While initially discovered for its role in sister chromatid cohesion, emerging evidence suggests that the cohesin complex (SMC1, SMC3, RAD21, and SA1/SA2), facilitated by NIPBL, mediates topologically associating domains (TADs) and chromatin loops through DNA loop extrusion. However, information on how conformational changes of cohesin-NIPBL drive its loading onto DNA, initiation, and growth of DNA loops is still lacking. In this study, high-speed atomic force microscopy (HS-AFM) imaging reveals that cohesin-NIPBL captures DNA through arm extension, assisted by feet (shorter protrusions), and followed by transfer of DNA to its lower compartment (SMC heads, RAD21, SA1 and NIPBL). While binding at the lower compartment, arm extension leads to the capture of a second DNA segment and the initiation of a DNA loop that is independent of ATP hydrolysis. The feet are likely contributed by the C-terminal domains of SA1 and NIPBL and can transiently bind to DNA to facilitate the loading of the cohesin complex onto DNA. Furthermore, HS-AFM imaging reveals distinct forward and reverse DNA loop extrusion steps by cohesin-NIPBL. These results advance our understanding of cohesin by establishing direct experimental evidence for a multi-step DNA binding mechanism mediated by dynamic protein conformational changes.},
}
@article {pmid37762117,
year = {2023},
author = {Yang, J and Zhu, X and Wang, R and Li, M and Tang, Q},
title = {Revisiting Assessment of Computational Methods for Hi-C Data Analysis.},
journal = {International journal of molecular sciences},
volume = {24},
number = {18},
pages = {},
doi = {10.3390/ijms241813814},
pmid = {37762117},
issn = {1422-0067},
support = {2021ZDZX0008//Qianzi Tang/ ; },
abstract = {The performances of algorithms for Hi-C data preprocessing, the identification of topologically associating domains, and the detection of chromatin interactions and promoter-enhancer interactions have been mostly evaluated using semi-quantitative or synthetic data approaches, without utilizing the most recent methods, since 2017. In this study, we comprehensively evaluated 24 popular state-of-the-art methods for the complete end-to-end pipeline of Hi-C data analysis, using manually curated or experimentally validated benchmark datasets, including a CRISPR dataset for promoter-enhancer interaction validation. Our results indicate that, although no single method exhibited superior performance in all situations, HiC-Pro, DomainCaller, and Fit-Hi-C2 showed relatively balanced performances of most evaluation metrics for preprocessing, topologically associating domain identification, and chromatin interaction/promoter-enhancer interaction detection, respectively. The comprehensive comparison presented in this manuscript provides a reference for researchers to choose Hi-C analysis tools that best suit their needs.},
}
@article {pmid37726281,
year = {2023},
author = {Nakato, R and Sakata, T and Wang, J and Nagai, LAE and Nagaoka, Y and Oba, GM and Bando, M and Shirahige, K},
title = {Context-dependent perturbations in chromatin folding and the transcriptome by cohesin and related factors.},
journal = {Nature communications},
volume = {14},
number = {1},
pages = {5647},
pmid = {37726281},
issn = {2041-1723},
support = {JP23gm6310012h0004//Japan Agency for Medical Research and Development (AMED)/ ; JPMJCR18S5//MEXT | Japan Science and Technology Agency (JST)/ ; },
abstract = {Cohesin regulates gene expression through context-specific chromatin folding mechanisms such as enhancer-promoter looping and topologically associating domain (TAD) formation by cooperating with factors such as cohesin loaders and the insulation factor CTCF. We developed a computational workflow to explore how three-dimensional (3D) structure and gene expression are regulated collectively or individually by cohesin and related factors. The main component is CustardPy, by which multi-omics datasets are compared systematically. To validate our methodology, we generated 3D genome, transcriptome, and epigenome data before and after depletion of cohesin and related factors and compared the effects of depletion. We observed diverse effects on the 3D genome and transcriptome, and gene expression changes were correlated with the splitting of TADs caused by cohesin loss. We also observed variations in long-range interactions across TADs, which correlated with their epigenomic states. These computational tools and datasets will be valuable for 3D genome and epigenome studies.},
}
@article {pmid37725346,
year = {2023},
author = {He, X and Huang, X and Long, Y and Liu, Z and Chang, X and Zhang, X and Wang, M},
title = {Tcbf: A novel user-friendly tool for pan-3D genome analysis of topologically associating domain in eukaryotic organisms.},
journal = {Bioinformatics (Oxford, England)},
volume = {},
number = {},
pages = {},
doi = {10.1093/bioinformatics/btad576},
pmid = {37725346},
issn = {1367-4811},
abstract = {SUMMARY: TAD boundaries are essential for organizing the chromatin spatial structure and regulating gene expression in eukaryotes. However, for large-scale pan-3D genome research, identifying conserved and specific TAD boundaries across different species or individuals is computationally challenging. Here, we present Tcbf, a rapid and powerful Python/R tool that integrates gene synteny blocks and homologous sequences to automatically detect conserved and specific TAD boundaries among multiple species, which can efficiently analyze huge genome datasets, greatly reduce the computational burden and enable pan-3D genome research.<br><br>Tcbf is implemented by Python/R and is available at https://github.com/TcbfGroup/Tcbf under the MIT license.<br><br>SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},
}
@article {pmid37705115,
year = {2023},
author = {Oprescu, SN and Baumann, N and Chen, X and Sun, Q and Zhao, Y and Yue, F and Wang, H and Kuang, S},
title = {Sox11 is enriched in myogenic progenitors but dispensable for development and regeneration of the skeletal muscle.},
journal = {Skeletal muscle},
volume = {13},
number = {1},
pages = {15},
pmid = {37705115},
issn = {2044-5040},
support = {F31AR077424/NH/NIH HHS/United States ; R01AR078695/NH/NIH HHS/United States ; },
abstract = {Transcription factors (TFs) play key roles in regulating differentiation and function of stem cells, including muscle satellite cells (MuSCs), a resident stem cell population responsible for postnatal regeneration of the skeletal muscle. Sox11 belongs to the Sry-related HMG-box (SOX) family of TFs that play diverse roles in stem cell behavior and tissue specification. Analysis of single-cell RNA-sequencing (scRNA-seq) datasets identify a specific enrichment of Sox11 mRNA in differentiating but not quiescent MuSCs. Consistent with the scRNA-seq data, Sox11 levels increase during differentiation of murine primary myoblasts in vitro. scRNA-seq data comparing muscle regeneration in young and old mice further demonstrate that Sox11 expression is reduced in aged MuSCs. Age-related decline of Sox11 expression is associated with reduced chromatin contacts within the topologically associating domains. Unexpectedly, Myod1[Cre]-driven deletion of Sox11 in embryonic myoblasts has no effects on muscle development and growth, resulting in apparently healthy muscles that regenerate normally. Pax7[CreER]- or Rosa26[CreER]- driven (MuSC-specific or global) deletion of Sox11 in adult mice similarly has no effects on MuSC differentiation or muscle regeneration. These results identify Sox11 as a novel myogenic differentiation marker with reduced expression in quiescent and aged MuSCs, but the specific function of Sox11 in myogenesis remains to be elucidated.},
}
@article {pmid37699887,
year = {2023},
author = {Chang, LH and Ghosh, S and Papale, A and Luppino, JM and Miranda, M and Piras, V and Degrouard, J and Edouard, J and Poncelet, M and Lecouvreur, N and Bloyer, S and Leforestier, A and Joyce, EF and Holcman, D and Noordermeer, D},
title = {Multi-feature clustering of CTCF binding creates robustness for loop extrusion blocking and Topologically Associating Domain boundaries.},
journal = {Nature communications},
volume = {14},
number = {1},
pages = {5615},
pmid = {37699887},
issn = {2041-1723},
support = {SPF201909009328//Fondation pour la Recherche M&#xe9;dicale (Foundation for Medical Research in France)/ ; SPF201909009284//Fondation pour la Recherche M&#xe9;dicale (Foundation for Medical Research in France)/ ; },
abstract = {Topologically Associating Domains (TADs) separate vertebrate genomes into insulated regulatory neighborhoods that focus genome-associated processes. TADs are formed by Cohesin-mediated loop extrusion, with many TAD boundaries consisting of clustered binding sites of the CTCF insulator protein. Here we determine how this clustering of CTCF binding contributes to the blocking of loop extrusion and the insulation between TADs. We identify enrichment of three features of CTCF binding at strong TAD boundaries, consisting of strongly bound and closely spaced CTCF binding peaks, with a further enrichment of DNA-binding motifs within these peaks. Using multi-contact Nano-C analysis in cells with normal and perturbed CTCF binding, we establish that individual CTCF binding sites contribute to the blocking of loop extrusion, but in an incomplete manner. When clustered, individual CTCF binding sites thus create a stepwise insulation between neighboring TADs. Based on these results, we propose a model whereby multiple instances of temporal loop extrusion blocking create strong insulation between TADs.},
}
@article {pmid37608075,
year = {2023},
author = {Chen, Y and Zhou, T and Liao, Z and Gao, W and Wu, J and Zhang, S and Li, Y and Liu, H and Zhou, H and Xu, C and Su, P},
title = {Hnrnpk is essential for embryonic limb bud development as a transcription activator and a collaborator of insulator protein Ctcf.},
journal = {Cell death and differentiation},
volume = {},
number = {},
pages = {},
pmid = {37608075},
issn = {1476-5403},
support = {92068105//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82172376//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82102518//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82072385//National Natural Science Foundation of China (National Science Foundation of China)/ ; 2021M693630//China Postdoctoral Science Foundation/ ; },
abstract = {Proper development of the limb bud relies on the concordance of various signals, but its molecular mechanisms have not yet been fully illustrated. Here we report that heterogeneous nuclear ribonucleoprotein K (hnRNPK) is essential for limb bud development. Its ablation in the limb bud results in limbless forelimbs and severe deformities of the hindlimbs. In terms of mechanism, hnRNPK functions as a transcription activator for the vital genes involved in the three regulatory axes of limb bud development. Simultaneously, for the first time we elucidate that hnRNPK binds to and coordinates with the insulator protein CCCTC binding factor (CTCF) to maintain a three-dimensional chromatin architecture. Ablation of hnRNPK weakens the binding strength of CTCF to topologically associating domain (TAD) boundaries, then leading to the loose TADs, and decreased interactions between promoters and enhancers, and further decreased transcription of developmental genes. Our study establishes a fundamental and novel role of hnRNPK in regulating limb bud development.},
}
@article {pmid37603403,
year = {2023},
author = {Agarwal, A and Korsak, S and Choudhury, A and Plewczynski, D},
title = {The dynamic role of cohesin in maintaining human genome architecture.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {},
number = {},
pages = {e2200240},
doi = {10.1002/bies.202200240},
pmid = {37603403},
issn = {1521-1878},
abstract = {Recent advances in genomic and imaging techniques have revealed the complex manner of organizing billions of base pairs of DNA necessary for maintaining their functionality and ensuring the proper expression of genetic information. The SMC proteins and cohesin complex primarily contribute to forming higher-order chromatin structures, such as chromosomal territories, compartments, topologically associating domains (TADs) and chromatin loops anchored by CCCTC-binding factor (CTCF) protein or other genome organizers. Cohesin plays a fundamental role in chromatin organization, gene expression and regulation. This review aims to describe the current understanding of the dynamic nature of the cohesin-DNA complex and its dependence on cohesin for genome maintenance. We discuss the current 3C technique and numerous bioinformatics pipelines used to comprehend structural genomics and epigenetics focusing on the analysis of Cohesin-centred interactions. We also incorporate our present comprehension of Loop Extrusion (LE) and insights from stochastic modelling.},
}
@article {pmid37592325,
year = {2023},
author = {Yan, T and Wang, K and Feng, K and Gao, X and Jin, Y and Wu, H and Zhang, W and Wei, L},
title = {Remodeling of the 3D chromatin architecture in the marine microalga Nannochloropsis oceanica during lipid accumulation.},
journal = {Biotechnology for biofuels and bioproducts},
volume = {16},
number = {1},
pages = {129},
pmid = {37592325},
issn = {2731-3654},
abstract = {BACKGROUND: Genomic three-dimensional (3D) spatial organization plays a key role in shaping gene expression and associated chromatin modification, and it is highly sensitive to environmental stress conditions. In microalgae, exposure to nitrogen stress can drive lipid accumulation, yet the associated functional alterations in the spatial organization of the microalgal genome have yet to be effectively characterized.<br><br>RESULTS: Accordingly, the present study employed RNA-seq, Hi-C, and ChIP-seq approaches to explore the relationship between 3D chromosomal architecture and gene expression during lipid accumulation in the marine microalga Nannochloropsis oceanica in response to nitrogen deprivation (ND). These analyses revealed that ND resulted in various changes in chromosomal organization, including A/B compartment transitions, topologically associating domain (TAD) shifts, and the disruption of short-range interactions. Significantly higher levels of gene expression were evident in A compartments and TAD boundary regions relative to B compartments and TAD interior regions, consistent with observed histone modification enrichment in these areas. ND-induced differentially expressed genes (DEGs) were notably enriched in altered TAD-associated regions and regions exhibiting differential genomic contact. These DEGs were subjected to Gene Ontology (GO) term analyses that indicated they were enriched in the 'fatty acid metabolism', 'response to stress', 'carbon fixation' and 'photosynthesis' functional categories, in line with the ND treatment conditions used to conduct this study. These data indicate that Nannochloropsis cells exhibit a clear association between chromatin organization and transcriptional activity under nitrogen stress conditions. Pronounced and extensive histone modifications were evident in response to ND. Observed changes in chromatin architecture were linked to shifts in histone modifications and gene expression.<br><br>CONCLUSIONS: Overall, the reprogramming of many lipid metabolism-associated genes was evident under nitrogen stress conditions with respect to both histone modifications and chromosomal organization. Together these results revealed that higher-order chromatin architecture represents a new layer that can guide efforts to understand the transcriptional regulation of lipid metabolism in nitrogen-deprived microalgae.},
}
@article {pmid37576549,
year = {2023},
author = {Tav, C and Fournier, &#xc9; and Fournier, M and Khadangi, F and Baguette, A and Côté, MC and Silveira, MAD and Bérubé-Simard, FA and Bourque, G and Droit, A and Bilodeau, S},
title = {Glucocorticoid stimulation induces regionalized gene responses within topologically associating domains.},
journal = {Frontiers in genetics},
volume = {14},
number = {},
pages = {1237092},
pmid = {37576549},
issn = {1664-8021},
abstract = {Transcription-factor binding to cis-regulatory regions regulates the gene expression program of a cell, but occupancy is often a poor predictor of the gene response. Here, we show that glucocorticoid stimulation led to the reorganization of transcriptional coregulators MED1 and BRD4 within topologically associating domains (TADs), resulting in active or repressive gene environments. Indeed, we observed a bias toward the activation or repression of a TAD when their activities were defined by the number of regions gaining and losing MED1 and BRD4 following dexamethasone (Dex) stimulation. Variations in Dex-responsive genes at the RNA levels were consistent with the redistribution of MED1 and BRD4 at the associated cis-regulatory regions. Interestingly, Dex-responsive genes without the differential recruitment of MED1 and BRD4 or binding by the glucocorticoid receptor were found within TADs, which gained or lost MED1 and BRD4, suggesting a role of the surrounding environment in gene regulation. However, the amplitude of the response of Dex-regulated genes was higher when the differential recruitment of the glucocorticoid receptor and transcriptional coregulators was observed, reaffirming the role of transcription factor-driven gene regulation and attributing a lesser role to the TAD environment. These results support a model where a signal-induced transcription factor induces a regionalized effect throughout the TAD, redefining the notion of direct and indirect effects of transcription factors on target genes.},
}
@article {pmid37559123,
year = {2023},
author = {Lyu, J and Chen, C},
title = {LAST-seq: single-cell RNA sequencing by direct amplification of single-stranded RNA without prior reverse transcription and second-strand synthesis.},
journal = {Genome biology},
volume = {24},
number = {1},
pages = {184},
pmid = {37559123},
issn = {1474-760X},
abstract = {Existing single-cell RNA sequencing (scRNA-seq) methods rely on reverse transcription (RT) and second-strand synthesis (SSS) to convert single-stranded RNA into double-stranded DNA prior to amplification, with the limited RT/SSS efficiency compromising RNA detectability. Here, we develop a new scRNA-seq method, Linearly Amplified Single-stranded-RNA-derived Transcriptome sequencing (LAST-seq), which directly amplifies the original single-stranded RNA molecules without prior RT/SSS. LAST-seq offers a high single-molecule capture efficiency and a low level of technical noise for single-cell transcriptome analyses. Using LAST-seq, we characterize transcriptional bursting kinetics in human cells, revealing a role of topologically associating domains in transcription regulation.},
}
@article {pmid37550699,
year = {2023},
author = {Deng, L and Zhou, Q and Zhou, J and Zhang, Q and Jia, Z and Zhu, G and Cheng, S and Cheng, L and Yin, C and Yang, C and Shen, J and Nie, J and Zhu, JK and Li, G and Zhao, L},
title = {3D organization of regulatory elements for transcriptional regulation in Arabidopsis.},
journal = {Genome biology},
volume = {24},
number = {1},
pages = {181},
pmid = {37550699},
issn = {1474-760X},
support = {32222063//National Natural Science Foundation of China/ ; 32188102//National Natural Science Foundation of China/ ; 31930032//National Natural Science Foundation of China/ ; 2662021PY005//Fundamental Research Funds for the Central Universities/ ; },
abstract = {BACKGROUND: Although spatial organization of compartments and topologically associating domains at large scale is relatively well studied, the spatial organization of regulatory elements at fine scale is poorly understood in plants.<br><br>RESULTS: Here we perform high-resolution chromatin interaction analysis using paired-end tag sequencing approach. We map chromatin interactions tethered with RNA polymerase II and associated with heterochromatic, transcriptionally active, and Polycomb-repressive histone modifications in Arabidopsis. Analysis of the regulatory repertoire shows that distal active cis-regulatory elements are linked to their target genes through long-range chromatin interactions with increased expression of the target genes, while poised cis-regulatory elements are linked to their target genes through long-range chromatin interactions with depressed expression of the target genes. Furthermore, we demonstrate that transcription factor MYC2 is critical for chromatin spatial organization, and propose that MYC2 occupancy and MYC2-mediated chromatin interactions coordinately facilitate transcription within the framework of 3D chromatin architecture. Analysis of functionally related gene-defined chromatin connectivity networks reveals that genes implicated in flowering-time control are functionally compartmentalized into separate subdomains via their spatial activity in the leaf or shoot apical meristem, linking active mark- or Polycomb-repressive mark-associated chromatin conformation to coordinated gene expression.<br><br>CONCLUSION: The results reveal that the regulation of gene transcription in Arabidopsis is not only by linear juxtaposition, but also by long-range chromatin interactions. Our study uncovers the fine scale genome organization of Arabidopsis and the potential roles of such organization in orchestrating transcription and development.},
}
@article {pmid37536338,
year = {2023},
author = {Mohana, G and Dorier, J and Li, X and Mouginot, M and Smith, RC and Malek, H and Leleu, M and Rodriguez, D and Khadka, J and Rosa, P and Cousin, P and Iseli, C and Restrepo, S and Guex, N and McCabe, BD and Jankowski, A and Levine, MS and Gambetta, MC},
title = {Chromosome-level organization of the regulatory genome in the Drosophila nervous system.},
journal = {Cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cell.2023.07.008},
pmid = {37536338},
issn = {1097-4172},
abstract = {Previous studies have identified topologically associating domains (TADs) as basic units of genome organization. We present evidence of a previously unreported level of genome folding, where distant TAD pairs, megabases apart, interact to form meta-domains. Within meta-domains, gene promoters and structural intergenic elements present in distant TADs are specifically paired. The associated genes encode neuronal determinants, including those engaged in axonal guidance and adhesion. These long-range associations occur in a large fraction of neurons but support transcription in only a subset of neurons. Meta-domains are formed by diverse transcription factors that are able to pair over long and flexible distances. We present evidence that two such factors, GAF and CTCF, play direct roles in this process. The relative simplicity of higher-order meta-domain interactions in Drosophila, compared with those previously described in mammals, allowed the demonstration that genomes can fold into highly specialized cell-type-specific scaffolds that enable megabase-scale regulatory associations.},
}
@article {pmid37537310,
year = {2023},
author = {Tettey, TT and Rinaldi, L and Hager, GL},
title = {Long-range gene regulation in hormone-dependent cancer.},
journal = {Nature reviews. Cancer},
volume = {},
number = {},
pages = {},
pmid = {37537310},
issn = {1474-1768},
abstract = {The human genome is organized into multiple structural layers, ranging from chromosome territories to progressively smaller substructures, such as topologically associating domains (TADs) and chromatin loops. These substructures, collectively referred to as long-range chromatin interactions (LRIs), have a significant role in regulating gene expression. TADs are regions of the genome that harbour groups of genes and regulatory elements that frequently interact with each other and are insulated from other regions, thereby preventing widespread uncontrolled DNA contacts. Chromatin loops formed within TADs through enhancer and promoter interactions are elastic, allowing transcriptional heterogeneity and stochasticity. Over the past decade, it has become evident that the 3D genome structure, also referred to as the chromatin architecture, is central to many transcriptional cellular decisions. In this Review, we delve into the intricate relationship between steroid receptors and LRIs, discussing how steroid receptors interact with and modulate these chromatin interactions. Genetic alterations in the many processes involved in organizing the nuclear architecture are often associated with the development of hormone-dependent cancers. A better understanding of the interplay between architectural proteins and hormone regulatory networks can ultimately be exploited to develop improved approaches for cancer treatment.},
}
@article {pmid37516964,
year = {2023},
author = {Oka, M and Otani, M and Miyamoto, Y and Oshima, R and Adachi, J and Tomonaga, T and Asally, M and Nagaoka, Y and Tanaka, K and Toyoda, A and Ichikawa, K and Morishita, S and Isono, K and Koseki, H and Nakato, R and Ohkawa, Y and Yoneda, Y},
title = {Phase-separated nuclear bodies of nucleoporin fusions promote condensation of MLL1/CRM1 and rearrangement of 3D genome structure.},
journal = {Cell reports},
volume = {42},
number = {8},
pages = {112884},
doi = {10.1016/j.celrep.2023.112884},
pmid = {37516964},
issn = {2211-1247},
abstract = {NUP98 and NUP214 form chimeric fusion proteins that assemble into phase-separated nuclear bodies containing CRM1, a nuclear export receptor. However, these nuclear bodies' function in controlling gene expression remains elusive. Here, we demonstrate that the nuclear bodies of NUP98::HOXA9 and SET::NUP214 promote the condensation of mixed lineage leukemia 1 (MLL1), a histone methyltransferase essential for the maintenance of HOX gene expression. These nuclear bodies are robustly associated with MLL1/CRM1 and co-localized on chromatin. Furthermore, whole-genome chromatin-conformation capture analysis reveals that NUP98::HOXA9 induces a drastic alteration in high-order genome structure at target regions concomitant with the generation of chromatin loops and/or rearrangement of topologically associating domains in a phase-separation-dependent manner. Collectively, these results show that the phase-separated nuclear bodies of nucleoporin fusion proteins can enhance the activation of target genes by promoting the condensation of MLL1/CRM1 and rearrangement of the 3D genome structure.},
}
@article {pmid37498561,
year = {2023},
author = {Wang, Y and Guo, Z and Cheng, J},
title = {Single-cell Hi-C data Enhancement with Deep Residual and Generative Adversarial Networks.},
journal = {Bioinformatics (Oxford, England)},
volume = {},
number = {},
pages = {},
doi = {10.1093/bioinformatics/btad458},
pmid = {37498561},
issn = {1367-4811},
abstract = {MOTIVATION: The spatial genome organization of a eukaryotic cell is important for its function. The development of single-cell technologies for probing the three-dimensional (3D) genome conformation, especially single-cell chromosome conformation capture techniques (ScHi-C), has enabled us to understand genome function better than before. However, due to extreme sparsity and high noise associated with single-cell Hi-C data, it is still difficult to study genome structure and function using the HiC-data of one single cell.<br><br>RESULTS: In this work, we developed a deep learning method ScHiCEDRN based on deep residual networks and generative adversarial networks for the imputation and enhancement of Hi-C data of a single cell. In terms of both image evaluation and Hi-C reproducibility metrics, ScHiCEDRN outperforms the four deep learning methods (DeepHiC, HiCPlus, HiCSR, and Loopenhance) on enhancing the raw single-cell Hi-C data of human and Drosophila. The experiments also show that it can generate single-cell Hi-C data more suitable for identifying topologically associating domain (TAD) boundaries and reconstructing 3D chromosome structures than the existing methods. Moreover, ScHiCEDRN's performance generalizes well across different single cells and cell types, and it can be applied to improving population Hi-C data.<br><br>AVAILABILITY: The source code of ScHiCEDRN is available at the GitHub repository: https://github.com/BioinfoMachineLearning/ScHiCEDRN.<br><br>SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},
}
@article {pmid37478379,
year = {2023},
author = {Liu, T and Wang, Z},
title = {HiC4D: forecasting spatiotemporal Hi-C data with residual ConvLSTM.},
journal = {Briefings in bioinformatics},
volume = {},
number = {},
pages = {},
doi = {10.1093/bib/bbad263},
pmid = {37478379},
issn = {1477-4054},
support = {/GM/NIGMS NIH HHS/United States ; R35GM137974/NH/NIH HHS/United States ; },
abstract = {The Hi-C experiments have been extensively used for the studies of genomic structures. In the last few years, spatiotemporal Hi-C has largely contributed to the investigation of genome dynamic reorganization. However, computationally modeling and forecasting spatiotemporal Hi-C data still have not been seen in the literature. We present HiC4D for dealing with the problem of forecasting spatiotemporal Hi-C data. We designed and benchmarked a novel network and named it residual ConvLSTM (ResConvLSTM), which is a combination of residual network and convolutional long short-term memory (ConvLSTM). We evaluated our new ResConvLSTM networks and compared them with the other five methods, including a naïve network (NaiveNet) that we designed as a baseline method and four outstanding video-prediction methods from the literature: ConvLSTM, spatiotemporal LSTM (ST-LSTM), self-attention LSTM (SA-LSTM) and simple video prediction (SimVP). We used eight different spatiotemporal Hi-C datasets for the blind test, including two from mouse embryogenesis, one from somatic cell nuclear transfer (SCNT) embryos, three embryogenesis datasets from different species and two non-embryogenesis datasets. Our evaluation results indicate that our ResConvLSTM networks almost always outperform the other methods on the eight blind-test datasets in terms of accurately predicting the Hi-C contact matrices at future time-steps. Our benchmarks also indicate that all of the methods that we benchmarked can successfully recover the boundaries of topologically associating domains called on the experimental Hi-C contact matrices. Taken together, our benchmarks suggest that HiC4D is an effective tool for predicting spatiotemporal Hi-C data. HiC4D is publicly available at both http://dna.cs.miami.edu/HiC4D/ and https://github.com/zwang-bioinformatics/HiC4D/.},
}
@article {pmid37467757,
year = {2023},
author = {Senapati, S and Irshad, IU and Sharma, AK and Kumar, H},
title = {Fundamental insights into the correlation between chromosome configuration and transcription.},
journal = {Physical biology},
volume = {},
number = {},
pages = {},
doi = {10.1088/1478-3975/ace8e5},
pmid = {37467757},
issn = {1478-3975},
abstract = {Eukaryotic chromosomes exhibit a hierarchical organization that spans a spectrum of length scales, ranging from sub-regions known as loops, which typically comprise hundreds of base pairs, to much larger chromosome territories that can encompass a few mega base pairs. Chromosome conformation capture experiments that involve high-throughput sequencing methods combined with microscopy techniques have enabled a new understanding of inter- and intra-chromosomal interactions with unprecedented details. This information also provides mechanistic insights on the relationship between genome architecture and gene expression. In this article, we review the recent findings on three-dimensional interactions among chromosomes at the compartment, topologically associating domain (TAD), and loop levels and the impact of these interactions on the transcription process. We also discuss current understanding of various biophysical processes involved in multi-layer structural organization of chromosomes. Then, we discuss the relationships between gene expression and genome structure from perturbative genome-wide association studies. Furthermore, for a better understanding of how chromosome architecture and function are linked, we emphasize the role of epigenetic modifications in the regulation of gene expression. Such an understanding of the relationship between genome architecture and gene expression can provide a new perspective on the range of potential future discoveries and therapeutic research. .},
}
@article {pmid37461500,
year = {2023},
author = {Goudarzi, S and Pagadala, M and Klie, A and Talwar, JV and Carter, H},
title = {Epigenetic Germline Variants Predict Cancer Prognosis and Risk and Distribute Uniquely in Topologically Associating Domains.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2023.07.04.547722},
pmid = {37461500},
abstract = {Cancer is a highly heterogeneous disease caused by genetic and epigenetic alterations in normal cells. A recent study uncovered methylation quantitative trait loci (meQTLs) associated with different levels of local DNA methylation in cancers. Here, we investigated whether the distribution of cancer meQTLs reflected functional organization of the genome in the form of chromatin topologically associated domains (TADs), and evaluated whether cancer meQTLs near known driver genes have the potential to influence cancer risk or progression. At TAD boundaries, we observed differences in the distribution of meQTLs when one or both of the adjacent TADs was transcriptionally active, with higher densities near inactive TADs. Furthermore, we found differences in cancer meQTL distributions in active versus inactive TADs and observed an enrichment of meQTLs in active TADs near tumor suppressors, whereas there was a depletion of such meQTLs near oncogenes. Several meQTLs were associated with cancer risk in the UKBioBank, and we were able to reproduce breast cancer risk associations in the DRIVE cohort. Survival analysis in TCGA implicated a number of meQTLs in 13 tumor types. In 10 of these, polygenic meQTL scores were associated with increased hazard in a CoxPH analysis. Risk and survival-associated meQTLs tended to affect cancer genes involved in DNA damage repair and cellular adhesion and reproduced cancer-specific associations reported in prior literature. In summary, this study provides evidence that genetic variants that influence local DNA methylation are affected by chromatin structure and can impact tumor evolution.},
}
@article {pmid37453058,
year = {2023},
author = {Kim, K and Kim, M and Lee, AJ and Song, SH and Kang, JK and Eom, J and Kang, GH and Bae, JM and Min, S and Kim, Y and Lim, Y and Kim, HS and Kim, YJ and Kim, TY and Jung, I},
title = {Spatial and clonality-resolved 3D cancer genome alterations reveal enhancer-hijacking as a potential prognostic marker for colorectal cancer.},
journal = {Cell reports},
volume = {42},
number = {7},
pages = {112778},
doi = {10.1016/j.celrep.2023.112778},
pmid = {37453058},
issn = {2211-1247},
abstract = {The regulatory effect of non-coding large-scale structural variations (SVs) on proto-oncogene activation remains unclear. This study investigated SV-mediated gene dysregulation by profiling 3D cancer genome maps from 40 patients with colorectal cancer (CRC). We developed a machine learning-based method for spatial characterization of the altered 3D cancer genome. This revealed a frequent establishment of "de novo chromatin contacts" that can span multiple topologically associating domains (TADs) in addition to the canonical TAD fusion/shuffle model. Using this information, we precisely identified super-enhancer (SE)-hijacking and its clonal characteristics. Clonal SE-hijacking genes, such as TOP2B, are recurrently associated with cell-cycle/DNA-processing functions, which can potentially be used as CRC prognostic markers. Oncogene activation and increased drug resistance due to SE-hijacking were validated by reconstructing the patient's SV using CRISPR-Cas9. Collectively, the spatial and clonality-resolved analysis of the 3D cancer genome reveals regulatory principles of large-scale SVs in oncogene activation and their clinical implications.},
}
@article {pmid37445616,
year = {2023},
author = {Lee, EG and Leong, L and Chen, S and Tulloch, J and Yu, CE},
title = {APOE Locus-Associated Mitochondrial Function and Its Implication in Alzheimer's Disease and Aging.},
journal = {International journal of molecular sciences},
volume = {24},
number = {13},
pages = {},
doi = {10.3390/ijms241310440},
pmid = {37445616},
issn = {1422-0067},
support = {BX000933 and BX004823//U.S. Department of Veterans Affairs Office of Research and Development Biomedical Laboratory Research Program/ ; },
abstract = {The Apolipoprotein E (APOE) locus has garnered significant clinical interest because of its association with Alzheimer's disease (AD) and longevity. This genetic association appears across multiple genes in the APOE locus. Despite the apparent differences between AD and longevity, both conditions share a commonality of aging-related changes in mitochondrial function. This commonality is likely due to accumulative biological effects partly exerted by the APOE locus. In this study, we investigated changes in mitochondrial structure/function-related markers using oxidative stress-induced human cellular models and postmortem brains (PMBs) from individuals with AD and normal controls. Our results reveal a range of expressional alterations, either upregulated or downregulated, in these genes in response to oxidative stress. In contrast, we consistently observed an upregulation of multiple APOE locus genes in all cellular models and AD PMBs. Additionally, the effects of AD status on mitochondrial DNA copy number (mtDNA CN) varied depending on APOE genotype. Our findings imply a potential coregulation of APOE locus genes possibly occurring within the same topologically associating domain (TAD) of the 3D chromosome conformation. The coordinated expression of APOE locus genes could impact mitochondrial function, contributing to the development of AD or longevity. Our study underscores the significant role of the APOE locus in modulating mitochondrial function and provides valuable insights into the underlying mechanisms of AD and aging, emphasizing the importance of this locus in clinical research.},
}
@article {pmid37438531,
year = {2023},
author = {Park, DS and Nguyen, SC and Isenhart, R and Shah, PP and Kim, W and Barnett, RJ and Chandra, A and Luppino, JM and Harke, J and Wai, M and Walsh, PJ and Abdill, RJ and Yang, R and Lan, Y and Yoon, S and Yunker, R and Kanemaki, MT and Vahedi, G and Phillips-Cremins, JE and Jain, R and Joyce, EF},
title = {High-throughput Oligopaint screen identifies druggable 3D genome regulators.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {37438531},
issn = {1476-4687},
abstract = {The human genome functions as a three-dimensional chromatin polymer, driven by a complex collection of chromosome interactions[1-3]. Although the molecular rules governing these interactions are being quickly elucidated, relatively few proteins regulating this process have been identified. Here, to address this gap, we developed high-throughput DNA or RNA labelling with optimized Oligopaints (HiDRO)-an automated imaging pipeline that enables the quantitative measurement of chromatin interactions in single cells across thousands of samples. By screening the human druggable genome, we identified more than 300 factors that influence genome folding during interphase. Among these, 43 genes were validated as either increasing or decreasing interactions between topologically associating domains. Our findings show that genetic or chemical inhibition of the ubiquitous kinase GSK3A leads to increased long-range chromatin looping interactions in a genome-wide and cohesin-dependent manner. These results demonstrate the importance of GSK3A signalling in nuclear architecture and the use of HiDRO for identifying mechanisms of spatial genome organization.},
}
@article {pmid37433821,
year = {2023},
author = {Kadam, S and Kumari, K and Manivannan, V and Dutta, S and Mitra, MK and Padinhateeri, R},
title = {Predicting scale-dependent chromatin polymer properties from systematic coarse-graining.},
journal = {Nature communications},
volume = {14},
number = {1},
pages = {4108},
pmid = {37433821},
issn = {2041-1723},
support = {BT/HRD/NBA/39/12/2018-19//Department of Biotechnology, Ministry of Science and Technology (DBT)/ ; },
abstract = {Simulating chromatin is crucial for predicting genome organization and dynamics. Although coarse-grained bead-spring polymer models are commonly used to describe chromatin, the relevant bead dimensions, elastic properties, and the nature of inter-bead potentials are unknown. Using nucleosome-resolution contact probability (Micro-C) data, we systematically coarse-grain chromatin and predict quantities essential for polymer representation of chromatin. We compute size distributions of chromatin beads for different coarse-graining scales, quantify fluctuations and distributions of bond lengths between neighboring regions, and derive effective spring constant values. Unlike the prevalent notion, our findings argue that coarse-grained chromatin beads must be considered as soft particles that can overlap, and we derive an effective inter-bead soft potential and quantify an overlap parameter. We also compute angle distributions giving insights into intrinsic folding and local bendability of chromatin. While the nucleosome-linker DNA bond angle naturally emerges from our work, we show two populations of local structural states. The bead sizes, bond lengths, and bond angles show different mean behavior at Topologically Associating Domain (TAD) boundaries and TAD interiors. We integrate our findings into a coarse-grained polymer model and provide quantitative estimates of all model parameters, which can serve as a foundational basis for all future coarse-grained chromatin simulations.},
}
@article {pmid37426677,
year = {2023},
author = {Liu, H and Tsai, H and Yang, M and Li, G and Bian, Q and Ding, G and Wu, D and Dai, J},
title = {Three-dimensional genome structure and function.},
journal = {MedComm},
volume = {4},
number = {4},
pages = {e326},
pmid = {37426677},
issn = {2688-2663},
abstract = {Linear DNA undergoes a series of compression and folding events, forming various three-dimensional (3D) structural units in mammalian cells, including chromosomal territory, compartment, topologically associating domain, and chromatin loop. These structures play crucial roles in regulating gene expression, cell differentiation, and disease progression. Deciphering the principles underlying 3D genome folding and the molecular mechanisms governing cell fate determination remains a challenge. With advancements in high-throughput sequencing and imaging techniques, the hierarchical organization and functional roles of higher-order chromatin structures have been gradually illuminated. This review systematically discussed the structural hierarchy of the 3D genome, the effects and mechanisms of cis-regulatory elements interaction in the 3D genome for regulating spatiotemporally specific gene expression, the roles and mechanisms of dynamic changes in 3D chromatin conformation during embryonic development, and the pathological mechanisms of diseases such as congenital developmental abnormalities and cancer, which are attributed to alterations in 3D genome organization and aberrations in key structural proteins. Finally, prospects were made for the research about 3D genome structure, function, and genetic intervention, and the roles in disease development, prevention, and treatment, which may offer some clues for precise diagnosis and treatment of related diseases.},
}
@article {pmid37418545,
year = {2023},
author = {Onrust-van Schoonhoven, A and de Bruijn, MJW and Stikker, B and Brouwer, RWW and Braunstahl, GJ and van IJcken, WFJ and Graf, T and Huylebroeck, D and Hendriks, RW and Stik, G and Stadhouders, R},
title = {3D chromatin reprogramming primes human memory TH2 cells for rapid recall and pathogenic dysfunction.},
journal = {Science immunology},
volume = {8},
number = {85},
pages = {eadg3917},
doi = {10.1126/sciimmunol.adg3917},
pmid = {37418545},
issn = {2470-9468},
abstract = {Memory T cells provide long-lasting defense responses through their ability to rapidly reactivate, but how they efficiently "recall" an inflammatory transcriptional program remains unclear. Here, we show that human CD4[+] memory T helper 2 (TH2) cells carry a chromatin landscape synergistically reprogrammed at both one-dimensional (1D) and 3D levels to accommodate recall responses, which is absent in naive T cells. In memory TH2 cells, recall genes were epigenetically primed through the maintenance of transcription-permissive chromatin at distal (super)enhancers organized in long-range 3D chromatin hubs. Precise transcriptional control of key recall genes occurred inside dedicated topologically associating domains ("memory TADs"), in which activation-associated promoter-enhancer interactions were preformed and exploited by AP-1 transcription factors to promote rapid transcriptional induction. Resting memory TH2 cells from patients with asthma showed premature activation of primed recall circuits, linking aberrant transcriptional control of recall responses to chronic inflammation. Together, our results implicate stable multiscale reprogramming of chromatin organization as a key mechanism underlying immunological memory and dysfunction in T cells.},
}
@article {pmid37398486,
year = {2023},
author = {Syed, SA and Shqillo, K and Nand, A and Zhan, Y and Dekker, J and Imbalzano, AN},
title = {Protein arginine methyltransferase 5 (Prmt5) localizes to chromatin loop anchors and modulates expression of genes at TAD boundaries during early adipogenesis.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2023.06.13.544859},
pmid = {37398486},
abstract = {Protein arginine methyltransferase 5 (Prmt5) is an essential regulator of embryonic development and adult progenitor cell functions. Prmt5 expression is mis-regulated in many cancers, and the development of Prmt5 inhibitors as cancer therapeutics is an active area of research. Prmt5 functions via effects on gene expression, splicing, DNA repair, and other critical cellular processes. We examined whether Prmt5 functions broadly as a genome-wide regulator of gene transcription and higher-order chromatin interactions during the initial stages of adipogenesis using ChIP-Seq, RNA-seq, and Hi-C using 3T3-L1 cells, a frequently utilized model for adipogenesis. We observed robust genome-wide Prmt5 chromatin-binding at the onset of differentiation. Prmt5 localized to transcriptionally active genomic regions, acting as both a positive and a negative regulator. A subset of Prmt5 binding sites co-localized with mediators of chromatin organization at chromatin loop anchors. Prmt5 knockdown decreased insulation strength at the boundaries of topologically associating domains (TADs) adjacent to sites with Prmt5 and CTCF co-localization. Genes overlapping such weakened TAD boundaries showed transcriptional dysregulation. This study identifies Prmt5 as a broad regulator of gene expression, including regulation of early adipogenic factors, and reveals an unappreciated requirement for Prmt5 in maintaining strong insulation at TAD boundaries and overall chromatin organization.},
}
@article {pmid37387127,
year = {2023},
author = {Zhang, Y and Blanchette, M},
title = {Reference panel-guided super-resolution inference of Hi-C data.},
journal = {Bioinformatics (Oxford, England)},
volume = {39},
number = {Supplement_1},
pages = {i386-i393},
doi = {10.1093/bioinformatics/btad266},
pmid = {37387127},
issn = {1367-4811},
support = {//Genome Quebec/ ; //Canada and Genome Quebec/ ; },
abstract = {MOTIVATION: Accurately assessing contacts between DNA fragments inside the nucleus with Hi-C experiment is crucial for understanding the role of 3D genome organization in gene regulation. This challenging task is due in part to the high sequencing depth of Hi-C libraries required to support high-resolution analyses. Most existing Hi-C data are collected with limited sequencing coverage, leading to poor chromatin interaction frequency estimation. Current computational approaches to enhance Hi-C signals focus on the analysis of individual Hi-C datasets of interest, without taking advantage of the facts that (i) several hundred Hi-C contact maps are publicly available and (ii) the vast majority of local spatial organizations are conserved across multiple cell types.<br><br>RESULTS: Here, we present RefHiC-SR, an attention-based deep learning framework that uses a reference panel of Hi-C datasets to facilitate the enhancement of Hi-C data resolution of a given study sample. We compare RefHiC-SR against tools that do not use reference samples and find that RefHiC-SR outperforms other programs across different cell types, and sequencing depths. It also enables high-accuracy mapping of structures such as loops and topologically associating domains.<br><br>https://github.com/BlanchetteLab/RefHiC.},
}
@article {pmid37386239,
year = {2023},
author = {Pandupuspitasari, NS and Khan, FA and Huang, C and Ali, A and Yousaf, MR and Shakeel, F and Putri, EM and Negara, W and Muktiani, A and Prasetiyono, BWHE and Kustiawan, L and Wahyuni, DS},
title = {Recent advances in chromosome capture techniques unraveling 3D genome architecture in germ cells, health, and disease.},
journal = {Functional &amp; integrative genomics},
volume = {23},
number = {3},
pages = {214},
pmid = {37386239},
issn = {1438-7948},
abstract = {In eukaryotes, the genome does not emerge in a specific shape but rather as a hierarchial bundle within the nucleus. This multifaceted genome organization consists of multiresolution cellular structures, such as chromosome territories, compartments, and topologically associating domains, which are frequently defined by architecture, design proteins including CTCF and cohesin, and chromatin loops. This review briefly discusses the advances in understanding the basic rules of control, chromatin folding, and functional areas in early embryogenesis. With the use of chromosome capture techniques, the latest advancements in technologies for visualizing chromatin interactions come close to revealing 3D genome formation frameworks with incredible detail throughout all genomic levels, including at single-cell resolution. The possibility of detecting variations in chromatin architecture might open up new opportunities for disease diagnosis and prevention, infertility treatments, therapeutic approaches, desired exploration, and many other application scenarios.},
}
@article {pmid37381832,
year = {2023},
author = {Zhang, Y and Cao, X and Gao, Z and Ma, X and Wang, Q and Xu, X and Cai, X and Zhang, Y and Zhang, Z and Wei, G and Wen, B},
title = {MATR3-antisense LINE1 RNA meshwork scaffolds higher-order chromatin organization.},
journal = {EMBO reports},
volume = {},
number = {},
pages = {e57550},
doi = {10.15252/embr.202357550},
pmid = {37381832},
issn = {1469-3178},
support = {2021YFA1100203//MOST | National Key Research and Development Program of China (NKPs)/ ; 32130019//MOST | National Natural Science Foundation of China (NSFC)/ ; },
abstract = {Long interspersed nuclear elements (LINEs) play essential roles in shaping chromatin states, while the factors that cooperate with LINEs and their roles in higher-order chromatin organization remain poorly understood. Here, we show that MATR3, a nuclear matrix protein, interplays with antisense LINE1 (AS L1) RNAs to form a meshwork via phase separation, providing a dynamic platform for chromatin spatial organization. MATR3 and AS L1 RNAs affect the nuclear localization of each other. After MATR3 depletion, the chromatin, particularly H3K27me3-modified chromatin, redistributes in the cell nuclei. Topologically associating domains (TADs) that highly transcribe MATR3-associated AS L1 RNAs show decreased intra-TAD interactions in both AML12 and ES cells. MATR3 depletion increases the accessibility of H3K27me3 domains adjacent to MATR3-associated AS L1, without affecting H3K27me3 modifications. Furthermore, amyotrophic lateral sclerosis (ALS)-associated MATR3 mutants alter biophysical features of the MATR3-AS L1 RNA meshwork and cause an abnormal H3K27me3 staining. Collectively, we reveal a role of the meshwork formed by MATR3 and AS L1 RNAs in gathering chromatin in the nucleus.},
}
@article {pmid37381036,
year = {2023},
author = {Sun, Y and Xu, X and Zhao, W and Zhang, Y and Chen, K and Li, Y and Wang, X and Zhang, M and Xue, B and Yu, W and Hou, Y and Wang, C and Xie, W and Li, C and Kong, D and Wang, S and Sun, Y},
title = {RAD21 is the core subunit of the cohesin complex involved in directing genome organization.},
journal = {Genome biology},
volume = {24},
number = {1},
pages = {155},
pmid = {37381036},
issn = {1474-760X},
support = {21825401//National Natural Science Foundation of China/ ; No. 2022YFA1303103//National Key Research and Development Program of China Stem Cell and Translational Research/ ; },
abstract = {BACKGROUND: The ring-shaped cohesin complex is an important factor for the formation of chromatin loops and topologically associating domains (TADs) by loop extrusion. However, the regulation of association between cohesin and chromatin is poorly understood. In this study, we use super-resolution imaging to reveal the unique role of cohesin subunit RAD21 in cohesin loading and chromatin structure regulation.<br><br>RESULTS: We directly visualize that up-regulation of RAD21 leads to excessive chromatin loop extrusion into a vermicelli-like morphology with RAD21 clustered into foci and excessively loaded cohesin bow-tying a TAD to form a beads-on-a-string-type pattern. In contrast, up-regulation of the other four cohesin subunits results in even distributions. Mechanistically, we identify that the essential role of RAD21 is attributed to the RAD21-loader interaction, which facilitates the cohesin loading process rather than increasing the abundance of cohesin complex upon up-regulation of RAD21. Furthermore, Hi-C and genomic analysis reveal how RAD21 up-regulation affects genome-wide higher-order chromatin structure. Accumulated contacts are shown at TAD corners while inter-TAD interactions increase after vermicelli formation. Importantly, we find that in breast cancer cells, the expression of RAD21 is aberrantly high with poor patient survival and RAD21 forms beads in the nucleus. Up-regulated RAD21 in HeLa cells leads to compartment switching and up-regulation of cancer-related genes.<br><br>CONCLUSIONS: Our results provide key insights into the molecular mechanism by which RAD21 facilitates the cohesin loading process and provide an explanation to how cohesin and loader work cooperatively to promote chromatin extrusion, which has important implications in construction of three-dimensional genome organization.},
}
@article {pmid37325549,
year = {2023},
author = {Wang, M and Sreenivas, P and Sunkel, BD and Wang, L and Ignatius, M and Stanton, BZ},
title = {The 3D chromatin landscape of rhabdomyosarcoma.},
journal = {NAR cancer},
volume = {5},
number = {3},
pages = {zcad028},
pmid = {37325549},
issn = {2632-8674},
abstract = {Rhabdomyosarcoma (RMS) is a pediatric soft tissue cancer with a lack of precision therapy options for patients. We hypothesized that with a general paucity of known mutations in RMS, chromatin structural driving mechanisms are essential for tumor proliferation. Thus, we carried out high-depth in situ Hi-C in representative cell lines and patient-derived xenografts (PDXs) to define chromatin architecture in each major RMS subtype. We report a comprehensive 3D chromatin structural analysis and characterization of fusion-positive (FP-RMS) and fusion-negative RMS (FN-RMS). We have generated spike-in in situ Hi-C chromatin interaction maps for the most common FP-RMS and FN-RMS cell lines and compared our data with PDX models. In our studies, we uncover common and distinct structural elements in large Mb-scale chromatin compartments, tumor-essential genes within variable topologically associating domains and unique patterns of structural variation. Our high-depth chromatin interactivity maps and comprehensive analyses provide context for gene regulatory events and reveal functional chromatin domains in RMS.},
}
@article {pmid37322110,
year = {2023},
author = {Rekaik, H and Lopez-Delisle, L and Hintermann, A and Mascrez, B and Bochaton, C and Mayran, A and Duboule, D},
title = {Sequential and directional insulation by conserved CTCF sites underlies the Hox timer in stembryos.},
journal = {Nature genetics},
volume = {},
number = {},
pages = {},
pmid = {37322110},
issn = {1546-1718},
abstract = {During development, Hox genes are temporally activated according to their relative positions on their clusters, contributing to the proper identities of structures along the rostrocaudal axis. To understand the mechanism underlying this Hox timer, we used mouse embryonic stem cell-derived stembryos. Following Wnt signaling, the process involves transcriptional initiation at the anterior part of the cluster and a concomitant loading of cohesin complexes enriched on the transcribed DNA segments, that is, with an asymmetric distribution favoring the anterior part of the cluster. Chromatin extrusion then occurs with successively more posterior CTCF sites acting as transient insulators, thus generating a progressive time delay in the activation of more posterior-located genes due to long-range contacts with a flanking topologically associating domain. Mutant stembryos support this model and reveal that the presence of evolutionary conserved and regularly spaced intergenic CTCF sites controls the precision and the pace of this temporal mechanism.},
}
@article {pmid37302180,
year = {2023},
author = {da Costa-Nunes, JA and Noordermeer, D},
title = {TADs: Dynamic structures to create stable regulatory functions.},
journal = {Current opinion in structural biology},
volume = {81},
number = {},
pages = {102622},
doi = {10.1016/j.sbi.2023.102622},
pmid = {37302180},
issn = {1879-033X},
abstract = {Mammalian chromosomes are organized at different length scales within the cell nucleus. Topologically Associating Domains (TADs) are structural units of 3D genome organization with functions in gene regulation, DNA replication, recombination and repair. Whereas TADs were initially interpreted as insulated domains, recent studies are revealing that these domains should be interpreted as dynamic collections of actively extruding loops. This process of loop extrusion is subsequently blocked at dedicated TAD boundaries, thereby promoting intra-domain interactions over their surroundings. In this review, we discuss how mammalian TAD structure can emerge from this dynamic process and we discuss recent evidence that TAD boundaries can have regulatory functions.},
}
@article {pmid37292994,
year = {2023},
author = {Xiong, K and Zhang, R and Ma, J},
title = {scGHOST: Identifying single-cell 3D genome subcompartments.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2023.05.24.542032},
pmid = {37292994},
abstract = {New single-cell Hi-C (scHi-C) technologies enable probing of the genome-wide cell-to-cell variability in 3D genome organization from individual cells. Several computational methods have been developed to reveal single-cell 3D genome features based on scHi-C data, including A/B compartments, topologically-associating domains, and chromatin loops. However, no scHi-C analysis method currently exists for annotating single-cell subcompartments, which are crucial for providing a more refined view of large-scale chromosome spatial localization in single cells. Here, we present SCGHOST, a single-cell subcompartment annotation method based on graph embedding with constrained random walk sampling. Applications of SCGHOST to scHi-C data and single-cell 3D genome imaging data demonstrate the reliable identification of single-cell subcompartments and offer new insights into cell-to-cell variability of nuclear subcompartments. Using scHi-C data from the human prefrontal cortex, SCGHOST identifies cell type-specific subcompartments that are strongly connected to cell type-specific gene expression, suggesting the functional implications of single-cell subcompartments. Overall, SCGHOST is an effective new method for single-cell 3D genome subcompartment annotation based on scHi-C data for a broad range of biological contexts.},
}
@article {pmid37279476,
year = {2023},
author = {Peng, X and Li, Y and Zou, M and Kong, X and Sheng, Y},
title = {CATAD: exploring topologically associating domains from an insight of core-attachment structure.},
journal = {Briefings in bioinformatics},
volume = {},
number = {},
pages = {},
doi = {10.1093/bib/bbad204},
pmid = {37279476},
issn = {1477-4054},
abstract = {Identifying topologically associating domains (TADs), which are considered as the basic units of chromosome structure and function, can facilitate the exploration of the 3D-structure of chromosomes. Methods have been proposed to identify TADs by detecting the boundaries of TADs or identifying the closely interacted regions as TADs, while the possible inner structure of TADs is seldom investigated. In this study, we assume that a TAD is composed of a core and its surrounding attachments, and propose a method, named CATAD, to identify TADs based on the core-attachment structure model. In CATAD, the cores of TADs are identified based on the local density and cosine similarity, and the surrounding attachments are determined based on boundary insulation. CATAD was applied to the Hi-C data of two human cell lines and two mouse cell lines, and the results show that the boundaries of TADs identified by CATAD are significantly enriched by structural proteins, histone modifications, transcription start sites and enzymes. Furthermore, CATAD outperforms other methods in many cases, in terms of the average peak, boundary tagged ratio and fold change. In addition, CATAD is robust and rarely affected by the different resolutions of Hi-C matrices. Conclusively, identifying TADs based on the core-attachment structure is useful, which may inspire researchers to explore TADs from the angles of possible spatial structures and formation process.},
}
@article {pmid37277355,
year = {2023},
author = {Kessler, S and Minoux, M and Joshi, O and Ben Zouari, Y and Ducret, S and Ross, F and Vilain, N and Salvi, A and Wolff, J and Kohler, H and Stadler, MB and Rijli, FM},
title = {A multiple super-enhancer region establishes inter-TAD interactions and controls Hoxa function in cranial neural crest.},
journal = {Nature communications},
volume = {14},
number = {1},
pages = {3242},
pmid = {37277355},
issn = {2041-1723},
abstract = {Enhancer-promoter interactions preferentially occur within boundary-insulated topologically associating domains (TADs), limiting inter-TAD interactions. Enhancer clusters in linear proximity, termed super-enhancers (SEs), ensure high target gene expression levels. Little is known about SE topological regulatory impact during craniofacial development. Here, we identify 2232 genome-wide putative SEs in mouse cranial neural crest cells (CNCCs), 147 of which target genes establishing CNCC positional identity during face formation. In second pharyngeal arch (PA2) CNCCs, a multiple SE-containing region, partitioned into Hoxa Inter-TAD Regulatory Element 1 and 2 (HIRE1 and HIRE2), establishes long-range inter-TAD interactions selectively with Hoxa2, that is required for external and middle ear structures. HIRE2 deletion in a Hoxa2 haploinsufficient background results in microtia. HIRE1 deletion phenocopies the full homeotic Hoxa2 knockout phenotype and induces PA3 and PA4 CNCC abnormalities correlating with Hoxa2 and Hoxa3 transcriptional downregulation. Thus, SEs can overcome TAD insulation and regulate anterior Hoxa gene collinear expression in a CNCC subpopulation-specific manner during craniofacial development.},
}
@article {pmid37259205,
year = {2023},
author = {Gu, J and Li, S and Zhu, B and Liang, Q and Chen, B and Tang, X and Chen, C and Wu, DD and Li, Y},
title = {Genetic variation and domestication of horses revealed by 10 chromosome-level genomes and whole-genome resequencing.},
journal = {Molecular ecology resources},
volume = {},
number = {},
pages = {},
doi = {10.1111/1755-0998.13818},
pmid = {37259205},
issn = {1755-0998},
abstract = {Understanding the genetic variations of the horse (Equus caballus) genome will improve breeding conservation and welfare. However, genetic variations in long segments, such as structural variants (SVs), remain understudied. We de novo assembled 10 chromosome-level three-dimensional horse genomes, each representing a distinct breed, and analysed horse SVs using a multi-assembly approach. Our findings suggest that SVs with the accumulation of mammalian-wide interspersed repeats related to long interspersed nuclear elements might be a horse-specific mechanism to modulate genome-wide gene regulatory networks. We found that olfactory receptors were commonly loss and accumulated deleterious mutations, but no purge of deleterious mutations occurred during horse domestication. We examined the potential effects of SVs on the spatial structure of chromatin via topologically associating domains (TADs). Breed-specific TADs were significantly enriched by breed-specific SVs. We identified 4199 unique breakpoint-resolved novel insertions across all chromosomes that account for 2.84 Mb sequences missing from the reference genome. Several novel insertions might have potential functional consequences, as 519 appeared to reside within 449 gene bodies. These genes are primarily involved in pathogen recognition, innate immune responses and drug metabolism. Moreover, 37 diverse horses were resequenced. Combining this with public data, we analysed 97 horses through a comparative population genomics approach to identify the genetic basis underlying breed characteristics using Thoroughbreds as a case study. We provide new scientific evidence for horse domestication, an understanding of the genetic mechanism underlying the phenotypic evolution of horses, and a comprehensive genetic variation resource for further genetic studies of horses.},
}
@article {pmid37254808,
year = {2023},
author = {Li, D and Zhao, XY and Zhou, S and Hu, Q and Wu, F and Lee, HY},
title = {Multidimensional profiling reveals GATA1-modulated stage-specific chromatin states and functional associations during human erythropoiesis.},
journal = {Nucleic acids research},
volume = {},
number = {},
pages = {},
doi = {10.1093/nar/gkad468},
pmid = {37254808},
issn = {1362-4962},
abstract = {Mammalian erythroid development can be divided into three stages: hematopoietic stem and progenitor cell (HSPC), erythroid progenitor (Ery-Pro), and erythroid precursor (Ery-Pre). However, the mechanisms by which the 3D genome changes to establish the stage-specific transcription programs that are critical for erythropoiesis remain unclear. Here, we analyze the chromatin landscape at multiple levels in defined populations from primary human erythroid culture. While compartments and topologically associating domains remain largely unchanged, ∼50% of H3K27Ac-marked enhancers are dynamic in HSPC versus Ery-Pre. The enhancer anchors of enhancer-promoter loops are enriched for occupancy of respective stage-specific transcription factors (TFs), indicating these TFs orchestrate the enhancer connectome rewiring. The master TF of erythropoiesis, GATA1, is found to occupy most erythroid gene promoters at the Ery-Pro stage, and mediate conspicuous local rewiring through acquiring binding at the distal regions in Ery-Pre, promoting productive erythroid transcription output. Knocking out GATA1 binding sites precisely abrogates local rewiring and corresponding gene expression. Interestingly, knocking down GATA1 can transiently revert the cell state to an earlier stage and prolong the window of progenitor state. This study reveals mechanistic insights underlying chromatin rearrangements during development by integrating multidimensional chromatin landscape analyses to associate with transcription output and cellular states.},
}
@article {pmid37254161,
year = {2023},
author = {Tolokh, IS and Kinney, NA and Sharakhov, IV and Onufriev, AV},
title = {Strong interactions between highly dynamic lamina-associated domains and the nuclear envelope stabilize the 3D architecture of Drosophila interphase chromatin.},
journal = {Epigenetics &amp; chromatin},
volume = {16},
number = {1},
pages = {21},
pmid = {37254161},
issn = {1756-8935},
support = {R01 GM144596/NH/NIH HHS/United States ; },
abstract = {BACKGROUND: Interactions among topologically associating domains (TADs), and between the nuclear envelope (NE) and lamina-associated domains (LADs) are expected to shape various aspects of three-dimensional (3D) chromatin structure and dynamics; however, relevant genome-wide experiments that may provide statistically significant conclusions remain difficult.<br><br>RESULTS: We have developed a coarse-grained dynamical model of D.&#xa0;melanogaster nuclei at TAD resolution that explicitly accounts for four distinct epigenetic classes of TADs and LAD-NE interactions. The model is parameterized to reproduce the experimental Hi-C map of the wild type (WT) nuclei; it describes time evolution of the chromatin over the G1 phase of the interphase. The simulations include an ensemble of nuclei, corresponding to the experimentally observed set of several possible mutual arrangements of chromosomal arms. The model is validated against multiple structural features of chromatin from several different experiments not used in model development. Predicted positioning of all LADs at the NE is highly dynamic-the same LAD can attach, detach and move far away from the NE multiple times during interphase. The probabilities of LADs to be in contact with the NE vary by an order of magnitude, despite all having the same affinity to the NE in the model. These probabilities are mostly determined by a highly variable local linear density of LADs along the genome, which also has the same&#xa0;strong effect on the predicted positioning of individual TADs&#xa0;-- higher probability of a TAD to be near NE is largely determined by a higher linear density of LADs surrounding this TAD. The distribution of LADs along the chromosome chains plays a notable role in maintaining a non-random average global structure of chromatin. Relatively high affinity of LADs to the NE in the WT nuclei substantially reduces sensitivity of the global radial chromatin distribution to variations in the strength of TAD-TAD interactions compared to the lamin depleted nuclei, where a small (0.5 kT) increase of cross-type TAD-TAD interactions doubles the chromatin density in the central nucleus region.<br><br>CONCLUSIONS: A dynamical model of the entire fruit fly genome makes multiple genome-wide predictions of biological interest. The distribution of LADs along the chromatin chains affects their probabilities to be in contact with the NE and radial positioning of highly mobile TADs, playing a notable role in creating a non-random average global structure of the chromatin. We conjecture that an important role of attractive LAD-NE interactions is to stabilize global chromatin structure against inevitable cell-to-cell variations in TAD-TAD interactions.},
}
@article {pmid37250307,
year = {2023},
author = {Hamba, Y and Kamatani, T and Miya, F and Boroevich, KA and Tsunoda, T},
title = {Topologically associating domain underlies tissue specific expression of long intergenic non-coding RNAs.},
journal = {iScience},
volume = {26},
number = {5},
pages = {106640},
pmid = {37250307},
issn = {2589-0042},
abstract = {Accumulating evidence indicates that long intergenic non-coding RNAs (lincRNAs) show more tissue-specific expression patterns than protein-coding genes (PCGs). However, although lincRNAs are subject to canonical transcriptional regulation like PCGs, the molecular basis for the specificity of their expression patterns remains unclear. Here, using expression data and coordinates of topologically associating domains (TADs) in human tissues, we show that lincRNA loci are significantly enriched in the more internal region of TADs compared to PCGs and that lincRNAs within TADs have higher tissue specificity than those outside TADs. Based on these, we propose an analytical framework to interpret transcriptional status using lincRNA as an indicator. We applied it to hypertrophic cardiomyopathy data and found disease-specific transcriptional regulation: ectopic expression of keratin at the TAD level and derepression of myocyte differentiation-related genes by E2F1 with down-regulation of LINC00881. Our results provide understanding of the function and regulation of lincRNAs according to genomic structure.},
}
@article {pmid37193952,
year = {2023},
author = {Zhang, X and Yu, G and Dai, Y and Zhang, H and Wang, K and Han, J},
title = {High-resolution Hi-C maps highlight multiscale chromatin architecture reorganization during cold stress in Brachypodium distachyon.},
journal = {BMC plant biology},
volume = {23},
number = {1},
pages = {260},
pmid = {37193952},
issn = {1471-2229},
abstract = {BACKGROUND: The adaptation of plants to cold stress involves changes in gene expression profiles that are associated with epigenetic regulation. Although the three-dimensional (3D) genome architecture is considered an important epigenetic regulator, the role of 3D genome organization in the cold stress response remains unclear.<br><br>RESULTS: In this study, we developed high-resolution 3D genomic maps using control and cold-treated leaf tissue of the model plant Brachypodium distachyon using Hi-C to determine how cold stress affects the 3D genome architecture. We generated&#x2009;~&#x2009;1.5&#xa0;kb resolution chromatin interaction maps and showed that cold stress disrupts different levels of chromosome organization, including A/B compartment transition, a reduction in chromatin compartmentalization and the size of topologically associating domains (TADs), and loss of long-range chromatin loops. Integrating RNA-seq information, we identified cold-response genes and revealed that transcription was largely unaffected by the A/B compartment transition. The cold-response genes were predominantly localized in compartment A. In contrast, transcriptional changes are required for TAD reorganization. We demonstrated that dynamic TAD events were associated with H3K27me3 and H3K27ac state alterations. Moreover, a loss of chromatin looping, rather than a gain of looping, coincides with alterations in gene expression, indicating that chromatin loop disruption may play a more important role than loop formation in the cold-stress response.<br><br>CONCLUSIONS: Our study highlights the multiscale 3D genome reprogramming that occurs during cold stress and expands our knowledge of the mechanisms underlying transcriptional regulation in response to cold stress in plants.},
}
@article {pmid37162822,
year = {2023},
author = {Parodi, L and Comeau, ME and Georgakis, MK and Mayerhofer, E and Chung, J and Falcone, GJ and Malik, R and Demel, SL and Worrall, BB and Koch, S and Testai, FD and Kittner, SJ and McCauley, JL and Hall, CE and Mayson, DJ and Elkind, MS and James, ML and Woo, D and Rosand, J and Langefeld, CD and Anderson, CD},
title = {Deep resequencing of the 1q22 locus in non-lobar intracerebral hemorrhage.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2023.04.18.23288754},
pmid = {37162822},
abstract = {OBJECTIVE: Genome-wide association studies have identified 1q22 as a susceptibility locus for cerebral small vessel diseases (CSVDs), including non-lobar intracerebral hemorrhage (ICH) and lacunar stroke. In the present study we performed targeted high-depth sequencing of 1q22 in ICH cases and controls to further characterize this locus and prioritize potential causal mechanisms, which remain unknown.<br><br>METHODS: 95,000 base pairs spanning 1q22 , including SEMA4A, SLC25A44 and PMF1 / PMF1-BGLAP were sequenced in 1,055 spontaneous ICH cases (534 lobar and 521 non-lobar) and 1,078 controls. Firth regression and RIFT analysis were used to analyze common and rare variants, respectively. Chromatin interaction analyses were performed using Hi-C, ChIP-Seq and ChIA-PET databases. Multivariable Mendelian randomization (MVMR) assessed whether alterations in gene-specific expression relative to regionally co-expressed genes at 1q22 could be causally related to ICH risk.<br><br>RESULTS: Common and rare variant analyses prioritized variants in SEMA4A 5'-UTR and PMF1 intronic regions, overlapping with active promoter and enhancer regions based on ENCODE annotation. Hi-C data analysis determined that 1q22 is spatially organized in a single chromatin loop and that the genes therein belong to the same Topologically Associating Domain. ChIP-Seq and ChIA-PET data analysis highlighted the presence of long-range interactions between the SEMA4A -promoter and PMF1 -enhancer regions prioritized by association testing. MVMR analyses demonstrated that PMF1 overexpression could be causally related to non-lobar ICH risk.<br><br>INTERPRETATION: Altered promoter-enhancer interactions leading to PMF1 overexpression, potentially dysregulating polyamine catabolism, could explain demonstrated associations with non-lobar ICH risk at 1q22 , offering a potential new target for prevention of ICH and CSVD.},
}
@article {pmid37162225,
year = {2023},
author = {Li, A and Zeng, G and Wang, H and Li, X and Zhang, Z},
title = {DeDoc2 Identifies and Characterizes the Hierarchy and Dynamics of Chromatin TAD-Like Domains in the Single Cells.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e2300366},
doi = {10.1002/advs.202300366},
pmid = {37162225},
issn = {2198-3844},
abstract = {Topologically associating domains (TADs) are functional chromatin units with hierarchical structure. However, the existence, prevalence, and dynamics of such hierarchy in single cells remain unexplored. Here, a new generation TAD-like domain (TLD) detection algorithm, named deDoc2, to decode the hierarchy of TLDs in single cells, is reported. With dynamic programming, deDoc2 seeks genome partitions with global minimal structure entropy for both whole and local contact matrix. Notably, deDoc2 outperforms state-of-the-art tools and is one of only two tools able to identify the hierarchy of TLDs in single cells. By applying deDoc2, it is showed that the hierarchy of TLDs in single cells is highly dynamic during cell cycle, as well as among human brain cortex cells, and that it is associated with cellular identity and functions. Thus, the results demonstrate the abundance of information potentially encoded by TLD hierarchy for functional regulation. The deDoc2 can be freely accessed at https://github.com/zengguangjie/deDoc2.},
}
@article {pmid37139561,
year = {2023},
author = {Liu, J and Li, P and Sun, J and Guo, J},
title = {LPAD: using network construction and label propagation to detect topologically associating domains from Hi-C data.},
journal = {Briefings in bioinformatics},
volume = {},
number = {},
pages = {},
doi = {10.1093/bib/bbad165},
pmid = {37139561},
issn = {1477-4054},
abstract = {With the development of chromosome conformation capture technique, the study of spatial conformation of a genome based on Hi-C technique has made a quantum leap. Previous studies reveal that genomes are folded into hierarchy of three-dimensional (3D) structures associated with topologically associating domains (TADs), and detecting TAD boundaries is of great significance in the chromosome-level analysis of 3D genome architecture. In this paper, we propose a novel TAD identification method, LPAD, which first extracts node correlations from global interactions of chromosomes based on the random walk with restart and then builds an undirected graph from Hi-C contact matrix. Next, LPAD designs a label propagation-based approach to discover communities and generates TADs. Experimental results verify the effectiveness and quality of TAD detections compared with existing methods. Furthermore, experimental evaluation of chromatin immunoprecipitation sequencing data shows that LPAD performs high enrichment of histone modifications remarkably nearby the TAD boundaries, and these results demonstrate LPAD's advantages on TAD identification accuracy.},
}
@article {pmid37116707,
year = {2023},
author = {Liu, P and Li, D and Zhang, J and He, M and Gao, D and Wang, Y and Lin, Y and Pan, D and Li, P and Wang, T and Li, J and Kong, F and Zeng, B and Lu, L and Ma, J and Long, K and Li, G and Tang, Q and Jin, L and Li, M},
title = {Comparative three-dimensional genome architectures of adipose tissues provide insight into human-specific regulation of metabolic homeostasis.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {104757},
doi = {10.1016/j.jbc.2023.104757},
pmid = {37116707},
issn = {1083-351X},
abstract = {Elucidating the regulatory mechanisms of human adipose tissues (ATs) evolution is essential for understanding human-specific metabolic regulation, but the functional importance and evolutionary dynamics of three-dimensional (3D) genome organizations of ATs are not well defined. Here, we compared the 3D genome architectures of anatomically distinct ATs from humans and six representative mammalian models. We recognized evolutionarily conserved and human-specific chromatin conformation in ATs at multiple scales, including compartmentalization, topologically associating domain (TAD), and promoter-enhancer interactions (PEI), which have not been described previously. We found promoter-enhancer interaction (PEI) are much more evolutionarily dynamic with respect to compartmentalization and topologically associating domain (TAD). Compared to conserved PEIs, human-specific PEIs are enriched for human-specific sequence and the binding motifs of their potential mediators (transcription factors) are less conserved. Our data also demonstrated that genes involved in the evolutionarily dynamics of chromatin organization have weaker transcriptional conservation than those associated with conserved chromatin organization. Furthermore, the genes involved in energy metabolism and the maintenance of metabolic homeostasis are enriched in human-specific chromatin organization, while housekeeping genes, health-related genes and genetic variations are enriched in evolutionarily conserved compared to human-specific chromatin organization. Finally, we showed extensively divergent human-specific 3D genome organizations among one subcutaneous and three visceral ATs. Together, these findings provide a global overview of 3D genome architecture dynamics between ATs from human and mammalian models, and new insights into understanding the regulatory evolution of human ATs.},
}
@article {pmid37104607,
year = {2023},
author = {Keough, KC and Whalen, S and Inoue, F and Przytycki, PF and Fair, T and Deng, C and Steyert, M and Ryu, H and Lindblad-Toh, K and Karlsson, E and , and Nowakowski, T and Ahituv, N and Pollen, A and Pollard, KS and Andrews, G and Armstrong, JC and Bianchi, M and Birren, BW and Bredemeyer, KR and Breit, AM and Christmas, MJ and Clawson, H and Damas, J and Di Palma, F and Diekhans, M and Dong, MX and Eizirik, E and Fan, K and Fanter, C and Foley, NM and Forsberg-Nilsson, K and Garcia, CJ and Gatesy, J and Gazal, S and Genereux, DP and Goodman, L and Grimshaw, J and Halsey, MK and Harris, AJ and Hickey, G and Hiller, M and Hindle, AG and Hubley, RM and Hughes, GM and Johnson, J and Juan, D and Kaplow, IM and Karlsson, EK and Keough, KC and Kirilenko, B and Koepfli, KP and Korstian, JM and Kowalczyk, A and Kozyrev, SV and Lawler, AJ and Lawless, C and Lehmann, T and Levesque, DL and Lewin, HA and Li, X and Lind, A and Lindblad-Toh, K and Mackay-Smith, A and Marinescu, VD and Marques-Bonet, T and Mason, VC and Meadows, JRS and Meyer, WK and Moore, JE and Moreira, LR and Moreno-Santillan, DD and Morrill, KM and Muntané, G and Murphy, WJ and Navarro, A and Nweeia, M and Ortmann, S and Osmanski, A and Paten, B and Paulat, NS and Pfenning, AR and Phan, BN and Pollard, KS and Pratt, HE and Ray, DA and Reilly, SK and Rosen, JR and Ruf, I and Ryan, L and Ryder, OA and Sabeti, PC and Schäffer, DE and Serres, A and Shapiro, B and Smit, AFA and Springer, M and Srinivasan, C and Steiner, C and Storer, JM and Sullivan, KAM and Sullivan, PF and Sundström, E and Supple, MA and Swofford, R and Talbot, JE and Teeling, E and Turner-Maier, J and Valenzuela, A and Wagner, F and Wallerman, O and Wang, C and Wang, J and Weng, Z and Wilder, AP and Wirthlin, ME and Xue, JR and Zhang, X},
title = {Three-dimensional genome rewiring in loci with human accelerated regions.},
journal = {Science (New York, N.Y.)},
volume = {380},
number = {6643},
pages = {eabm1696},
doi = {10.1126/science.abm1696},
pmid = {37104607},
issn = {1095-9203},
abstract = {Human accelerated regions (HARs) are conserved genomic loci that evolved at an accelerated rate in the human lineage and may underlie human-specific traits. We generated HARs and chimpanzee accelerated regions with an automated pipeline and an alignment of 241 mammalian genomes. Combining deep learning with chromatin capture experiments in human and chimpanzee neural progenitor cells, we discovered a significant enrichment of HARs in topologically associating domains containing human-specific genomic variants that change three-dimensional (3D) genome organization. Differential gene expression between humans and chimpanzees at these loci suggests rewiring of regulatory interactions between HARs and neurodevelopmental genes. Thus, comparative genomics together with models of 3D genome folding revealed enhancer hijacking as an explanation for the rapid evolution of HARs.},
}
@article {pmid37099832,
year = {2023},
author = {Zhang, H and Blobel, GA},
title = {Genome folding dynamics during the M-to-G1-phase transition.},
journal = {Current opinion in genetics &amp; development},
volume = {80},
number = {},
pages = {102036},
doi = {10.1016/j.gde.2023.102036},
pmid = {37099832},
issn = {1879-0380},
abstract = {All measurable features of higher-order chromosomal architecture undergo drastic reorganization as cells enter and exit mitosis. During mitosis, gene transcription is temporarily halted, the nuclear envelope is dismantled, and chromosomes undergo condensation. At this time, chromatin compartments, topologically associating domains (TADs), and loops that connect enhancers with promoters as well as CTCF/cohesin loops are dissolved. Upon G1 entry, genome organization is rebuilt in the daughter nuclei to resemble that of the mother nucleus. We survey recent studies that traced these features in relation to gene expression during the mitosis-to-G1-phase transition at high temporal resolution. Dissection of fluctuating architectural features informed the hierarchical relationships of chromosomal organization, the mechanisms by which they are formed, and their mutual (in-) dependence. These studies highlight the importance of considering the cell cycle dynamics for studies of chromosomal organization.},
}
@article {pmid37085539,
year = {2023},
author = {Okonechnikov, K and Camgöz, A and Chapman, O and Wani, S and Park, DE and Hübner, JM and Chakraborty, A and Pagadala, M and Bump, R and Chandran, S and Kraft, K and Acuna-Hidalgo, R and Reid, D and Sikkink, K and Mauermann, M and Juarez, EF and Jenseit, A and Robinson, JT and Pajtler, KW and Milde, T and Jäger, N and Fiesel, P and Morgan, L and Sridhar, S and Coufal, NG and Levy, M and Malicki, D and Hobbs, C and Kingsmore, S and Nahas, S and Snuderl, M and Crawford, J and Wechsler-Reya, RJ and Davidson, TB and Cotter, J and Michaiel, G and Fleischhack, G and Mundlos, S and Schmitt, A and Carter, H and Michealraj, KA and Kumar, SA and Taylor, MD and Rich, J and Buchholz, F and Mesirov, JP and Pfister, SM and Ay, F and Dixon, JR and Kool, M and Chavez, L},
title = {3D genome mapping identifies subgroup-specific chromosome conformations and tumor-dependency genes in ependymoma.},
journal = {Nature communications},
volume = {14},
number = {1},
pages = {2300},
pmid = {37085539},
issn = {2041-1723},
abstract = {Ependymoma is a tumor of the brain or spinal cord. The two most common and aggressive molecular groups of ependymoma are the supratentorial ZFTA-fusion associated and the posterior fossa ependymoma group A. In both groups, tumors occur mainly in young children and frequently recur after treatment. Although molecular mechanisms underlying these diseases have recently been uncovered, they remain difficult to target and innovative therapeutic approaches are urgently needed. Here, we use genome-wide chromosome conformation capture (Hi-C), complemented with CTCF and H3K27ac ChIP-seq, as well as gene expression and DNA methylation analysis in primary and relapsed ependymoma tumors, to identify chromosomal conformations and regulatory mechanisms associated with aberrant gene expression. In particular, we observe the formation of new topologically associating domains ('neo-TADs') caused by structural variants, group-specific 3D chromatin loops, and the replacement of CTCF insulators by DNA hyper-methylation. Through inhibition experiments, we validate that genes implicated by these 3D genome conformations are essential for the survival of patient-derived ependymoma models in a group-specific manner. Thus, this study extends our ability to reveal tumor-dependency genes by 3D genome conformations even in tumors that lack targetable genetic alterations.},
}
@article {pmid37084258,
year = {2023},
author = {Wang, B and Liu, K and Li, Y and Wang, J},
title = {DFHiC: A dilated full convolution model to enhance the resolution of Hi-C data.},
journal = {Bioinformatics (Oxford, England)},
volume = {},
number = {},
pages = {},
doi = {10.1093/bioinformatics/btad211},
pmid = {37084258},
issn = {1367-4811},
abstract = {MOTIVATION: Hi-C technology has been the most widely used chromosome conformation capture(3C) experiment that measures the frequency of all paired interactions in the entire genome, which is a powerful tool for studying the 3D structure of the genome. The fineness of the constructed genome structure depends on the resolution of Hi-C data. However, due to the fact that high-resolution Hi-C data require deep sequencing and thus high experimental cost, most available Hi-C data are in low-resolution. Hence, it is essential to enhance the quality of Hi-C data by developing the effective computational methods.<br><br>RESULTS: In this work, we propose a novel method, so-called DFHiC, which generates the high-resolution Hi-C matrix from the low-resolution Hi-C matrix in the framework of the dilated convolutional neural network. The dilated convolution is able to effectively explore the global patterns in the overall Hi-C matrix by taking advantage of the information of the Hi-C matrix in a way of the longer genomic distance. Consequently, DFHiC can improve the resolution of the Hi-C matrix reliably and accurately. More importantly, the super-resolution Hi-C data enhanced by DFHiC is more in line with the real high-resolution Hi-C data than those done by the other existing methods, in terms of both chromatin significant interactions and identifying topologically associating domains (TADs).<br><br>AVAILABILITY: https://github.com/BinWangCSU/DFHiC.<br><br>SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},
}
@article {pmid37081156,
year = {2023},
author = {Rajderkar, S and Barozzi, I and Zhu, Y and Hu, R and Zhang, Y and Li, B and Alcaina Caro, A and Fukuda-Yuzawa, Y and Kelman, G and Akeza, A and Blow, MJ and Pham, Q and Harrington, AN and Godoy, J and Meky, EM and von Maydell, K and Hunter, RD and Akiyama, JA and Novak, CS and Plajzer-Frick, I and Afzal, V and Tran, S and Lopez-Rios, J and Talkowski, ME and Lloyd, KCK and Ren, B and Dickel, DE and Visel, A and Pennacchio, LA},
title = {Topologically associating domain boundaries are required for normal genome function.},
journal = {Communications biology},
volume = {6},
number = {1},
pages = {435},
pmid = {37081156},
issn = {2399-3642},
abstract = {Topologically associating domain (TAD) boundaries partition the genome into distinct regulatory territories. Anecdotal evidence suggests that their disruption may interfere with normal gene expression and cause disease phenotypes[1-3], but the overall extent to which this occurs remains unknown. Here we demonstrate that targeted deletions of TAD boundaries cause a range of disruptions to normal in vivo genome function and organismal development. We used CRISPR genome editing in mice to individually delete eight TAD boundaries (11-80 kb in size) from the genome. All deletions examined resulted in detectable molecular or organismal phenotypes, which included altered chromatin interactions or gene expression, reduced viability, and anatomical phenotypes. We observed changes in local 3D chromatin architecture in 7 of 8 (88%) cases, including the merging of TADs and altered contact frequencies within TADs adjacent to the deleted boundary. For 5 of 8 (63%) loci examined, boundary deletions were associated with increased embryonic lethality or other developmental phenotypes. For example, a TAD boundary deletion near Smad3/Smad6 caused complete embryonic lethality, while a deletion near Tbx5/Lhx5 resulted in a severe lung malformation. Our findings demonstrate the importance of TAD boundary sequences for in vivo genome function and reinforce the critical need to carefully consider the potential pathogenicity of noncoding deletions affecting TAD boundaries in clinical genetics screening.},
}
@article {pmid37076620,
year = {2023},
author = {Davidson, IF and Barth, R and Zaczek, M and van der Torre, J and Tang, W and Nagasaka, K and Janissen, R and Kerssemakers, J and Wutz, G and Dekker, C and Peters, JM},
title = {CTCF is a DNA-tension-dependent barrier to cohesin-mediated loop extrusion.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {37076620},
issn = {1476-4687},
abstract = {In eukaryotes, genomic DNA is extruded into loops by cohesin[1]. By restraining this process, the DNA-binding protein CCCTC-binding factor (CTCF) generates topologically associating domains (TADs)[2,3] that have important roles in gene regulation and recombination during development and disease[1,4-7]. How CTCF establishes TAD boundaries and to what extent these are permeable to cohesin is unclear[8]. Here, to address these questions, we visualize interactions of single CTCF and cohesin molecules on DNA in vitro. We show that CTCF is sufficient to block diffusing cohesin, possibly reflecting how cohesive cohesin accumulates at TAD boundaries, and is also sufficient to block loop-extruding cohesin, reflecting how CTCF establishes TAD boundaries. CTCF functions asymmetrically, as predicted; however, CTCF is dependent on DNA tension. Moreover, CTCF regulates cohesin's loop-extrusion activity by changing its direction and by inducing loop shrinkage. Our data indicate that CTCF is not, as previously assumed, simply a barrier to cohesin-mediated loop extrusion but is an active regulator of this process, whereby the permeability of TAD boundaries can be modulated by DNA tension. These results reveal mechanistic principles of how CTCF controls loop extrusion and genome architecture.},
}
@article {pmid37070946,
year = {2023},
author = {Yin, X and Romero-Campero, FJ and Yang, M and Baile, F and Cao, Y and Shu, J and Luo, L and Wang, D and Sun, S and Yan, P and Gong, Z and Mo, X and Qin, G and Calonje, M and Zhou, Y},
title = {Binding by the Polycomb complex component BMI1 and H2A monoubiquitination shape local and long-range interactions in the Arabidopsis genome.},
journal = {The Plant cell},
volume = {},
number = {},
pages = {},
doi = {10.1093/plcell/koad112},
pmid = {37070946},
issn = {1532-298X},
abstract = {Three-dimensional (3D) chromatin organization is highly dynamic during development and seems to play a crucial role in regulating gene expression. Self-interacting domains, commonly called topologically associating domains (TADs) or compartment domains (CDs), have been proposed as the basic structural units of chromatin organization. Surprisingly, although these units have been found in several plant species, they escaped detection in Arabidopsis (Arabidopsis thaliana). Here, we show that the Arabidopsis genome is partitioned into contiguous CDs with different epigenetic features, which are required to maintain appropriate intra-CD and long-range interactions. Consistent with this notion, the histone-modifying Polycomb group machinery is involved in 3D chromatin organization. Yet, while it is clear that Polycomb Repressive Complex 2 (PRC2)-mediated trimethylation of histone H3 on lysine 27 (H3K27me3) helps establish local and long-range chromatin interactions in plants, the implications of PRC1-mediated histone H2A monoubiquitination on lysine 121 (H2AK121ub) are unclear. We found that PRC1, together with PRC2, maintains intra-CD interactions, but it also hinders the formation of H3K4me3-enriched local chromatin loops when acting independently of PRC2. Moreover, the loss of PRC1 or PRC2 activity differentially affects long-range chromatin interactions, and these 3D changes differentially affect gene expression. Our results suggest that H2AK121ub helps prevent the formation of transposable element/H3K27me1-rich long loops and serves as a docking point for H3K27me3 incorporation.},
}
@article {pmid37063858,
year = {2023},
author = {Guo, M and Yao, Z and Jiang, C and Songyang, Z and Gan, L and Xiong, Y},
title = {Three-dimensional and single-cell sequencing of liver cancer reveals comprehensive host-virus interactions in HBV infection.},
journal = {Frontiers in immunology},
volume = {14},
number = {},
pages = {1161522},
pmid = {37063858},
issn = {1664-3224},
abstract = {BACKGROUNDS: Hepatitis B virus (HBV) infection is a major risk factor for chronic liver diseases and liver cancer (mainly hepatocellular carcinoma, HCC), while the underlying mechanisms and host-virus interactions are still largely elusive.<br><br>METHODS: We applied HiC sequencing to HepG2 (HBV-) and HepG2-2.2.15 (HBV+) cell lines and combined them with public HCC single-cell RNA-seq data, HCC bulk RNA-seq data, and both genomic and epigenomic ChIP-seq data to reveal potential disease mechanisms of HBV infection and host-virus interactions reflected by 3D genome organization.<br><br>RESULTS: We found that HBV enhanced overall proximal chromatin interactions (CIs) of liver cells and primarily affected regional CIs on chromosomes 13, 14, 17, and 22. Interestingly, HBV altered the boundaries of many topologically associating domains (TADs), and genes nearby these boundaries showed functional enrichment in cell adhesion which may promote cancer metastasis. Moreover, A/B compartment analysis revealed dramatic changes on chromosomes 9, 13 and 21, with more B compartments (inactive or closed) shifting to A compartments (active or open). The A-to-B regions (closing) harbored enhancers enriched in the regulation of inflammatory responses, whereas B-to-A regions (opening) were enriched for transposable elements (TE). Furthermore, we identified large HBV-induced structural variations (SVs) that disrupted tumor suppressors, NLGN4Y and PROS1. Finally, we examined differentially expressed genes and TEs in single hepatocytes with or without HBV infection, by using single-cell RNA-seq data. Consistent with our HiC sequencing findings, two upregulated genes that promote HBV replication, HNF4A and NR5A2, were located in regions with HBV-enhanced CIs, and five TEs were located in HBV-activated regions. Therefore, HBV may promote liver diseases by affecting the human 3D genome structure.<br><br>CONCLUSION: Our work promotes mechanistic understanding of HBV infection and host-virus interactions related to liver diseases that affect billions of people worldwide. Our findings may also have implications for novel immunotherapeutic strategies targeting HBV infection.},
}
@article {pmid37055796,
year = {2023},
author = {Cheng, J and Cao, X and Wang, X and Wang, J and Yue, B and Sun, W and Huang, Y and Lan, X and Ren, G and Lei, C and Chen, H},
title = {Dynamic chromatin architectures provide insights into the genetics of cattle myogenesis.},
journal = {Journal of animal science and biotechnology},
volume = {14},
number = {1},
pages = {59},
pmid = {37055796},
issn = {1674-9782},
abstract = {BACKGROUND: Sharply increased beef consumption is propelling the genetic improvement projects of beef cattle in China. Three-dimensional genome structure is confirmed to be an important layer of transcription regulation. Although genome-wide interaction data of several livestock species have already been produced, the genome structure states and its regulatory rules in cattle muscle are still limited.<br><br>RESULTS: Here we present the first 3D genome data in Longissimus dorsi muscle of fetal and adult cattle (Bos taurus). We showed that compartments, topologically associating domains (TADs), and loop undergo re-organization and the structure dynamics were consistent with transcriptomic divergence during muscle development. Furthermore, we annotated cis-regulatory elements in cattle genome during myogenesis and demonstrated the enrichments of promoter and enhancer in selection sweeps. We further validated the regulatory function of one HMGA2 intronic enhancer near a strong sweep region on primary bovine myoblast proliferation.<br><br>CONCLUSIONS: Our data provide key insights of the regulatory function of high order chromatin structure and cattle myogenic biology, which will benefit the progress of genetic improvement of beef cattle.},
}
@article {pmid37047368,
year = {2023},
author = {Mao, A and Chen, C and Portillo-Ledesma, S and Schlick, T},
title = {Effect of Single-Residue Mutations on CTCF Binding to DNA: Insights from Molecular Dynamics Simulations.},
journal = {International journal of molecular sciences},
volume = {24},
number = {7},
pages = {},
doi = {10.3390/ijms24076395},
pmid = {37047368},
issn = {1422-0067},
support = {R35-GM122562/NH/NIH HHS/United States ; },
abstract = {In humans and other eukaryotes, DNA is condensed into chromatin fibers that are further wound into chromosomes. This organization allows regulatory elements in the genome, often distant from each other in the linear DNA, to interact and facilitate gene expression through regions known as topologically associating domains (TADs). CCCTC-binding factor (CTCF) is one of the major components of TAD formation and is responsible for recruiting a partner protein, cohesin, to perform loop extrusion and facilitate proper gene expression within TADs. Because single-residue CTCF mutations have been linked to the development of a variety of cancers in humans, we aim to better understand how these mutations affect the CTCF structure and its interaction with DNA. To this end, we compare all-atom molecular dynamics simulations of a wildtype CTCF-DNA complex to those of eight different cancer-linked CTCF mutant sequences. We find that most mutants have lower binding energies compared to the wildtype protein, leading to the formation of less stable complexes. Depending on the type and position of the mutation, this loss of stability can be attributed to major changes in the electrostatic potential, loss of hydrogen bonds between the CTCF and DNA, and/or destabilization of specific zinc fingers. Interestingly, certain mutations in specific fingers can affect the interaction with the DNA of other fingers, explaining why mere single mutations can impair CTCF function. Overall, these results shed mechanistic insights into experimental observations and further underscore CTCF's importance in the regulation of chromatin architecture and gene expression.},
}
@article {pmid37041182,
year = {2023},
author = {Tan, ZW and Toong, PJ and Guarnera, E and Berezovsky, IN},
title = {Disrupted chromatin architecture in olfactory sensory neurons: looking for the link from COVID-19 infection to anosmia.},
journal = {Scientific reports},
volume = {13},
number = {1},
pages = {5906},
pmid = {37041182},
issn = {2045-2322},
abstract = {We tackle here genomic mechanisms of a rapid onset and recovery from anosmia-a potential diagnostic indicator for early-stage COVID-19 infection. Based on previous observations on how olfactory receptor (OR) gene expression is regulated via chromatin structure in mice, we hypothesized that the disruption of the OR gene expression and, respectively, deficiency of the OR function can be caused by chromatin reorganization taking place upon SARS-CoV-2 infection. We obtained chromatin ensemble reconstructions from COVID-19 patients and control samples using our original computational framework for the whole-genome 3D chromatin ensemble reconstruction. Specifically, we used megabase-scale structural units and effective interactions between them obtained in the Markov State modelling of the Hi-C contact network as an unput in the stochastic embedding procedure of the whole-genome 3D chromatin ensemble reconstruction. We have also developed here a new procedure for analyzing fine structural hierarchy with (sub)TAD-size units in local chromatin regions, which we apply here to parts of chromosomes containing OR genes and corresponding regulatory elements. We observed structural modifications in COVID-19 patients on different levels of chromatin organization, from the alteration of whole genome structure and chromosomal intermingling to reorganization of contacts between chromatin loops at the level of topologically associating domains. While complementary data on known regulatory elements point to potential pathology-associated changes within the overall picture of chromatin alterations, further investigation using additional epigenetic factors mapped on 3D reconstructions with improved resolution will be required for better understanding of anosmia caused by SARS-CoV-2 infection.},
}
@article {pmid37041138,
year = {2023},
author = {Melo, US and Jatzlau, J and Prada-Medina, CA and Flex, E and Hartmann, S and Ali, S and Schöpflin, R and Bernardini, L and Ciolfi, A and Moeinzadeh, MH and Klever, MK and Altay, A and Vallecillo-García, P and Carpentieri, G and Delledonne, M and Ort, MJ and Schwestka, M and Ferrero, GB and Tartaglia, M and Brusco, A and Gossen, M and Strunk, D and Geißler, S and Mundlos, S and Stricker, S and Knaus, P and Giorgio, E and Spielmann, M},
title = {Enhancer hijacking at the ARHGAP36 locus is associated with connective tissue to bone transformation.},
journal = {Nature communications},
volume = {14},
number = {1},
pages = {2034},
pmid = {37041138},
issn = {2041-1723},
abstract = {Heterotopic ossification is a disorder caused by abnormal mineralization of soft tissues in which signaling pathways such as BMP, TGFβ and WNT are known key players in driving ectopic bone formation. Identifying novel genes and pathways related to the mineralization process are important steps for future gene therapy in bone disorders. In this study, we detect an inter-chromosomal insertional duplication in a female proband disrupting a topologically associating domain and causing an ultra-rare progressive form of heterotopic ossification. This structural variant lead to enhancer hijacking and misexpression of ARHGAP36 in fibroblasts, validated here by orthogonal in vitro studies. In addition, ARHGAP36 overexpression inhibits TGFβ, and activates hedgehog signaling and genes/proteins related to extracellular matrix production. Our work on the genetic cause of this heterotopic ossification case has revealed that ARHGAP36 plays a role in bone formation and metabolism, outlining first details of this gene contributing to bone-formation and -disease.},
}
@article {pmid37017672,
year = {2023},
author = {Fritz, AJ and Ghule, PN and Toor, R and Dillac, L and Perelman, J and Boyd, J and Lian, JB and Gordon, JAR and Frietze, S and Van Wijnen, A and Stein, JL and Stein, GS},
title = {Spatiotemporal Epigenetic Control of the Histone Gene Chromatin Landscape during the Cell Cycle.},
journal = {Critical reviews in eukaryotic gene expression},
volume = {33},
number = {3},
pages = {85-97},
doi = {10.1615/CritRevEukaryotGeneExpr.2022046190},
pmid = {37017672},
issn = {1045-4403},
abstract = {Higher-order genomic organization supports the activation of histone genes in response to cell cycle regulatory cues that epigenetically mediates stringent control of transcription at the G1/S-phase transition. Histone locus bodies (HLBs) are dynamic, non-membranous, phase-separated nuclear domains where the regulatory machinery for histone gene expression is organized and assembled to support spatiotemporal epigenetic control of histone genes. HLBs provide molecular hubs that support synthesis and processing of DNA replication-dependent histone mRNAs. These regulatory microenvironments support long-range genomic interactions among non-contiguous histone genes within a single topologically associating domain (TAD). HLBs respond to activation of the cyclin E/CDK2/NPAT/HINFP pathway at the G1/S transition. HINFP and its coactivator NPAT form a complex within HLBs that controls histone mRNA transcription to support histone protein synthesis and packaging of newly replicated DNA. Loss of HINFP compromises H4 gene expression and chromatin formation, which may result in DNA damage and impede cell cycle progression. HLBs provide a paradigm for higher-order genomic organization of a subnuclear domain that executes an obligatory cell cycle-controlled function in response to cyclin E/CDK2 signaling. Understanding the coordinately and spatiotemporally organized regulatory programs in focally defined nuclear domains provides insight into molecular infrastructure for responsiveness to cell signaling pathways that mediate biological control of growth, differentiation phenotype, and are compromised in cancer.},
}
@article {pmid37016431,
year = {2023},
author = {Narang, S and Evensen, NA and Saliba, J and Pierro, J and Loh, ML and Brown, PA and Kolekar, P and Mulder, H and Shao, Y and Easton, J and Ma, X and Tsirigos, A and Carroll, WL},
title = {NSD2 E1099K drives relapse in pediatric acute lymphoblastic leukemia by disrupting 3D chromatin organization.},
journal = {Genome biology},
volume = {24},
number = {1},
pages = {64},
pmid = {37016431},
issn = {1474-760X},
abstract = {BACKGROUND: The NSD2 p.E1099K (EK) mutation is shown to be enriched in patients with relapsed acute lymphoblastic leukemia (ALL), indicating a role in clonal evolution and drug resistance.<br><br>RESULTS: To uncover 3D chromatin architecture-related mechanisms underlying drug resistance, we perform Hi-C on three B-ALL cell lines heterozygous for NSD2 EK. The NSD2 mutation leads to widespread remodeling of the 3D genome, most dramatically in terms of compartment changes with a strong bias towards A compartment shifts. Systematic integration of the Hi-C data with previously published ATAC-seq, RNA-seq, and ChIP-seq data show an expansion in H3K36me2 and a shrinkage in H3K27me3 within A compartments as well as increased gene expression and chromatin accessibility. These results suggest that NSD2 EK plays a prominent role in chromatin decompaction through enrichment of H3K36me2. In contrast, we identify few changes in intra-topologically associating domain activity. While compartment changes vary across cell lines, a common core of decompacting loci are shared, driving the expression of genes/pathways previously implicated in drug resistance. We further perform RNA sequencing on a cohort of matched diagnosis/relapse ALL patients harboring the relapse-specific NSD2 EK mutation. Changes in patient gene expression upon relapse significantly correlate with core compartment changes, further implicating the role of NSD2 EK in genome decompaction.<br><br>CONCLUSIONS: In spite of cell-context-dependent changes mediated by EK, there appears to be a shared transcriptional program dependent on compartment shifts which could explain phenotypic differences across EK cell lines. This core program is an attractive target for therapeutic intervention.},
}
@article {pmid37012431,
year = {2023},
author = {Dozmorov, MG and Marshall, MA and Rashid, NS and Grible, JM and Valentine, A and Olex, AL and Murthy, K and Chakraborty, A and Reyna, J and Figueroa, DS and Hinojosa-Gonzalez, L and Da-Inn Lee, E and Baur, BA and Roy, S and Ay, F and Harrell, JC},
title = {Rewiring of the 3D genome during acquisition of carboplatin resistance in a triple-negative breast cancer patient-derived xenograft.},
journal = {Scientific reports},
volume = {13},
number = {1},
pages = {5420},
pmid = {37012431},
issn = {2045-2322},
support = {R35-GM128938/GM/NIGMS NIH HHS/United States ; R35-GM128938/GM/NIGMS NIH HHS/United States ; 1R01CA246182-01A1/CA/NCI NIH HHS/United States ; CCR19608826/KOMEN/Susan G. Komen/United States ; },
abstract = {Changes in the three-dimensional (3D) structure of the genome are an emerging hallmark of cancer. Cancer-associated copy number variants and single nucleotide polymorphisms promote rewiring of chromatin loops, disruption of topologically associating domains (TADs), active/inactive chromatin state switching, leading to oncogene expression and silencing of tumor suppressors. However, little is known about 3D changes during cancer progression to a chemotherapy-resistant state. We integrated chromatin conformation capture (Hi-C), RNA-seq, and whole-genome sequencing obtained from triple-negative breast cancer patient-derived xenograft primary tumors (UCD52) and carboplatin-resistant samples and found increased short-range (< 2 Mb) interactions, chromatin looping, formation of TAD, chromatin state switching into a more active state, and amplification of ATP-binding cassette transporters. Transcriptome changes suggested the role of long-noncoding RNAs in carboplatin resistance. Rewiring of the 3D genome was associated with TP53, TP63, BATF, FOS-JUN family of transcription factors and led to activation of aggressiveness-, metastasis- and other cancer-related pathways. Integrative analysis highlighted increased ribosome biogenesis and oxidative phosphorylation, suggesting the role of mitochondrial energy metabolism. Our results suggest that 3D genome remodeling may be a key mechanism underlying carboplatin resistance.},
}
@article {pmid37000624,
year = {2023},
author = {Wang, B and Ji, L and Bian, Q},
title = {SATB1 regulates 3D genome architecture in T cells by constraining chromatin interactions surrounding CTCF-binding sites.},
journal = {Cell reports},
volume = {42},
number = {4},
pages = {112323},
doi = {10.1016/j.celrep.2023.112323},
pmid = {37000624},
issn = {2211-1247},
abstract = {Special AT-rich sequence binding protein 1 (SATB1) has long been proposed to act as a global chromatin loop organizer in T cells. However, the exact functions of SATB1 in spatial genome organization remain elusive. Here we show that the depletion of SATB1 in human and murine T cells leads to transcriptional dysregulation for genes involved in T cell activation, as well as alterations of 3D genome architecture at multiple levels, including compartments, topologically associating domains, and loops. Importantly, SATB1 extensively colocalizes with CTCF throughout the genome. Depletion of SATB1 leads to increased chromatin contacts among and across the SATB1/CTCF co-occupied sites, thereby affecting the transcription of critical regulators of T cell activation. The loss of SATB1 does not affect CTCF occupancy but significantly reduces the retention of CTCF in the nuclear matrix. Collectively, our data show that SATB1 contributes to 3D genome organization by constraining chromatin topology surrounding CTCF-binding sites.},
}
@article {pmid36996812,
year = {2023},
author = {Chen, LF and Long, HK and Park, M and Swigut, T and Boettiger, AN and Wysocka, J},
title = {Structural elements promote architectural stripe formation and facilitate ultra-long-range gene regulation at a human disease locus.},
journal = {Molecular cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.molcel.2023.03.009},
pmid = {36996812},
issn = {1097-4164},
abstract = {Enhancer clusters overlapping disease-associated mutations in Pierre Robin sequence (PRS) patients regulate SOX9 expression at genomic distances over 1.25 Mb. We applied optical reconstruction of chromatin architecture (ORCA) imaging to trace 3D locus topology during PRS-enhancer activation. We observed pronounced changes in locus topology between cell types. Subsequent analysis of single-chromatin fiber traces revealed that these ensemble-average differences arise through changes in the frequency of commonly sampled topologies. We further identified two CTCF-bound elements, internal to the SOX9 topologically associating domain, which promote stripe formation, are positioned near the domain's 3D geometric center, and bridge enhancer-promoter contacts in a series of chromatin loops. Ablation of these elements results in diminished SOX9 expression and altered domain-wide contacts. Polymer models with uniform loading across the domain and frequent cohesin collisions recapitulate this multi-loop, centrally clustered geometry. Together, we provide mechanistic insights into architectural stripe formation and gene regulation over ultra-long genomic ranges.},
}
@article {pmid36990727,
year = {2023},
author = {Aldersey, JE and Liu, N and Tearle, R and Low, WY and Breen, J and Williams, JL and Bottema, CDK},
title = {Topologically associating domains in the POLLED region are the same for Angus- and Brahman-specific Hi-C reads from F1 hybrid fetal tissue.},
journal = {Animal genetics},
volume = {},
number = {},
pages = {},
doi = {10.1111/age.13322},
pmid = {36990727},
issn = {1365-2052},
abstract = {Horns, a form of headgear carried by Bovidae, have ethical and economic implications for ruminant production species such as cattle and goats. Hornless (polled) individuals are preferred. In cattle, four genetic variants (Celtic, Friesian, Mongolian and Guarani) are associated with the polled phenotype, which are clustered in a 300-kb region on chromosome 1. As the variants are intergenic, the functional effect is unknown. The aim of this study was to determine if the POLLED variants affect chromatin structure or disrupt enhancers using publicly available data. Topologically associating domains (TADs) were analyzed using Angus- and Brahman-specific Hi-C reads from lung tissue of an Angus (Celtic allele) cross Brahman (horned) fetus. Predicted bovine enhancers and chromatin immunoprecipitation sequencing peaks for histone modifications associated with enhancers (H3K27ac and H3K4me1) were mapped to the POLLED region. TADs analyzed from Angus- and Brahman-specific Hi-C reads were the same, therefore, the Celtic variant does not appear to affect this level of chromatin structure. The Celtic variant is located in a different TAD from the Friesian, Mongolian, and Guarani variants. Predicted enhancers and histone modifications overlapped with the Guarani and Friesian variants but not the Celtic or Mongolian variants. This study provides insight into the mechanisms of the POLLED variants for disrupting horn development. These results should be validated using data produced from the horn bud region of horned and polled bovine fetuses.},
}
@article {pmid36941615,
year = {2023},
author = {Li, X and Wang, J and Yu, Y and Li, G and Wang, J and Li, C and Zeng, Z and Li, N and Zhang, Z and Dong, Q and Yu, Y and Wang, X and Wang, T and Grover, CE and Wang, B and Liu, B and Wendel, JF and Gong, L},
title = {Genomic rearrangements and evolutionary changes in 3D chromatin topologies in the cotton tribe (Gossypieae).},
journal = {BMC biology},
volume = {21},
number = {1},
pages = {56},
pmid = {36941615},
issn = {1741-7007},
abstract = {BACKGROUND: Analysis of the relationship between chromosomal structural variation (synteny breaks) and 3D-chromatin architectural changes among closely related species has the potential to reveal causes and correlates between chromosomal change and chromatin remodeling. Of note, contrary to extensive studies in animal species, the pace and pattern of chromatin architectural changes following the speciation of plants remain unexplored; moreover, there is little exploration of the occurrence of synteny breaks in the context of multiple genome topological hierarchies within the same model species.<br><br>RESULTS: Here we used Hi-C and epigenomic analyses to characterize and compare the profiles of hierarchical chromatin architectural features in representative species of the cotton tribe (Gossypieae), including Gossypium arboreum, Gossypium raimondii, and Gossypioides kirkii, which differ with respect to chromosome rearrangements. We found that (i) overall chromatin architectural territories were preserved in Gossypioides and Gossypium, which was reflected in their similar intra-chromosomal contact patterns and spatial chromosomal distributions; (ii) the non-random preferential occurrence of synteny breaks in A compartment significantly associate with the B-to-A compartment switch in syntenic blocks flanking synteny breaks; (iii) synteny changes co-localize with open-chromatin boundaries of topologically associating domains, while TAD stabilization has a greater influence on regulating orthologous expression divergence than do rearrangements; and (iv) rearranged chromosome segments largely maintain ancestral in-cis interactions.<br><br>CONCLUSIONS: Our findings provide insights into the non-random occurrence of epigenomic remodeling relative to the genomic landscape and its evolutionary and functional connections to alterations of hierarchical chromatin architecture, on a known evolutionary timescale.},
}
@article {pmid36914797,
year = {2023},
author = {Li, D and Wu, F and Zhou, S and Huang, XJ and Lee, HY},
title = {Heterochromatin rewiring and domain disruption-mediated chromatin compaction during erythropoiesis.},
journal = {Nature structural &amp; molecular biology},
volume = {},
number = {},
pages = {},
pmid = {36914797},
issn = {1545-9985},
abstract = {Mammalian erythropoiesis involves progressive chromatin compaction and subsequent enucleation in terminal differentiation, but the mechanisms underlying the three-dimensional chromatin reorganization remain obscure. Here, we systematically analyze the higher-order chromatin in purified populations of primary human erythroblasts. Our results reveal that heterochromatin regions undergo substantial compression, with H3K9me3 markers relocalizing to the nuclear periphery and forming a significant number of long-range interactions, and that ~58% of the topologically associating domain (TAD) boundaries are disrupted, while certain TADs enriched for markers of the active transcription state and erythroid master regulators, GATA1 and KLF1, are selectively maintained during terminal erythropoiesis. Finally, we demonstrate that GATA1 is involved in safeguarding selected essential chromatin domains during terminal erythropoiesis. Our study therefore delineates the molecular characteristics of a development-driven chromatin compaction process, which reveals transcription competence as a key indicator of the selected domain maintenance to ensure appropriate gene expression during the extreme compaction of chromatin.},
}
@article {pmid36894325,
year = {2023},
author = {Dang, D and Zhang, SW and Duan, R and Zhang, S},
title = {Defining the separation landscape of topological domains for decoding consensus domain organization of 3D genome.},
journal = {Genome research},
volume = {},
number = {},
pages = {},
doi = {10.1101/gr.277187.122},
pmid = {36894325},
issn = {1549-5469},
abstract = {Topologically associating domains (TADs) have emerged as basic structural and functional units of genome organization, and have been determined by many computational methods from Hi-C contact maps. However, the TADs obtained by different methods vary greatly, which makes the accurate determination of TADs a challenging issue and hinders subsequent biological analyses about their organization and functions. Obvious inconsistencies among the TADs identified by different methods indeed make the statistical and biological properties of TADs overly depend on the method we chose rather than on the data. To this end, we employ the consensus structural information captured by these methods to define the TAD separation landscape for decoding the consensus domain organization of the 3D genome. We demonstrate that the TAD separation landscape could be used to compare domain boundaries across multiple cell types for discovering conserved and divergent topological structures, decipher three types of boundary regions with diverse biological features, and identify Consensus TADs (ConsTADs). We illustrate that these analyses could deepen our understanding of the relationships between the topological domains and chromatin states, gene expression, and DNA replication timing.},
}
@article {pmid36869353,
year = {2023},
author = {Richer, S and Tian, Y and Schoenfelder, S and Hurst, L and Murrell, A and Pisignano, G},
title = {Widespread allele-specific topological domains in the human genome are not confined to imprinted gene clusters.},
journal = {Genome biology},
volume = {24},
number = {1},
pages = {40},
pmid = {36869353},
issn = {1474-760X},
support = {MR/P000711/1/MRC_/Medical Research Council/United Kingdom ; },
abstract = {BACKGROUND: There is widespread interest in the three-dimensional chromatin conformation of the genome and its impact on gene expression. However, these studies frequently do not consider parent-of-origin differences, such as genomic imprinting, which result in monoallelic expression. In addition, genome-wide allele-specific chromatin conformation associations have not been extensively explored. There are few accessible bioinformatic workflows for investigating allelic conformation differences and these require pre-phased haplotypes which are not widely available.<br><br>RESULTS: We developed a bioinformatic pipeline, "HiCFlow," that performs haplotype assembly and visualization of parental chromatin architecture. We benchmarked the pipeline using prototype haplotype phased Hi-C data from GM12878 cells at three disease-associated imprinted gene clusters. Using Region Capture Hi-C and Hi-C data from human cell lines (1-7HB2, IMR-90, and H1-hESCs), we can robustly identify the known stable allele-specific interactions at the IGF2-H19 locus. Other imprinted loci (DLK1 and SNRPN) are more variable and there is no "canonical imprinted 3D structure," but we could detect allele-specific differences in A/B compartmentalization. Genome-wide, when topologically associating domains (TADs) are unbiasedly ranked according to their allele-specific contact frequencies, a set of allele-specific TADs could be defined. These occur in genomic regions of high sequence variation. In addition to imprinted genes, allele-specific TADs are also enriched for allele-specific expressed genes. We find loci that have not previously been identified as allele-specific expressed genes such as the bitter taste receptors (TAS2Rs).<br><br>CONCLUSIONS: This study highlights the widespread differences in chromatin conformation between heterozygous loci and provides a new framework for understanding allele-specific expressed genes.},
}
@article {pmid36842325,
year = {2023},
author = {Karpinska, MA and Oudelaar, AM},
title = {The role of loop extrusion in enhancer-mediated gene activation.},
journal = {Current opinion in genetics &amp; development},
volume = {79},
number = {},
pages = {102022},
doi = {10.1016/j.gde.2023.102022},
pmid = {36842325},
issn = {1879-0380},
abstract = {Gene expression patterns in complex multicellular organisms are regulated by enhancers, which communicate with their target gene promoters in three-dimensional (3D) chromatin structures. Despite advances in our understanding of the mechanisms that organize mammalian genomes into compartments and topologically associating domains (TADs), it is not well understood how specific interactions between enhancers and promoters are controlled in this 3D context. In this review, we give an overview of recent evidence that shows that a process of loop extrusion plays an important role in the regulation of enhancer-promoter communication and discuss recent insights into the molecular mechanism by which loop extrusion contributes to enhancer-mediated gene activation.},
}
@article {pmid36840746,
year = {2023},
author = {Sabaté, T and Lelandais, B and Bertrand, E and Zimmer, C},
title = {Polymer simulations guide the detection and quantification of chromatin loop extrusion by imaging.},
journal = {Nucleic acids research},
volume = {},
number = {},
pages = {},
doi = {10.1093/nar/gkad034},
pmid = {36840746},
issn = {1362-4962},
abstract = {Genome-wide chromosome conformation capture (Hi-C) has revealed the organization of chromatin into topologically associating domains (TADs) and loops, which are thought to help regulate genome functions. TADs and loops are understood as the result of DNA extrusion mediated by the cohesin complex. However, despite recent efforts, direct visualization and quantification of this process in single cells remains an open challenge. Here, we use polymer simulations and dedicated analysis methods to explore if, and under which conditions, DNA loop extrusion can be detected and quantitatively characterized by imaging pairs of fluorescently labeled loci located near loop or TAD anchors in fixed or living cells. We find that under realistic conditions, extrusion can be detected and the frequency of loop formation can be quantified from fixed cell images alone, while the lifetime of loops and the speed of extrusion can be estimated from dynamic live-cell data. Our delineation of appropriate imaging conditions and the proposed analytical methods lay the groundwork for a systematic quantitative characterization of loop extrusion in fixed or living cells.},
}
@article {pmid36800432,
year = {2023},
author = {Zhao, Y and Ding, Y and He, L and Zhou, Q and Chen, X and Li, Y and Alfonsi, MV and Wu, Z and Sun, H and Wang, H},
title = {Multiscale 3D genome reorganization during skeletal muscle stem cell lineage progression and aging.},
journal = {Science advances},
volume = {9},
number = {7},
pages = {eabo1360},
doi = {10.1126/sciadv.abo1360},
pmid = {36800432},
issn = {2375-2548},
abstract = {Little is known about three-dimensional (3D) genome organization in skeletal muscle stem cells [also called satellite cells (SCs)]. Here, we comprehensively map the 3D genome topology reorganization during mouse SC lineage progression. Specifically, rewiring at the compartment level is most pronounced when SCs become activated. Marked loss in topologically associating domain (TAD) border insulation and chromatin looping also occurs during early activation process. Meanwhile, TADs can form TAD clusters and super-enhancer-containing TAD clusters orchestrate stage-specific gene expression. Furthermore, we uncover that transcription factor PAX7 is pivotal in enhancer-promoter (E-P) loop formation. We also identify cis-regulatory elements that are crucial for local chromatin organization at Pax7 locus and Pax7 expression. Lastly, we unveil that geriatric SC displays a prominent gain in long-range contacts and loss of TAD border insulation. Together, our results uncover that 3D chromatin extensively reorganizes at multiple architectural levels and underpins the transcriptome remodeling during SC lineage development and SC aging.},
}
@article {pmid36759336,
year = {2023},
author = {Kobets, VA and Ulianov, SV and Galitsyna, AA and Doronin, SA and Mikhaleva, EA and Gelfand, MS and Shevelyov, YY and Razin, SV and Khrameeva, EE},
title = {HiConfidence: a novel approach uncovering the biological signal in Hi-C data affected by technical biases.},
journal = {Briefings in bioinformatics},
volume = {},
number = {},
pages = {},
doi = {10.1093/bib/bbad044},
pmid = {36759336},
issn = {1477-4054},
abstract = {The chromatin interaction assays, particularly Hi-C, enable detailed studies of genome architecture in multiple organisms and model systems, resulting in a deeper understanding of gene expression regulation mechanisms mediated by epigenetics. However, the analysis and interpretation of Hi-C data remain challenging due to technical biases, limiting direct comparisons of datasets obtained in different experiments and laboratories. As a result, removing biases from Hi-C-generated chromatin contact matrices is a critical data analysis step. Our novel approach, HiConfidence, eliminates biases from the Hi-C data by weighing chromatin contacts according to their consistency between replicates so that low-quality replicates do not substantially influence the result. The algorithm is effective for the analysis of global changes in chromatin structures such as compartments and topologically associating domains. We apply the HiConfidence approach to several Hi-C datasets with significant technical biases, that could not be analyzed effectively using existing methods, and obtain meaningful biological conclusions. In particular, HiConfidence aids in the study of how changes in histone acetylation pattern affect chromatin organization in Drosophila melanogaster S2 cells. The method is freely available at GitHub: https://github.com/victorykobets/HiConfidence.},
}
@article {pmid36750787,
year = {2023},
author = {Maslova, A and Plotnikov, V and Nuriddinov, M and Gridina, M and Fishman, V and Krasikova, A},
title = {Hi-C analysis of genomic contacts revealed karyotype abnormalities in chicken HD3 cell line.},
journal = {BMC genomics},
volume = {24},
number = {1},
pages = {66},
pmid = {36750787},
issn = {1471-2164},
mesh = {Animals ; *Chickens/genetics ; Karyotype ; *Genomics ; Sex Chromosomes ; Chromosome Aberrations ; Mammals/genetics ; },
abstract = {BACKGROUND: Karyotype abnormalities are frequent in immortalized continuous cell lines either transformed or derived from primary tumors. Chromosomal rearrangements can cause dramatic changes in gene expression and affect cellular phenotype and behavior during in vitro culture. Structural variations of chromosomes in many continuous mammalian cell lines are well documented, but chromosome aberrations in cell lines from other vertebrate models often remain understudied. The chicken LSCC-HD3 cell line (HD3), generated from erythroid precursors, was used as an avian model for erythroid differentiation and lineage-specific gene expression. However, karyotype abnormalities in the HD3 cell line were not assessed. In the present study, we applied high-throughput chromosome conformation capture to analyze 3D genome organization and to detect chromosome rearrangements in the HD3 cell line.<br><br>RESULTS: We obtained Hi-C maps of genomic interactions for the HD3 cell line and compared A/B compartments and topologically associating domains between HD3 and several other cell types. By analysis of contact patterns in the Hi-C maps of HD3 cells, we identified more than 25 interchromosomal translocations of regions&#x2009;&#x2265;&#x2009;200&#xa0;kb on both micro- and macrochromosomes. We classified most of the observed translocations as unbalanced, leading to the formation of heteromorphic chromosomes. In many cases of microchromosome rearrangements, an entire microchromosome together with other macro- and microchromosomes participated in the emergence of a derivative chromosome, resembling "chromosomal fusions'' between acrocentric microchromosomes. Intrachromosomal inversions, deletions and duplications were also detected in HD3 cells. Several of the identified simple and complex chromosomal rearrangements, such as between GGA2 and GGA1qter; GGA5, GGA4p and GGA7p; GGA4q, GGA6 and GGA19; and duplication of the sex chromosome GGAW, were confirmed by FISH.<br><br>CONCLUSIONS: In the erythroid progenitor HD3 cell line, in contrast to mature and immature erythrocytes, the genome is organized into distinct topologically associating domains. The HD3 cell line has a severely rearranged karyotype with most of the chromosomes engaged in translocations and can be used in studies of genome structure-function relationships. Hi-C proved to be a reliable tool for simultaneous assessment of the spatial genome organization and chromosomal aberrations in karyotypes of birds with a large number of microchromosomes.},
}
@article {pmid36744801,
year = {2023},
author = {Yang, L and Akgol Oksuz, B and Dekker, J and Gibcus, JH},
title = {Capturing Chromosome Conformation Across Length Scales.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {191},
pages = {},
doi = {10.3791/64001},
pmid = {36744801},
issn = {1940-087X},
mesh = {*Chromosomes/genetics/metabolism ; *Chromatin/genetics ; DNA/genetics/chemistry ; Cell Nucleus/metabolism ; DNA Restriction Enzymes/metabolism ; Formaldehyde/chemistry ; Nucleic Acid Conformation ; },
abstract = {Chromosome conformation capture (3C) is used to detect three-dimensional chromatin interactions. Typically, chemical crosslinking with formaldehyde (FA) is used to fix chromatin interactions. Then, chromatin digestion with a restriction enzyme and subsequent religation of fragment ends converts three-dimensional (3D) proximity into unique ligation products. Finally, after reversal of crosslinks, protein removal, and DNA isolation, DNA is sheared and prepared for high-throughput sequencing. The frequency of proximity ligation of pairs of loci is a measure of the frequency of their colocalization in three-dimensional space in a cell population. A sequenced Hi-C library provides genome-wide information on interaction frequencies between all pairs of loci. The resolution and precision of Hi-C relies on efficient crosslinking that maintains chromatin contacts and frequent and uniform fragmentation of the chromatin. This paper describes an improved in situ Hi-C protocol, Hi-C 3.0, that increases the efficiency of crosslinking by combining two crosslinkers (formaldehyde [FA] and disuccinimidyl glutarate [DSG]), followed by finer digestion using two restriction enzymes (DpnII and DdeI). Hi-C 3.0 is a single protocol for the accurate quantification of genome folding features at smaller scales such as loops and topologically associating domains (TADs), as well as features at larger nucleus-wide scales such as compartments.},
}
@article {pmid36740586,
year = {2023},
author = {Selcen, I and Prentice, E and Casaccia, P},
title = {The epigenetic landscape of oligodendrocyte lineage cells.},
journal = {Annals of the New York Academy of Sciences},
volume = {},
number = {},
pages = {},
doi = {10.1111/nyas.14959},
pmid = {36740586},
issn = {1749-6632},
abstract = {The epigenetic landscape of oligodendrocyte lineage cells refers to the cell-specific modifications of DNA, chromatin, and RNA that define a unique gene expression pattern of functionally specialized cells. Here, we focus on the epigenetic changes occurring as progenitors differentiate into myelin-forming cells and respond to the local environment. First, modifications of DNA, RNA, nucleosomal histones, key principles of chromatin organization, topologically associating domains, and local remodeling will be reviewed. Then, the relationship between epigenetic modulators and RNA processing will be explored. Finally, the reciprocal relationship between the epigenome as a determinant of the mechanical properties of cell nuclei and the target of mechanotransduction will be discussed. The overall goal is to provide an interpretative key on how epigenetic changes may account for the heterogeneity of the transcriptional profiles identified in this lineage.},
}
@article {pmid36736317,
year = {2023},
author = {Costea, J and Schoeberl, UE and Malzl, D and von der Linde, M and Fitz, J and Gupta, A and Makharova, M and Goloborodko, A and Pavri, R},
title = {A de novo transcription-dependent TAD boundary underpins critical multiway interactions during antibody class switch recombination.},
journal = {Molecular cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.molcel.2023.01.014},
pmid = {36736317},
issn = {1097-4164},
abstract = {Interactions between transcription and cohesin-mediated loop extrusion can influence 3D chromatin architecture. However, their relevance in biology is unclear. Here, we report a direct role for such interactions in the mechanism of antibody class switch recombination (CSR) at the murine immunoglobulin heavy chain locus (Igh). Using Tri-C to measure higher-order multiway interactions on single alleles, we find that the juxtaposition (synapsis) of transcriptionally active donor and acceptor Igh switch (S) sequences, an essential step in CSR, occurs via the interaction of loop extrusion complexes with a de novo topologically associating domain (TAD) boundary formed via transcriptional activity across S regions. Surprisingly, synapsis occurs predominantly in proximity to the 3' CTCF-binding element (3'CBE) rather than the Igh super-enhancer, suggesting a two-step mechanism whereby transcription of S regions is not topologically coupled to synapsis, as has been previously proposed. Altogether, these insights advance our understanding of how 3D chromatin architecture regulates CSR.},
}
@article {pmid36735786,
year = {2023},
author = {Cavalheiro, GR and Girardot, C and Viales, RR and Pollex, T and Cao, TBN and Lacour, P and Feng, S and Rabinowitz, A and Furlong, EEM},
title = {CTCF, BEAF-32, and CP190 are not required for the establishment of TADs in early Drosophila embryos but have locus-specific roles.},
journal = {Science advances},
volume = {9},
number = {5},
pages = {eade1085},
pmid = {36735786},
issn = {2375-2548},
mesh = {Animals ; *Drosophila/genetics/metabolism ; *Drosophila Proteins/metabolism ; Genome ; Chromatin/genetics ; Chromosomes ; DNA-Binding Proteins/metabolism ; Eye Proteins/genetics/metabolism ; Microtubule-Associated Proteins/metabolism ; Nuclear Proteins/metabolism ; CCCTC-Binding Factor/genetics ; },
abstract = {The boundaries of topologically associating domains (TADs) are delimited by insulators and/or active promoters; however, how they are initially established during embryogenesis remains unclear. Here, we examined this during the first hours of Drosophila embryogenesis. DNA-FISH confirms that intra-TAD pairwise proximity is established during zygotic genome activation (ZGA) but with extensive cell-to-cell heterogeneity. Most newly formed boundaries are occupied by combinations of CTCF, BEAF-32, and/or CP190. Depleting each insulator individually from chromatin revealed that TADs can still establish, although with lower insulation, with a subset of boundaries (~10%) being more dependent on specific insulators. Some weakened boundaries have aberrant gene expression due to unconstrained enhancer activity. However, the majority of misexpressed genes have no obvious direct relationship to changes in domain-boundary insulation. Deletion of an active promoter (thereby blocking transcription) at one boundary had a greater impact than deleting the insulator-bound region itself. This suggests that cross-talk between insulators and active promoters and/or transcription might reinforce domain boundary insulation during embryogenesis.},
}
@article {pmid36719724,
year = {2023},
author = {Landshammer, A and Bolondi, A and Kretzmer, H and Much, C and Buschow, R and Rose, A and Wu, HJ and Mackowiak, SD and Braendl, B and Giesselmann, P and Tornisiello, R and Parsi, KM and Huey, J and Mielke, T and Meierhofer, D and Maehr, R and Hnisz, D and Michor, F and Rinn, JL and Meissner, A},
title = {T-REX17 is a transiently expressed non-coding RNA essential for human endoderm formation.},
journal = {eLife},
volume = {12},
number = {},
pages = {},
pmid = {36719724},
issn = {2050-084X},
mesh = {Pregnancy ; Female ; Humans ; *RNA, Long Noncoding/genetics/metabolism ; Epithelial-Mesenchymal Transition ; Endoderm ; Gene Expression Regulation, Developmental ; SOXF Transcription Factors/genetics/metabolism ; Cell Differentiation/genetics ; },
abstract = {Long non-coding RNAs (lncRNAs) have emerged as fundamental regulators in various biological processes, including embryonic development and cellular differentiation. Despite much progress over the past decade, the genome-wide annotation of lncRNAs remains incomplete and many known non-coding loci are still poorly characterized. Here, we report the discovery of a previously unannotated lncRNA that is transcribed 230 kb upstream of the SOX17 gene and located within the same topologically associating domain. We termed it T-REX17 (Transcript Regulating Endoderm and activated by soX17) and show that it is induced following SOX17 activation but its expression is more tightly restricted to early definitive endoderm. Loss of T-REX17 affects crucial functions independent of SOX17 and leads to an aberrant endodermal transcriptome, signaling pathway deregulation and epithelial to mesenchymal transition defects. Consequently, cells lacking the lncRNA cannot further differentiate into more mature endodermal cell types. Taken together, our study identified and characterized T-REX17 as a transiently expressed and essential non-coding regulator in early human endoderm differentiation.},
}
@article {pmid36717722,
year = {2023},
author = {Barajas-Mora, EM and Lee, L and Lu, H and Valderrama, JA and Bjanes, E and Nizet, V and Feeney, AJ and Hu, M and Murre, C},
title = {Enhancer-instructed epigenetic landscape and chromatin compartmentalization dictate a primary antibody repertoire protective against specific bacterial pathogens.},
journal = {Nature immunology},
volume = {24},
number = {2},
pages = {320-336},
pmid = {36717722},
issn = {1529-2916},
mesh = {Mice ; Animals ; *Chromatin/genetics ; Immunoglobulin Variable Region/genetics ; Immunoglobulin kappa-Chains/genetics ; *Methicillin-Resistant Staphylococcus aureus/genetics ; B-Lymphocytes ; Epigenesis, Genetic ; },
abstract = {Antigen receptor loci are organized into variable (V), diversity (D) and joining (J) gene segments that rearrange to generate antigen receptor repertoires. Here, we identified an enhancer (E34) in the murine immunoglobulin kappa (Igk) locus that instructed rearrangement of Vκ genes located in a sub-topologically associating domain, including a Vκ gene encoding for antibodies targeting bacterial phosphorylcholine. We show that E34 instructs the nuclear repositioning of the E34 sub-topologically associating domain from a recombination-repressive compartment to a recombination-permissive compartment that is marked by equivalent activating histone modifications. Finally, we found that E34-instructed Vκ-Jκ rearrangement was essential to combat Streptococcus pneumoniae but not methicillin-resistant Staphylococcus aureus or influenza infections. We propose that the merging of Vκ genes with Jκ elements is instructed by one-dimensional epigenetic information imposed by enhancers across Vκ and Jκ genomic regions. The data also reveal how enhancers generate distinct antibody repertoires that provide protection against lethal bacterial infection.},
}
@article {pmid36708949,
year = {2023},
author = {Nayak, S and Jiang, K and Hope, E and Cross, M and Overmiller, A and Naz, F and Worrell, S and Bajpai, D and Hasneen, K and Brooks, SR and Dell'Orso, S and Morasso, MI},
title = {Chromatin landscape governing murine epidermal differentiation.},
journal = {The Journal of investigative dermatology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jid.2022.12.020},
pmid = {36708949},
issn = {1523-1747},
abstract = {Chromatin landscape and regulatory networks are determinant in lineage specification and differentiation. To define the temporospatial differentiation axis in murine epidermal cells in vivo, we generated datasets profiling expression dynamics (RNA-Seq), chromatin accessibility (ATAC-Seq), architecture (Hi-C), and histone modifications (ChIP-Seq) in the epidermis. We show that many differentially regulated genes are suppressed during the differentiation process, with super-enhancers (SEs) controlling differentiation-specific epigenomic changes. Our data shows the relevance of the Dlx/Klf/Grhl combinatorial regulatory network in maintaining correct temporospatial gene expression during epidermal differentiation. We determined differential open compartments, topologically associating domain (TAD) score and looping in the Basal cell (B) and Suprabasal cell (SB) epidermal fractions, with the evolutionarily conserved Epidermal Differentiation Complex (EDC) region showing distinct SB-specific TAD and loop formation that coincided with SE sites. Overall, our study provides a global genome-wide resource of chromatin dynamics that define unrecognized regulatory networks and the epigenetic control of Dlx3-bound SE elements during epidermal differentiation.},
}
@article {pmid36708167,
year = {2023},
author = {Fan, S and Dang, D and Ye, Y and Zhang, SW and Gao, L and Zhang, S},
title = {scHi-CSim: a flexible simulator that generates high-fidelity single-cell Hi-C data for benchmarking.},
journal = {Journal of molecular cell biology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jmcb/mjad003},
pmid = {36708167},
issn = {1759-4685},
abstract = {Single-cell Hi-C technology provides an unprecedented opportunity to reveal chromatin structure in individual cells. However, high sequencing cost impedes the generation of biological Hi-C data with high sequencing depths and multiple replicates for downstream analysis. Here we developed a single-cell Hi-C simulator (scHi-CSim) that generates high-fidelity data for benchmarking. scHi-CSim merges neighboring cells to overcome the sparseness of data, samples interactions in distance-stratified chromosomes to maintain the heterogeneity of single cells, and estimates the empirical distribution of restriction fragments to generate simulated data. We demonstrated that scHi-CSim can generate high-fidelity data by comparing the performance of single-cell clustering and detection of chromosomal high-order structures with raw data. Furthermore, scHi-CSim is flexible to change sequencing depths and the number of simulated replicates. We showed that increasing sequencing depths could improve the accuracy of detecting topologically associating domains. We also used scHi-CSim to generate a series of simulated datasets with different sequencing depths to benchmark single-cell Hi-C clustering methods.},
}
@article {pmid36693380,
year = {2023},
author = {Kim, S and Wysocka, J},
title = {Deciphering the multi-scale, quantitative cis-regulatory code.},
journal = {Molecular cell},
volume = {83},
number = {3},
pages = {373-392},
pmid = {36693380},
issn = {1097-4164},
support = {R35 GM131757/GM/NIGMS NIH HHS/United States ; },
mesh = {*Enhancer Elements, Genetic ; *Transcription Factors/genetics/metabolism ; Promoter Regions, Genetic ; Gene Expression Regulation ; Base Sequence ; Chromatin/genetics ; },
abstract = {Uncovering the cis-regulatory code that governs when and how much each gene is transcribed in a given genome and cellular state remains a central goal of biology. Here, we discuss major layers of regulation that influence how transcriptional outputs are encoded by DNA sequence and cellular context. We first discuss how transcription factors bind specific DNA sequences in a dosage-dependent and cooperative manner and then proceed to the cofactors that facilitate transcription factor function and mediate the activity of modular cis-regulatory elements such as enhancers, silencers, and promoters. We then consider the complex and poorly understood interplay of these diverse elements within regulatory landscapes and its relationships with chromatin states and nuclear organization. We propose that a mechanistically informed, quantitative model of transcriptional regulation that integrates these multiple regulatory layers will be the key to ultimately cracking the cis-regulatory code.},
}
@article {pmid36658660,
year = {2023},
author = {Ni, L and Liu, Y and Ma, X and Liu, T and Yang, X and Wang, Z and Liang, Q and Liu, S and Zhang, M and Wang, Z and Shen, Y and Tian, Z},
title = {Pan-3D genome analysis reveals structural and functional differentiation of soybean genomes.},
journal = {Genome biology},
volume = {24},
number = {1},
pages = {12},
pmid = {36658660},
issn = {1474-760X},
mesh = {*Soybeans/genetics ; *Genome ; Gene Expression Regulation ; Retroelements ; Genome, Plant ; Chromatin ; },
abstract = {BACKGROUND: High-order chromatin structure plays important roles in gene regulation. However, the diversity of the three-dimensional (3D) genome across plant accessions are seldom reported.<br><br>RESULTS: Here, we perform the pan-3D genome analysis using Hi-C sequencing data from 27 soybean accessions and comprehensively investigate the relationships between 3D genomic variations and structural variations&#xa0;(SVs) as well as gene expression. We find that intersection regions between A/B compartments largely contribute to compartment divergence. Topologically associating domain (TAD) boundaries in A compartments exhibit significantly higher density compared to those in B compartments. Pan-3D genome analysis shows that core TAD boundaries have the highest transcription start site&#xa0;(TSS) density and lowest GC content and repeat percentage. Further investigation shows that non-long terminal repeat (non-LTR) retrotransposons play important roles in maintaining TAD boundaries, while Gypsy elements and satellite repeats are associated with private TAD boundaries. Moreover, presence and absence variation&#xa0;(PAV) is found to be the major contributor to 3D genome variations. Nevertheless, approximately 55% of 3D genome variations are not associated with obvious genetic variations, and half of them affect the flanking gene expression. In addition, we find that the 3D genome may also undergo selection during soybean domestication.<br><br>CONCLUSION: Our study sheds light on the role of 3D genomes in plant genetic diversity and provides a valuable resource for studying gene regulation and genome evolution.},
}
@article {pmid36650052,
year = {2023},
author = {Islam, Z and Saravanan, B and Walavalkar, K and Farooq, U and Singh, AK and Radhakrishnan, S and Thakur, J and Pandit, A and Henikoff, S and Notani, D},
title = {Active enhancers strengthen insulation by RNA-mediated CTCF binding at chromatin domain boundaries.},
journal = {Genome research},
volume = {33},
number = {1},
pages = {1-17},
doi = {10.1101/gr.276643.122},
pmid = {36650052},
issn = {1549-5469},
support = {//Wellcome Trust/United Kingdom ; },
mesh = {*Chromatin/genetics ; CCCTC-Binding Factor/metabolism ; Binding Sites ; Promoter Regions, Genetic ; *RNA ; Enhancer Elements, Genetic ; },
abstract = {Vertebrate genomes are partitioned into chromatin domains or topologically associating domains (TADs), which are typically bound by head-to-head pairs of CTCF binding sites. Transcription at domain boundaries correlates with better insulation; however, it is not known whether the boundary transcripts themselves contribute to boundary function. Here we characterize boundary-associated RNAs genome-wide, focusing on the disease-relevant INK4a/ARF and MYC TAD. Using CTCF site deletions and boundary-associated RNA knockdowns, we observe that boundary-associated RNAs facilitate recruitment and clustering of CTCF at TAD borders. The resulting CTCF enrichment enhances TAD insulation, enhancer-promoter interactions, and TAD gene expression. Importantly, knockdown of boundary-associated RNAs results in loss of boundary insulation function. Using enhancer deletions and CRISPRi of promoters, we show that active TAD enhancers, but not promoters, induce boundary-associated RNA transcription, thus defining a novel class of regulatory enhancer RNAs.},
}
@article {pmid36642680,
year = {2023},
author = {Yeo, SJ and Ying, C and Fullwood, MJ and Tergaonkar, V},
title = {Emerging regulatory mechanisms of noncoding RNAs in topologically associating domains.},
journal = {Trends in genetics : TIG},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tig.2022.12.003},
pmid = {36642680},
issn = {0168-9525},
abstract = {Topologically associating domains (TADs) are integral to spatial genome organization, instructing gene expression, and cell fate. Recently, several advances have uncovered roles for noncoding RNAs (ncRNAs) in the regulation of the form and function of mammalian TADs. Phase separation has also emerged as a potential arbiter of ncRNAs in the regulation of TADs. In this review we discuss the implications of these novel findings in relation to how ncRNAs might structurally and functionally regulate TADs from two perspectives: moderating loop extrusion through interactions with architectural proteins, and facilitating TAD phase separation. Additionally, we propose future studies and directions to investigate these phenomena.},
}
@article {pmid36617663,
year = {2023},
author = {Mulhair, PO and Crowley, L and Boyes, DH and Harper, A and Lewis, OT and , and Holland, PWH},
title = {Diversity, duplication, and genomic organization of homeobox genes in Lepidoptera.},
journal = {Genome research},
volume = {33},
number = {1},
pages = {32-44},
doi = {10.1101/gr.277118.122},
pmid = {36617663},
issn = {1549-5469},
support = {218328/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Animals ; *Genes, Homeobox ; *Butterflies ; Phylogeny ; Multigene Family ; Genomics ; Evolution, Molecular ; },
abstract = {Homeobox genes encode transcription factors with essential roles in patterning and cell fate in developing animal embryos. Many homeobox genes, including Hox and NK genes, are arranged in gene clusters, a feature likely related to transcriptional control. Sparse taxon sampling and fragmentary genome assemblies mean that little is known about the dynamics of homeobox gene evolution across Lepidoptera or about how changes in homeobox gene number and organization relate to diversity in this large order of insects. Here we analyze an extensive data set of high-quality genomes to characterize the number and organization of all homeobox genes in 123 species of Lepidoptera from 23 taxonomic families. We find most Lepidoptera have around 100 homeobox loci, including an unusual Hox gene cluster in which the lab gene is repositioned and the ro gene is next to pb A topologically associating domain spans much of the gene cluster, suggesting deep regulatory conservation of the Hox cluster arrangement in this insect order. Most Lepidoptera have four Shx genes, divergent zen-derived loci, but these loci underwent dramatic duplication in several lineages, with some moths having over 165 homeobox loci in the Hox gene cluster; this expansion is associated with local LINE element density. In contrast, the NK gene cluster content is more stable, although there are differences in organization compared with other insects, as well as major rearrangements within butterflies. Our analysis represents the first description of homeobox gene content across the order Lepidoptera, exemplifying the potential of newly generated genome assemblies for understanding genome and gene family evolution.},
}
@article {pmid36609218,
year = {2023},
author = {Zhang, L and Xu, M and Zhang, W and Zhu, C and Cui, Z and Fu, H and Ma, Y and Huang, S and Cui, J and Liang, S and Huang, L and Wang, H},
title = {Three-dimensional genome landscape comprehensively reveals patterns of spatial gene regulation in papillary and anaplastic thyroid cancers: a study using representative cell lines for each cancer type.},
journal = {Cellular &amp; molecular biology letters},
volume = {28},
number = {1},
pages = {1},
pmid = {36609218},
issn = {1689-1392},
mesh = {Humans ; Cell Line ; Chromatin/genetics ; DNA Copy Number Variations/genetics ; Homeodomain Proteins/genetics ; Methyltransferases/genetics ; *Thyroid Carcinoma, Anaplastic/genetics ; *Thyroid Neoplasms/genetics ; Transcription Factors/genetics ; Genome ; },
abstract = {BACKGROUND: Spatial chromatin structure is intricately linked with somatic aberrations, and somatic mutations of various cancer-related genes, termed co-mutations (CoMuts), occur in certain patterns during cancer initiation and progression. The functional mechanisms underlying these genetic events remain largely unclear in thyroid cancer (TC). With discrepant differentiation, papillary thyroid cancer (PTC) and anaplastic thyroid cancer (ATC) differ greatly in characteristics and prognosis. We aimed to reveal the spatial gene alterations and regulations between the two TC subtypes.<br><br>METHODS: We systematically investigated and compared the spatial co-mutations between ATC (8305C), PTC (BCPAP and TPC-1), and normal thyroid cells (Nthy-ori-3-1). We constructed a framework integrating whole-genome sequencing (WGS), high-throughput chromosome conformation capture (Hi-C), and transcriptome sequencing, to systematically detect the associations between the somatic co-mutations of cancer-related genes, structural variations (SVs), copy number variations (CNVs), and high-order chromatin conformation.<br><br>RESULTS: Spatial co-mutation hotspots were enriched around topologically associating domains (TADs) in TC. A common set of 227 boundaries were identified in both ATC and PTC, with significant overlaps between them. The spatial proximities of the co-mutated gene pairs in the two TC types were significantly greater than in the gene-level and overall backgrounds, and ATC cells had higher TAD contact frequency with CoMuts&#x2009;>&#x2009;10 compared with PTC cells. Compared with normal thyroid cells, in ATC the number of the created novel three-dimensional chromatin structural domains increased by 10%, and the number of shifted TADs decreased by 7%. We found five TAD blocks with CoMut genes/events specific to ATC with certain mutations in genes including MAST-NSUN4, AM129B/TRUB2, COL5A1/PPP1R26, PPP1R26/GPSM1/CCDC183, and PRAC2/DLX4. For the majority of ATC and PTC cells, the HOXA10 and HIF2&#x3b1; signals close to the transcription start sites of CoMut genes within TADs were significantly stronger than those at the background. CNV breakpoints significantly overlapped with TAD boundaries in both TC subtypes. ATCs had more CNV losses overlapping with TAD boundaries, and noncoding SVs involved in intrachromosomal SVs, amplified inversions, and tandem duplication differed between ATC and PTC. TADs with short range were more abundant in ATC than PTC. More switches of A/B compartment types existed in ATC cells compared with PTC. Gene expression was significantly synchronized, and orchestrated by complex epigenetics and regulatory elements.<br><br>CONCLUSION: Chromatin interactions and gene alterations and regulations are largely heterogeneous in TC. CNVs and complex SVs may function in the TC genome by interplaying with TADs, and are largely different between ATC and PTC. Complexity of TC genomes, which are highly organized by 3D genome-wide interactions mediating mutational and structural variations and gene activation, may have been largely underappreciated. Our comprehensive analysis may provide key evidence and targets for more customized diagnosis and treatment of TC.},
}
@article {pmid36549923,
year = {2023},
author = {van Mierlo, G and Pushkarev, O and Kribelbauer, JF and Deplancke, B},
title = {Chromatin modules and their implication in genomic organization and gene regulation.},
journal = {Trends in genetics : TIG},
volume = {39},
number = {2},
pages = {140-153},
doi = {10.1016/j.tig.2022.11.003},
pmid = {36549923},
issn = {0168-9525},
mesh = {*Chromatin/genetics ; *Gene Expression Regulation/genetics ; Genome/genetics ; Genomics ; Regulatory Sequences, Nucleic Acid/genetics ; },
abstract = {Regulation of gene expression is a complex but highly guided process. While genomic technologies and computational approaches have allowed high-throughput mapping of cis-regulatory elements (CREs) and their interactions in 3D, their precise role in regulating gene expression remains obscure. Recent complementary observations revealed that interactions between CREs frequently result in the formation of small-scale functional modules within topologically associating domains. Such chromatin modules likely emerge from a complex interplay between regulatory machineries assembled at CREs, including site-specific binding of transcription factors. Here, we review the methods that allow identifying chromatin modules, summarize possible mechanisms that steer CRE interactions within these modules, and discuss outstanding challenges to uncover how chromatin modules fit in our current understanding of the functional 3D genome.},
}
@article {pmid36511816,
year = {2022},
author = {Kato, H and Tateishi, K and Iwadate, D and Yamamoto, K and Fujiwara, H and Nakatsuka, T and Kudo, Y and Hayakawa, Y and Ijichi, H and Otsuka, M and Kishikawa, T and Takahashi, R and Miyabayashi, K and Nakai, Y and Hirata, Y and Toyoda, A and Morishita, S and Fujishiro, M},
title = {HNF1B-driven three-dimensional chromatin structure for molecular classification in pancreatic cancers.},
journal = {Cancer science},
volume = {},
number = {},
pages = {},
doi = {10.1111/cas.15690},
pmid = {36511816},
issn = {1349-7006},
abstract = {The molecular subtypes of pancreatic cancer (PC), either classical/progenitor-like or basal/squamous-like, are currently a major topic of research because of their direct association with clinical outcomes. Some transcription factors (TFs) have been reported to be associated with these subtypes. However, the mechanisms by which these molecular signatures of PCs are established remain unknown. Epigenetic regulatory processes, supported by dynamic changes in the chromatin structure, are essential for transcriptional profiles. Previously, we reported the importance of open chromatin profiles in the biological features and transcriptional status of PCs. Here, we aimed to analyze the relationships between three-dimensional (3D) genome structures and the molecular subtypes of human PCs using Hi-C analysis. We observed a correlation of the specific elements of 3D genome modules, including compartments, topologically associating domains, and enhancer-promoter loops, with the expression of related genes. We focused on HNF1B, a TF that is implicated in the progenitor subtype. Forced expression of HNF1B in squamous-type PC organoids induced the upregulation and downregulation of genes associated with progenitor and squamous subtypes, respectively. Long-range genomic interactions induced by HNF1B were accompanied by compartment modulation and H3K27ac redistribution. We also found that these HNF1B-induced changes in subtype-related gene expression required an intrinsically disordered region, suggesting a possible involvement of phase separation in compartment modulation. Thus, mapping of 3D structural changes induced by TFs, such as HNF1B, may become a useful resource for further understanding the molecular features of PCs.},
}
@article {pmid36493778,
year = {2023},
author = {Alavattam, KG and Mitzelfelt, KA and Bonora, G and Fields, PA and Yang, X and Chiu, HS and Pabon, L and Bertero, A and Palpant, NJ and Noble, WS and Murry, CE},
title = {Dynamic chromatin organization and regulatory interactions in human endothelial cell differentiation.},
journal = {Stem cell reports},
volume = {18},
number = {1},
pages = {159-174},
pmid = {36493778},
issn = {2213-6711},
support = {U54 DK107979/DK/NIDDK NIH HHS/United States ; R01 HL146868/HL/NHLBI NIH HHS/United States ; },
mesh = {Humans ; *Endothelial Cells ; *Chromatin ; Cell Differentiation/genetics ; Gene Expression Regulation ; },
abstract = {Vascular endothelial cells are a mesoderm-derived lineage with many essential functions, including angiogenesis and coagulation. The gene-regulatory mechanisms underpinning endothelial specialization are largely unknown, as are the roles of chromatin organization in regulating endothelial cell transcription. To investigate the relationships between chromatin organization and gene expression, we induced endothelial cell differentiation from human pluripotent stem cells and performed Hi-C and RNA-sequencing assays at specific time points. Long-range intrachromosomal contacts increase over the course of differentiation, accompanied by widespread heteroeuchromatic compartment transitions that are tightly associated with transcription. Dynamic topologically associating domain boundaries strengthen and converge on an endothelial cell state, and function to regulate gene expression. Chromatin pairwise point interactions (DNA loops) increase in frequency during differentiation and are linked to the expression of genes essential to vascular biology. Chromatin dynamics guide transcription in endothelial cell development and promote the divergence of endothelial cells from cardiomyocytes.},
}
@article {pmid36482308,
year = {2022},
author = {Yang, JY and Chang, JM},
title = {Pattern recognition of topologically associating domains using deep learning.},
journal = {BMC bioinformatics},
volume = {22},
number = {Suppl 10},
pages = {634},
pmid = {36482308},
issn = {1471-2105},
mesh = {Humans ; Animals ; Mice ; *Deep Learning ; Genomics ; },
abstract = {BACKGROUND: Recent increasing evidence indicates that three-dimensional chromosome structure plays an important role in genomic function. Topologically associating domains (TADs) are self-interacting regions that have been shown to be a chromosomal structural unit. During evolution, these are conserved based on checking synteny block cross species. Are there common TAD patterns across species or cell lines?<br><br>RESULTS: To address the above question, we propose a novel task-TAD recognition-as opposed to traditional TAD identification. Specifically, we treat Hi-C maps as images, thus re-casting TAD recognition as image pattern recognition, for which we use a convolutional neural network and a residual neural network. In addition, we propose an elegant way to generate non-TAD data for binary classification. We demonstrate deep learning performance which is quite promising,&#xa0;AUC&#x2009;>&#x2009;0.80,&#xa0;through cross-species and cell-type validation.<br><br>CONCLUSIONS: TADs have been shown to be conserved during evolution. Interestingly, our results confirm that the TAD recognition model is practical across species, which indicates that TADs between human and mouse show common patterns from an image classification point of view. Our approach could be a new way to identify TAD variations or patterns among Hi-C maps. For example, TADs of two Hi-C maps are conserved if the two classification models are exchangeable.},
}
@article {pmid36471076,
year = {2022},
author = {Mach, P and Kos, PI and Zhan, Y and Cramard, J and Gaudin, S and Tünnermann, J and Marchi, E and Eglinger, J and Zuin, J and Kryzhanovska, M and Smallwood, S and Gelman, L and Roth, G and Nora, EP and Tiana, G and Giorgetti, L},
title = {Cohesin and CTCF control the dynamics of chromosome folding.},
journal = {Nature genetics},
volume = {54},
number = {12},
pages = {1907-1918},
pmid = {36471076},
issn = {1546-1718},
mesh = {*Chromosomes/genetics ; },
abstract = {In mammals, interactions between sequences within topologically associating domains enable control of gene expression across large genomic distances. Yet it is unknown how frequently such contacts occur, how long they last and how they depend on the dynamics of chromosome folding and loop extrusion activity of cohesin. By imaging chromosomal locations at high spatial and temporal resolution in living cells, we show that interactions within topologically associating domains are transient and occur frequently during the course of a cell cycle. Interactions become more frequent and longer in the presence of convergent CTCF sites, resulting in suppression of variability in chromosome folding across time. Supported by physical models of chromosome dynamics, our data suggest that CTCF-anchored loops last around 10 min. Our results show that long-range transcriptional regulation might rely on transient physical proximity, and that cohesin and CTCF stabilize highly dynamic chromosome structures, facilitating selected subsets of chromosomal interactions.},
}
@article {pmid36469845,
year = {2022},
author = {Zhao, X and Zhu, S and Peng, W and Xue, HH},
title = {The Interplay of Transcription and Genome Topology Programs T Cell Development and Differentiation.},
journal = {Journal of immunology (Baltimore, Md. : 1950)},
volume = {209},
number = {12},
pages = {2269-2278},
pmid = {36469845},
issn = {1550-6606},
support = {I01 BX005771/BX/BLRD VA/United States ; R01 AI112579/AI/NIAID NIH HHS/United States ; R01 AI121080/AI/NIAID NIH HHS/United States ; R01 AI139874/AI/NIAID NIH HHS/United States ; },
mesh = {CCCTC-Binding Factor/genetics ; *Chromatin/genetics ; *Cell Cycle Proteins/metabolism ; Genome ; Chromosomes ; Cell Differentiation/genetics ; },
abstract = {T cells are essential for mounting defense against various pathogens and malignantly transformed cells. Thymic development and peripheral T cell differentiation are highly orchestrated biological processes that require precise gene regulation. Higher-order genome organization on multiple scales, in the form of chromatin loops, topologically associating domains and compartments, provides pivotal control of T cell gene expression. CTCF and the cohesin machinery are ubiquitously expressed architectural proteins responsible for establishing chromatin structures. Recent studies indicate that transcription factors, such as T lineage-defining Tcf1 and TCR-induced Batf, may have intrinsic ability and/or engage CTCF to shape chromatin architecture. In this article, we summarize current knowledge on the dynamic changes in genome topology that underlie normal or leukemic T cell development, CD4+ helper T cell differentiation, and CD8+ cytotoxic T cell functions. The knowledge lays a solid foundation for elucidating the causative link of spatial chromatin configuration to transcriptional and functional output in T cells.},
}
@article {pmid36466643,
year = {2022},
author = {Wang, X and Yang, B and Zhao, W and Cao, W and Shen, Y and Li, Z and Bao, X},
title = {Capture Hi-C reveals the influence on dynamic three-dimensional chromosome organization perturbed by genetic variation or vanillin stress in Saccharomyces cerevisiae.},
journal = {Frontiers in microbiology},
volume = {13},
number = {},
pages = {1012377},
pmid = {36466643},
issn = {1664-302X},
abstract = {Studying the mechanisms of resistance to vanillin in microorganisms, which is derived from lignin and blocks a major pathway of DNA double-strand break repair in yeast, will benefit the design of robust cell factories that produce biofuels and chemicals using lignocellulosic materials. A high vanillin-tolerant Saccharomyces cerevisiae strain EMV-8 carrying site mutations compared to its parent strain NAN-27 was selected for the analyses. The dynamics of the chromatin structure of eukaryotic cells play a critical role in transcription and the regulation of gene expression and thus the phenotype. Consequently, Hi-C and transcriptome analyses were conducted in EMV-8 and NAN-27 in the log phase with or without vanillin stress to determine the effects of mutations and vanillin disturbance on the dynamics of three-dimensional chromosome organization and the influence of the organization on the transcriptome. The outcomes indicated that the chromosome interaction pattern disturbed by vanillin stress or genetic mutations in the log phase was similar to that in mouse cells. The short chromosomes contact the short chromosomes, and the long chromosomes contact the long chromosomes. In response to vanillin stress, the boundaries of the topologically associating domain (TAD) in the vanillin-tolerant strain EMV-8 were more stable than those in its parent strain NAN-27. The motifs of SFL1, STB3, and NHP6A/B were enriched at TAD boundaries in both EMV-8 and NAN-27 with or without vanillin, indicating that these four genes were probably related to TAD formation. The Indel mutation of YRR1, whose absence was confirmed to benefit vanillin tolerance in EMV-8, caused two new interaction sites that contained three genes, WTM2, PUP1, and ALE1, whose overexpression did not affect vanillin resistance in yeast. Overall, our results revealed that in the log phase, genetic mutations and vanillin disturbance have a negligible effect on three-dimensional chromosome organization, and the reformation or disappearance of TAD boundaries did not show an association with gene expression, which provides an example for studying yeast chromatin structure during stress tolerance using Hi-C technology.},
}
@article {pmid36465116,
year = {2022},
author = {Bi, H and Hou, Y and Wang, J and Xia, Z and Wang, D and Liu, Y and Bao, H and Han, X and Ren, K and Li, E and Yue, F and Ji, P},
title = {Chromatin reconstruction during mouse terminal erythropoiesis.},
journal = {iScience},
volume = {25},
number = {12},
pages = {105554},
pmid = {36465116},
issn = {2589-0042},
abstract = {Mammalian terminal erythropoiesis involves chromatin and nuclear condensation followed by enucleation. Late-stage erythroblasts undergo caspase-mediated nuclear opening that is important for nuclear condensation through partial histone release. It remains unknown the dynamic changes of three-dimensional (3D) genomic organization during terminal erythropoiesis. Here, we used Hi-C to determine the chromatin structural change during primary mouse erythroblast terminal differentiation. We also performed RNA-sequencing and ATAC-sequencing under the same experimental setting to further reveal the genome accessibility and gene expression changes during this process. We found that late-stage terminal erythropoiesis involves global loss of topologically associating domains and establishment of inter-chromosomal interactions of the heterochromatin regions, which are associated with globally increased chromatin accessibility and upregulation of erythroid-related genes.},
}
@article {pmid36460680,
year = {2022},
author = {Zhang, Y and Blanchette, M},
title = {Reference panel guided topological structure annotation of Hi-C data.},
journal = {Nature communications},
volume = {13},
number = {1},
pages = {7426},
pmid = {36460680},
issn = {2041-1723},
abstract = {Accurately annotating topological structures (e.g., loops and topologically associating domains) from Hi-C data is critical for understanding the role of 3D genome organization in gene regulation. This is a challenging task, especially at high resolution, in part due to the limited sequencing coverage of Hi-C data. Current approaches focus on the analysis of individual Hi-C data sets of interest, without taking advantage of the facts that (i) several hundred Hi-C contact maps are publicly available, and (ii) the vast majority of topological structures are conserved across multiple cell types. Here, we present RefHiC, an attention-based deep learning framework that uses a reference panel of Hi-C datasets to facilitate topological structure annotation from a given study sample. We compare RefHiC against tools that do not use reference samples and find that RefHiC outperforms other programs at both topological associating domain and loop annotation across different cell types, species, and sequencing depths.},
}
@article {pmid36448318,
year = {2023},
author = {Miyata, M and Yoshida, J and Takagishi, I and Horie, K},
title = {Comparison of CRISPR-Cas9-mediated megabase-scale genome deletion methods in mouse embryonic stem cells.},
journal = {DNA research : an international journal for rapid publication of reports on genes and genomes},
volume = {30},
number = {1},
pages = {},
pmid = {36448318},
issn = {1756-1663},
mesh = {Animals ; Mice ; *CRISPR-Cas Systems ; *Mouse Embryonic Stem Cells ; Gene Editing/methods ; Genome ; Recombinational DNA Repair ; DNA End-Joining Repair ; },
abstract = {The genome contains large functional units ranging in size from hundreds of kilobases to megabases, such as gene clusters and topologically associating domains. To analyse these large functional units, the technique of deleting the entire functional unit is effective. However, deletion of such large regions is less efficient than conventional genome editing, especially in cultured cells, and a method that can ensure success is anticipated. Here, we compared methods to delete the 2.5-Mb Krüppel-associated box zinc finger protein (KRAB-ZFP) gene cluster in mouse embryonic stem cells using CRISPR-Cas9. Three methods were used: first, deletion by non-homologous end joining (NHEJ); second, homology-directed repair (HDR) using a single-stranded oligodeoxynucleotide (ssODN); and third, HDR employing targeting vectors with a selectable marker and 1-kb homology arms. NHEJ-mediated deletion was achieved in 9% of the transfected cells. Inversion was also detected at similar efficiency. The deletion frequency of NHEJ and HDR was found to be comparable when the ssODN was transfected. Deletion frequency was highest when targeting vectors were introduced, with deletions occurring in 31-63% of the drug-resistant clones. Biallelic deletion was observed when targeting vectors were used. This study will serve as a benchmark for the introduction of large deletions into the genome.},
}
@article {pmid36443333,
year = {2022},
author = {Wang, Y and Mak, TSH and Dattani, S and Garcia-Barcelo, MM and Fu, AX and Yip, KY and Ngan, ES and Tam, PK and Tang, CS and Sham, PC},
title = {Whole genome sequencing reveals epistasis effects within RET for Hirschsprung disease.},
journal = {Scientific reports},
volume = {12},
number = {1},
pages = {20423},
pmid = {36443333},
issn = {2045-2322},
mesh = {Humans ; *Hirschsprung Disease/genetics ; Epistasis, Genetic ; Whole Genome Sequencing ; Alleles ; Asian People ; Proto-Oncogene Proteins c-ret/genetics ; },
abstract = {Common variants in RET and NRG1 have been associated with Hirschsprung disease (HSCR), a congenital disorder characterised by incomplete innervation of distal gut, in East Asian (EA) populations. However, the allelic effects so far identified do not fully explain its heritability, suggesting the presence of epistasis, where effect of one genetic variant differs depending on other (modifier) variants. Few instances of epistasis have been documented in complex diseases due to modelling complexity and data challenges. We proposed four epistasis models to comprehensively capture epistasis for HSCR between and within RET and NRG1 loci using whole genome sequencing (WGS) data in EA samples. 65 variants within the Topologically Associating Domain (TAD) of RET demonstrated significant epistasis with the lead enhancer variant (RET+3; rs2435357). These epistatic variants formed two linkage disequilibrium (LD) clusters represented by rs2506026 and rs2506028 that differed in minor allele frequency and the best-supported epistatic model. Intriguingly, rs2506028 is in high LD with one cis-regulatory variant (rs2506030) highlighted previously, suggesting that detected epistasis might be mediated through synergistic effects on transcription regulation of RET. Our findings demonstrated the advantages of WGS data for detecting epistasis, and support the presence of interactive effects of regulatory variants in RET for HSCR.},
}
@article {pmid36409894,
year = {2022},
author = {Zhao, H and Yang, M and Bishop, J and Teng, Y and Cao, Y and Beall, BD and Li, S and Liu, T and Fang, Q and Fang, C and Xin, H and Nützmann, HW and Osbourn, A and Meng, F and Jiang, J},
title = {Identification and functional validation of super-enhancers in Arabidopsis thaliana.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {119},
number = {48},
pages = {e2215328119},
pmid = {36409894},
issn = {1091-6490},
support = {BBS/E/J/00PR9790/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Animals ; *Arabidopsis/genetics ; Regulatory Sequences, Nucleic Acid ; *Triterpenes ; Chromatin/genetics ; Mammals/genetics ; },
abstract = {Super-enhancers (SEs) are exceptionally large enhancers and are recognized to play prominent roles in cell identity in mammalian species. We surveyed the genomic regions containing large clusters of accessible chromatin regions (ACRs) marked by deoxyribonuclease (DNase) I hypersensitivity in Arabidopsis thaliana. We identified a set of 749 putative SEs, which have a minimum length of 1.5 kilobases and represent the top 2.5% of the largest ACR clusters. We demonstrate that the genomic regions associating with these SEs were more sensitive to DNase I than other nonpromoter ACRs. The SEs were preferentially associated with topologically associating domains. Furthermore, the SEs and their predicted cognate genes were frequently associated with organ development and tissue identity in A. thaliana. Therefore, the A. thaliana SEs and their cognate genes mirror the functional characteristics of those reported in mammalian species. We developed CRISPR/Cas-mediated deletion lines of a 3,578-bp SE associated with the thalianol biosynthetic gene cluster (BGC). Small deletions (131-157 bp) within the SE resulted in distinct phenotypic changes and transcriptional repression of all five thalianol genes. In addition, T-DNA insertions in the SE region resulted in transcriptional alteration of all five thalianol genes. Thus, this SE appears to play a central role in coordinating the operon-like expression pattern of the thalianol BGC.},
}
@article {pmid36357311,
year = {2022},
author = {Yancoskie, MN and Maritz, C and van Eijk, P and Reed, SH and Naegeli, H},
title = {To incise or not and where: SET-domain methyltransferases know.},
journal = {Trends in biochemical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tibs.2022.10.003},
pmid = {36357311},
issn = {0968-0004},
abstract = {The concept of the histone code posits that histone modifications regulate gene functions once interpreted by epigenetic readers. A well-studied case is trimethylation of lysine 4 of histone H3 (H3K4me3), which is enriched at gene promoters. However, H3K4me3 marks are not needed for the expression of most genes, suggesting extra roles, such as influencing the 3D genome architecture. Here, we highlight an intriguing analogy between the H3K4me3-dependent induction of double-strand breaks in several recombination events and the impact of this same mark on DNA incisions for the repair of bulky lesions. We propose that Su(var)3-9, Enhancer-of-zeste and Trithorax (SET)-domain methyltransferases generate H3K4me3 to guide nucleases into chromatin spaces, the favorable accessibility of which ensures that DNA break intermediates are readily processed, thereby safeguarding genome stability.},
}
@article {pmid36331876,
year = {2022},
author = {Kim, J and Jimenez, DS and Ragipani, B and Zhang, B and Street, LA and Kramer, M and Albritton, SE and Winterkorn, LH and Morao, AK and Ercan, S},
title = {Condensin DC loads and spreads from recruitment sites to create loop-anchored TADs in C. elegans.},
journal = {eLife},
volume = {11},
number = {},
pages = {},
pmid = {36331876},
issn = {2050-084X},
support = {R35 GM130311/GM/NIGMS NIH HHS/United States ; T32 HD007520/HD/NICHD NIH HHS/United States ; R33 EB019784/EB/NIBIB NIH HHS/United States ; R01 DC005991/DC/NIDCD NIH HHS/United States ; },
mesh = {Animals ; *Caenorhabditis elegans/genetics ; *Gene Expression Regulation ; Dosage Compensation, Genetic ; X Chromosome/genetics ; },
abstract = {Condensins are molecular motors that compact DNA via linear translocation. In Caenorhabditis elegans, the X-chromosome harbors a specialized condensin that participates in dosage compensation (DC). Condensin DC is recruited to and spreads from a small number of recruitment elements on the X-chromosome (rex) and is required for the formation of topologically associating domains (TADs). We take advantage of autosomes that are largely devoid of condensin DC and TADs to address how rex sites and condensin DC give rise to the formation of TADs. When an autosome and X-chromosome are physically fused, despite the spreading of condensin DC into the autosome, no TAD was created. Insertion of a strong rex on the X-chromosome results in the TAD boundary formation regardless of sequence orientation. When the same rex is inserted on an autosome, despite condensin DC recruitment, there was no spreading or features of a TAD. On the other hand, when a 'super rex' composed of six rex sites or three separate rex sites are inserted on an autosome, recruitment and spreading of condensin DC led to the formation of TADs. Therefore, recruitment to and spreading from rex sites are necessary and sufficient for recapitulating loop-anchored TADs observed on the X-chromosome. Together our data suggest a model in which rex sites are both loading sites and bidirectional barriers for condensin DC, a one-sided loop-extruder with movable inactive anchor.},
}
@article {pmid36325618,
year = {2022},
author = {Attou, A and Zülske, T and Wedemann, G},
title = {Cohesin and CTCF complexes mediate contacts in chromatin loops depending on nucleosome positions.},
journal = {Biophysical journal},
volume = {121},
number = {24},
pages = {4788-4799},
pmid = {36325618},
issn = {1542-0086},
mesh = {CCCTC-Binding Factor/chemistry/genetics/metabolism ; *Nucleosomes ; Protein Binding ; *Cell Cycle Proteins/metabolism ; Chromatin ; },
abstract = {The spatial organization of the eukaryotic genome plays an important role in regulating transcriptional activity. In the nucleus, chromatin forms loops that assemble into fundamental units called topologically associating domains that facilitate or inhibit long-range contacts. These loops are formed and held together by the ring-shaped cohesin protein complex, and this can involve binding of CCCTC-binding factor (CTCF). High-resolution conformation capture experiments provide the frequency at which two DNA fragments physically associate in three-dimensional space. However, technical limitations of this approach, such as low throughput, low resolution, or noise in contact maps, make data interpretation and identification of chromatin intraloop contacts, e.g., between distal regulatory elements and their target genes, challenging. Herein, an existing coarse-grained model of chromatin at single-nucleosome resolution was extended by integrating potentials describing CTCF and cohesin. We performed replica-exchange Monte Carlo simulations with regularly spaced nucleosomes and experimentally determined nucleosome positions in the presence of cohesin-CTCF, as well as depleted systems as controls. In fully extruded loops caused by the presence of cohesin and CTCF, the number of contacts within the formed loops was increased. The number and types of these contacts were impacted by the nucleosome distribution and loop size. Microloops were observed within cohesin-mediated loops due to thermal fluctuations without additional influence of other factors, and the number, size, and shape of microloops were determined by nucleosome distribution and loop size. Nucleosome positions directly affect the spatial structure and contact probability within a loop, with presumed consequences for transcriptional activity.},
}
@article {pmid36323253,
year = {2022},
author = {Zhu, X and Qi, C and Wang, R and Lee, JH and Shao, J and Bei, L and Xiong, F and Nguyen, PT and Li, G and Krakowiak, J and Koh, SP and Simon, LM and Han, L and Moore, TI and Li, W},
title = {Acute depletion of human core nucleoporin reveals direct roles in transcription control but dispensability for 3D genome organization.},
journal = {Cell reports},
volume = {41},
number = {5},
pages = {111576},
pmid = {36323253},
issn = {2211-1247},
support = {R21 GM132778/GM/NIGMS NIH HHS/United States ; R01 HG011633/HG/NHGRI NIH HHS/United States ; R01 CA262623/CA/NCI NIH HHS/United States ; K01 HL143111/HL/NHLBI NIH HHS/United States ; U01 HL156059/HL/NHLBI NIH HHS/United States ; R01 GM136922/GM/NIGMS NIH HHS/United States ; K22 CA204468/CA/NCI NIH HHS/United States ; },
mesh = {Humans ; *Nuclear Pore Complex Proteins/genetics ; *Nuclear Proteins/genetics ; Transcription Factors/genetics ; Nuclear Pore ; Genome ; Chromatin ; Cell Cycle Proteins/genetics ; },
abstract = {The nuclear pore complex (NPC) comprises more than 30 nucleoporins (NUPs) and is a hallmark of eukaryotes. NUPs have been suggested to be important in regulating gene transcription and 3D genome organization. However, evidence in support of their direct roles remains limited. Here, by Cut&amp;Run, we find that core NUPs display broad but also cell-type-specific association with active promoters and enhancers in human cells. Auxin-mediated rapid depletion of two NUPs demonstrates that NUP93, but not NUP35, directly and specifically controls gene transcription. NUP93 directly activates genes with high levels of RNA polymerase II loading and transcriptional elongation by facilitating full BRD4 recruitment to their active enhancers. dCas9-based tethering confirms a direct and causal role of NUP93 in gene transcriptional activation. Unexpectedly, in situ Hi-C and H3K27ac or H3K4me1 HiChIP results upon acute NUP93 depletion show negligible changesS2211-1247(22)01437-1 of 3D genome organization ranging from A/B compartments and topologically associating domains (TADs) to enhancer-promoter contacts.},
}
@article {pmid36318264,
year = {2023},
author = {Wang, Y and Song, C and Zhao, J and Zhang, Y and Zhao, X and Feng, C and Zhang, G and Zhu, J and Wang, F and Qian, F and Zhou, L and Zhang, J and Bai, X and Ai, B and Liu, X and Wang, Q and Li, C},
title = {SEdb 2.0: a comprehensive super-enhancer database of human and mouse.},
journal = {Nucleic acids research},
volume = {51},
number = {D1},
pages = {D280-D290},
pmid = {36318264},
issn = {1362-4962},
mesh = {Animals ; Humans ; Mice ; Chromatin/genetics ; *Databases, Genetic ; *Enhancer Elements, Genetic ; Gene Expression Regulation ; Transcription Factors/genetics/metabolism ; },
abstract = {Super-enhancers (SEs) are cell-specific DNA cis-regulatory elements that can supervise the transcriptional regulation processes of downstream genes. SEdb 2.0 (http://www.licpathway.net/sedb) aims to provide a comprehensive SE resource and annotate their potential roles in gene transcriptions. Compared with SEdb 1.0, we have made the following improvements: (i) Newly added the mouse SEs and expanded the scale of human SEs. SEdb 2.0 contained 1 167 518 SEs from 1739 human H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq) samples and 550 226 SEs from 931 mouse H3K27ac ChIP-seq samples, which was five times that of SEdb 1.0. (ii) Newly added transcription factor binding sites (TFBSs) in SEs identified by TF motifs and TF ChIP-seq data. (iii) Added comprehensive (epi)genetic annotations of SEs, including chromatin accessibility regions, methylation sites, chromatin interaction regions and topologically associating domains (TADs). (iv) Newly embedded and updated search and analysis tools, including 'Search SE by TF-based', 'Differential-Overlapping-SE analysis' and 'SE-based TF-Gene analysis'. (v) Newly provided quality control (QC) metrics for ChIP-seq processing. In summary, SEdb 2.0 is a comprehensive update of SEdb 1.0, which curates more SEs and annotation information than SEdb 1.0. SEdb 2.0 provides a friendly platform for researchers to more comprehensively clarify the important role of SEs in the biological process.},
}
@article {pmid36316347,
year = {2022},
author = {Telonis, AG and Yang, Q and Huang, HT and Figueroa, ME},
title = {MIR retrotransposons link the epigenome and the transcriptome of coding genes in acute myeloid leukemia.},
journal = {Nature communications},
volume = {13},
number = {1},
pages = {6524},
pmid = {36316347},
issn = {2041-1723},
mesh = {Mice ; Animals ; *Epigenome ; Retroelements/genetics ; Transcriptome/genetics ; Mutation ; *Leukemia, Myeloid, Acute/genetics/metabolism ; DNA Methylation/genetics ; },
abstract = {DNMT3A and IDH1/2 mutations combinatorically regulate the transcriptome and the epigenome in acute myeloid leukemia; yet the mechanisms of this interplay are unknown. Using a systems approach within topologically associating domains, we find that genes with significant expression-methylation correlations are enriched in signaling and metabolic pathways. The common denominator across these methylation-regulated genes is the density in MIR retrotransposons of their introns. Moreover, a discrete number of CpGs overlapping enhancers are responsible for regulating most of these genes. Established mouse models recapitulate the dependency of MIR-rich genes on the balanced expression of epigenetic modifiers, while projection of leukemic profiles onto normal hematopoiesis ones further consolidates the dependencies of methylation-regulated genes on MIRs. Collectively, MIR elements on genes and enhancers are susceptible to changes in DNA methylation activity and explain the cooperativity of proteins in this pathway in normal and malignant hematopoiesis.},
}
@article {pmid36309531,
year = {2022},
author = {Schöpflin, R and Melo, US and Moeinzadeh, H and Heller, D and Laupert, V and Hertzberg, J and Holtgrewe, M and Alavi, N and Klever, MK and Jungnitsch, J and Comak, E and Türkmen, S and Horn, D and Duffourd, Y and Faivre, L and Callier, P and Sanlaville, D and Zuffardi, O and Tenconi, R and Kurtas, NE and Giglio, S and Prager, B and Latos-Bielenska, A and Vogel, I and Bugge, M and Tommerup, N and Spielmann, M and Vitobello, A and Kalscheuer, VM and Vingron, M and Mundlos, S},
title = {Integration of Hi-C with short and long-read genome sequencing reveals the structure of germline rearranged genomes.},
journal = {Nature communications},
volume = {13},
number = {1},
pages = {6470},
pmid = {36309531},
issn = {2041-1723},
mesh = {Humans ; *Genome/genetics ; Base Sequence ; *Chromatin ; Chromosome Mapping ; Germ Cells ; },
abstract = {Structural variants are a common cause of disease and contribute to a large extent to inter-individual variability, but their detection and interpretation remain a challenge. Here, we investigate 11 individuals with complex genomic rearrangements including germline chromothripsis by combining short- and long-read genome sequencing (GS) with Hi-C. Large-scale genomic rearrangements are identified in Hi-C interaction maps, allowing for an independent assessment of breakpoint calls derived from the GS methods, resulting in >300 genomic junctions. Based on a comprehensive breakpoint detection and Hi-C, we achieve a reconstruction of whole rearranged chromosomes. Integrating information on the three-dimensional organization of chromatin, we observe that breakpoints occur more frequently than expected in lamina-associated domains (LADs) and that a majority reshuffle topologically associating domains (TADs). By applying phased RNA-seq, we observe an enrichment of genes showing allelic imbalanced expression (AIG) within 100 kb around the breakpoints. Interestingly, the AIGs hit by a breakpoint (19/22) display both up- and downregulation, thereby suggesting different mechanisms at play, such as gene disruption and rearrangements of regulatory information. However, the majority of interpretable genes located 200 kb around a breakpoint do not show significant expression changes. Thus, there is an overall robustness in the genome towards large-scale chromosome rearrangements.},
}
@article {pmid36289338,
year = {2022},
author = {Xu, J and Song, F and Lyu, H and Kobayashi, M and Zhang, B and Zhao, Z and Hou, Y and Wang, X and Luan, Y and Jia, B and Stasiak, L and Wong, JH and Wang, Q and Jin, Q and Jin, Q and Fu, Y and Yang, H and Hardison, RC and Dovat, S and Platanias, LC and Diao, Y and Yang, Y and Yamada, T and Viny, AD and Levine, RL and Claxton, D and Broach, JR and Zheng, H and Yue, F},
title = {Subtype-specific 3D genome alteration in acute myeloid leukaemia.},
journal = {Nature},
volume = {611},
number = {7935},
pages = {387-398},
pmid = {36289338},
issn = {1476-4687},
support = {R35 GM124820/GM/NIGMS NIH HHS/United States ; R01 HG009906/HG/NHGRI NIH HHS/United States ; R01 HG011207/HG/NHGRI NIH HHS/United States ; U01 CA200060/CA/NCI NIH HHS/United States ; R24 DK106766/DK/NIDDK NIH HHS/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; R01 CA216421/CA/NCI NIH HHS/United States ; K08 CA215317/CA/NCI NIH HHS/United States ; U01 DA053691/DA/NIDA NIH HHS/United States ; },
mesh = {Humans ; Chromatin/genetics ; DNA Methylation ; *Leukemia, Myeloid, Acute/genetics ; *Genome, Human/genetics ; Promoter Regions, Genetic ; Enhancer Elements, Genetic ; Gene Silencing ; Reproducibility of Results ; CRISPR-Cas Systems ; Sequence Analysis ; DNA (Cytosine-5-)-Methyltransferases ; Gene Expression Regulation, Leukemic ; },
abstract = {Acute myeloid leukaemia (AML) represents a set of heterogeneous myeloid malignancies, and hallmarks include mutations in epigenetic modifiers, transcription factors and kinases[1-5]. The extent to which mutations in AML drive alterations in chromatin 3D structure and contribute to myeloid transformation is unclear. Here we use Hi-C and whole-genome sequencing to analyse 25 samples from patients with AML and 7 samples from healthy donors. Recurrent and subtype-specific alterations in A/B compartments, topologically associating domains and chromatin loops were identified. RNA sequencing, ATAC with sequencing and CUT&amp;Tag for CTCF, H3K27ac and H3K27me3 in the same AML samples also revealed extensive and recurrent AML-specific promoter-enhancer and promoter-silencer loops. We validated the role of repressive loops on their target genes by CRISPR deletion and interference. Structural variation-induced enhancer-hijacking and silencer-hijacking events were further identified in AML samples. Hijacked enhancers play a part in AML cell growth, as demonstrated by CRISPR screening, whereas hijacked silencers have a downregulating role, as evidenced by CRISPR-interference-mediated de-repression. Finally, whole-genome bisulfite sequencing of 20 AML and normal samples revealed the delicate relationship between DNA methylation, CTCF binding and 3D genome structure. Treatment of AML cells with a DNA hypomethylating agent and triple knockdown of DNMT1, DNMT3A and DNMT3B enabled the manipulation of DNA methylation to revert 3D genome organization and gene expression. Overall, this study provides a resource for leukaemia studies and highlights the role of repressive loops and hijacked cis elements in human diseases.},
}
@article {pmid36283406,
year = {2022},
author = {Mohajeri, K and Yadav, R and D'haene, E and Boone, PM and Erdin, S and Gao, D and Moyses-Oliveira, M and Bhavsar, R and Currall, BB and O'Keefe, K and Burt, ND and Lowther, C and Lucente, D and Salani, M and Larson, M and Redin, C and Dudchenko, O and Aiden, EL and Menten, B and Tai, DJC and Gusella, JF and Vergult, S and Talkowski, ME},
title = {Transcriptional and functional consequences of alterations to MEF2C and its topological organization in neuronal models.},
journal = {American journal of human genetics},
volume = {109},
number = {11},
pages = {2049-2067},
pmid = {36283406},
issn = {1537-6605},
support = {R01 MH123155/MH/NIMH NIH HHS/United States ; R01 MH115957/MH/NIMH NIH HHS/United States ; R03 HD099547/HD/NICHD NIH HHS/United States ; U01 HG011755/HG/NHGRI NIH HHS/United States ; R01 NS093200/NS/NINDS NIH HHS/United States ; R01 HD096326/HD/NICHD NIH HHS/United States ; T32 GM007748/GM/NIGMS NIH HHS/United States ; K08 NS117891/NS/NINDS NIH HHS/United States ; P01 GM061354/GM/NIGMS NIH HHS/United States ; },
mesh = {Humans ; Genome ; Haploinsufficiency ; *Induced Pluripotent Stem Cells ; MEF2 Transcription Factors/genetics ; *Neural Stem Cells ; Neurons ; Transcription, Genetic ; },
abstract = {Point mutations and structural variants that directly disrupt the coding sequence of MEF2C have been associated with a spectrum of neurodevelopmental disorders (NDDs). However, the impact of MEF2C haploinsufficiency on neurodevelopmental pathways and synaptic processes is not well understood, nor are the complex mechanisms that govern its regulation. To explore the functional changes associated with structural variants that alter MEF2C expression and/or regulation, we generated an allelic series of 204 isogenic human induced pluripotent stem cell (hiPSC)-derived neural stem cells and glutamatergic induced neurons. These neuronal models harbored CRISPR-engineered mutations that involved direct deletion of MEF2C or deletion of the boundary points for topologically associating domains (TADs) and chromatin loops encompassing MEF2C. Systematic profiling of mutation-specific alterations, contrasted to unedited controls that were exposed to the same guide RNAs for each edit, revealed that deletion of MEF2C caused differential expression of genes associated with neurodevelopmental pathways and synaptic function. We also discovered significant reduction in synaptic activity measured by multielectrode arrays (MEAs) in neuronal cells. By contrast, we observed robust buffering against MEF2C regulatory disruption following deletion of a distal 5q14.3 TAD and loop boundary, whereas homozygous loss of a proximal loop boundary resulted in down-regulation of MEF2C expression and reduced electrophysiological activity on MEA that was comparable to direct gene disruption. Collectively, these studies highlight the considerable functional impact of MEF2C deletion in neuronal cells and systematically characterize the complex interactions that challenge a priori predictions of regulatory consequences from structural variants that disrupt three-dimensional genome organization.},
}
@article {pmid36201625,
year = {2022},
author = {Torosin, NS and Golla, TR and Lawlor, MA and Cao, W and Ellison, CE},
title = {Mode and Tempo of 3D Genome Evolution in Drosophila.},
journal = {Molecular biology and evolution},
volume = {39},
number = {11},
pages = {},
pmid = {36201625},
issn = {1537-1719},
support = {R01 GM130698/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; *Drosophila/genetics ; Phylogeny ; *Genome ; Chromatin/genetics ; Evolution, Molecular ; },
abstract = {Topologically associating domains (TADs) are thought to play an important role in preventing gene misexpression by spatially constraining enhancer-promoter contacts. The deleterious nature of gene misexpression implies that TADs should, therefore, be conserved among related species. Several early studies comparing chromosome conformation between species reported high levels of TAD conservation; however, more recent studies have questioned these results. Furthermore, recent work suggests that TAD reorganization is not associated with extensive changes in gene expression. Here, we investigate the evolutionary conservation of TADs among 11 species of Drosophila. We use Hi-C data to identify TADs in each species and employ a comparative phylogenetic approach to derive empirical estimates of the rate of TAD evolution. Surprisingly, we find that TADs evolve rapidly. However, we also find that the rate of evolution depends on the chromatin state of the TAD, with TADs enriched for developmentally regulated chromatin evolving significantly slower than TADs enriched for broadly expressed, active chromatin. We also find that, after controlling for differences in chromatin state, highly conserved TADs do not exhibit higher levels of gene expression constraint. These results suggest that, in general, most TADs evolve rapidly and their divergence is not associated with widespread changes in gene expression. However, higher levels of evolutionary conservation and gene expression constraints in TADs enriched for developmentally regulated chromatin suggest that these TAD subtypes may be more important for regulating gene expression, likely due to the larger number of long-distance enhancer-promoter contacts associated with developmental genes.},
}
@article {pmid36197938,
year = {2022},
author = {Simmons, JR and An, R and Amankwaa, B and Zayac, S and Kemp, J and Labrador, M},
title = {Phosphorylated histone variant γH2Av is associated with chromatin insulators in Drosophila.},
journal = {PLoS genetics},
volume = {18},
number = {10},
pages = {e1010396},
pmid = {36197938},
issn = {1553-7404},
support = {P40 OD010949/OD/NIH HHS/United States ; P40 OD018537/OD/NIH HHS/United States ; R21 MH108956/MH/NIMH NIH HHS/United States ; },
mesh = {Animals ; Chromatin/genetics/metabolism ; DNA/metabolism ; *Drosophila/genetics ; *Drosophila Proteins/genetics/metabolism ; Drosophila melanogaster/genetics/metabolism ; Histones/genetics/metabolism ; Insulator Elements/genetics ; Microtubule-Associated Proteins/genetics ; Nuclear Proteins/genetics ; Phosphoric Monoester Hydrolases/genetics ; Polytene Chromosomes/genetics ; },
abstract = {Chromatin insulators are responsible for orchestrating long-range interactions between enhancers and promoters throughout the genome and align with the boundaries of Topologically Associating Domains (TADs). Here, we demonstrate an association between gypsy insulator proteins and the phosphorylated histone variant H2Av (γH2Av), normally a marker of DNA double strand breaks. Gypsy insulator components colocalize with γH2Av throughout the genome, in polytene chromosomes and in diploid cells in which Chromatin IP data shows it is enriched at TAD boundaries. Mutation of insulator components su(Hw) and Cp190 results in a significant reduction in γH2Av levels in chromatin and phosphatase inhibition strengthens the association between insulator components and γH2Av and rescues γH2Av localization in insulator mutants. We also show that γH2Av, but not H2Av, is a component of insulator bodies, which are protein condensates that form during osmotic stress. Phosphatase activity is required for insulator body dissolution after stress recovery. Together, our results implicate the H2A variant with a novel mechanism of insulator function and boundary formation.},
}
@article {pmid36196855,
year = {2023},
author = {Jouret, G and Egloff, M and Landais, E and Tassy, O and Giuliano, F and Karmous-Benailly, H and Coutton, C and Satre, V and Devillard, F and Dieterich, K and Vieville, G and Kuentz, P and le Caignec, C and Beneteau, C and Isidor, B and Nizon, M and Callier, P and Marquet, V and Bieth, E and Lévy, J and Tabet, AC and Lyonnet, S and Baujat, G and Rio, M and Cartault, F and Scheidecker, S and Gouronc, A and Schalk, A and Jacquin, C and Spodenkiewicz, M and Angélini, C and Pennamen, P and Rooryck, C and Doco-Fenzy, M and Poirsier, C},
title = {Clinical and genomic delineation of the new proximal 19p13.3 microduplication syndrome.},
journal = {American journal of medical genetics. Part A},
volume = {191},
number = {1},
pages = {52-63},
doi = {10.1002/ajmg.a.62983},
pmid = {36196855},
issn = {1552-4833},
mesh = {Humans ; Comparative Genomic Hybridization ; *Abnormalities, Multiple/genetics ; *Microcephaly/genetics ; Syndrome ; Genetic Association Studies ; },
abstract = {A small but growing body of scientific literature is emerging about clinical findings in patients with 19p13.3 microdeletion or duplication. Recently, a proximal 19p13.3 microduplication syndrome was described, associated with growth delay, microcephaly, psychomotor delay and dysmorphic features. The aim of our study was to better characterize the syndrome associated with duplications in the proximal 19p13.3 region (prox 19p13.3 dup), and to propose a comprehensive analysis of the underlying genomic mechanism. We report the largest cohort of patients with prox 19p13.3 dup through a collaborative study. We collected 24 new patients with terminal or interstitial 19p13.3 duplication characterized by array-based Comparative Genomic Hybridization (aCGH). We performed mapping, phenotype-genotype correlations analysis, critical region delineation and explored three-dimensional chromatin interactions by analyzing Topologically Associating Domains (TADs). We define a new 377 kb critical region (CR 1) in chr19: 3,116,922-3,494,377, GRCh37, different from the previously described critical region (CR 2). The new 377 kb CR 1 includes a TAD boundary and two enhancers whose common target is PIAS4. We hypothesize that duplications of CR 1 are responsible for tridimensional structural abnormalities by TAD disruption and misregulation of genes essentials for the control of head circumference during development, by breaking down the interactions between enhancers and the corresponding targeted gene.},
}
@article {pmid36179666,
year = {2022},
author = {Ringel, AR and Szabo, Q and Chiariello, AM and Chudzik, K and Schöpflin, R and Rothe, P and Mattei, AL and Zehnder, T and Harnett, D and Laupert, V and Bianco, S and Hetzel, S and Glaser, J and Phan, MHQ and Schindler, M and Ibrahim, DM and Paliou, C and Esposito, A and Prada-Medina, CA and Haas, SA and Giere, P and Vingron, M and Wittler, L and Meissner, A and Nicodemi, M and Cavalli, G and Bantignies, F and Mundlos, S and Robson, MI},
title = {Repression and 3D-restructuring resolves regulatory conflicts in evolutionarily rearranged genomes.},
journal = {Cell},
volume = {185},
number = {20},
pages = {3689-3704.e21},
pmid = {36179666},
issn = {1097-4172},
support = {ALTF1554-2016/WT_/Wellcome Trust/United Kingdom ; 206475/Z/17/Z/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Animals ; CCCTC-Binding Factor/metabolism ; *Chromatin ; Chromatin Assembly and Disassembly ; Enhancer Elements, Genetic ; Evolution, Molecular ; Female ; Genome ; Mammals/metabolism ; *Placenta/metabolism ; Pregnancy ; Promoter Regions, Genetic ; Transcription Factors/genetics/metabolism ; },
abstract = {Regulatory landscapes drive complex developmental gene expression, but it remains unclear how their integrity is maintained when incorporating novel genes and functions during evolution. Here, we investigated how a placental mammal-specific gene, Zfp42, emerged in an ancient vertebrate topologically associated domain (TAD) without adopting or disrupting the conserved expression of its gene, Fat1. In ESCs, physical TAD partitioning separates Zfp42 and Fat1 with distinct local enhancers that drive their independent expression. This separation is driven by chromatin activity and not CTCF/cohesin. In contrast, in embryonic limbs, inactive Zfp42 shares Fat1's intact TAD without responding to active Fat1 enhancers. However, neither Fat1 enhancer-incompatibility nor nuclear envelope-attachment account for Zfp42's unresponsiveness. Rather, Zfp42's promoter is rendered inert to enhancers by context-dependent DNA methylation. Thus, diverse mechanisms enabled the integration of independent Zfp42 regulation in the Fat1 locus. Critically, such regulatory complexity appears common in evolution as, genome wide, most TADs contain multiple independently expressed genes.},
}
@article {pmid36163358,
year = {2022},
author = {Martinez-Fundichely, A and Dixon, A and Khurana, E},
title = {Modeling tissue-specific breakpoint proximity of structural variations from whole-genomes to identify cancer drivers.},
journal = {Nature communications},
volume = {13},
number = {1},
pages = {5640},
pmid = {36163358},
issn = {2041-1723},
support = {R01 CA218668/CA/NCI NIH HHS/United States ; },
mesh = {*Chromatin ; Genome ; Genomics ; Humans ; *Neoplasms/genetics ; },
abstract = {Structural variations (SVs) in cancer cells often impact large genomic regions with functional consequences. However, identification of SVs under positive selection is a challenging task because little is known about the genomic features related to the background breakpoint distribution in different cancers. We report a method that uses a generalized additive model to investigate the breakpoint proximity curves from 2,382 whole-genomes of 32 cancer types. We find that a multivariate model, which includes linear and nonlinear partial contributions of various tissue-specific features and their interaction terms, can explain up to 57% of the observed deviance of breakpoint proximity. In particular, three-dimensional genomic features such as topologically associating domains (TADs), TAD-boundaries and their interaction with other features show significant contributions. The model is validated by identification of known cancer genes and revealed putative drivers in cancers different than those with previous evidence of positive selection.},
}
@article {pmid36161960,
year = {2022},
author = {Damas, J and Corbo, M and Kim, J and Turner-Maier, J and Farré, M and Larkin, DM and Ryder, OA and Steiner, C and Houck, ML and Hall, S and Shiue, L and Thomas, S and Swale, T and Daly, M and Korlach, J and Uliano-Silva, M and Mazzoni, CJ and Birren, BW and Genereux, DP and Johnson, J and Lindblad-Toh, K and Karlsson, EK and Nweeia, MT and Johnson, RN and , and Lewin, HA},
title = {Evolution of the ancestral mammalian karyotype and syntenic regions.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {119},
number = {40},
pages = {e2209139119},
pmid = {36161960},
issn = {1091-6490},
mesh = {Animals ; Cattle/genetics ; Chromosomes, Mammalian/genetics ; Eutheria/genetics ; *Evolution, Molecular ; Humans ; *Karyotype ; *Mammals/genetics ; Phylogeny ; Sloths/genetics ; *Synteny/genetics ; },
abstract = {Decrypting the rearrangements that drive mammalian chromosome evolution is critical to understanding the molecular bases of speciation, adaptation, and disease susceptibility. Using 8 scaffolded and 26 chromosome-scale genome assemblies representing 23/26 mammal orders, we computationally reconstructed ancestral karyotypes and syntenic relationships at 16 nodes along the mammalian phylogeny. Three different reference genomes (human, sloth, and cattle) representing phylogenetically distinct mammalian superorders were used to assess reference bias in the reconstructed ancestral karyotypes and to expand the number of clades with reconstructed genomes. The mammalian ancestor likely had 19 pairs of autosomes, with nine of the smallest chromosomes shared with the common ancestor of all amniotes (three still conserved in extant mammals), demonstrating a striking conservation of synteny for ∼320 My of vertebrate evolution. The numbers and types of chromosome rearrangements were classified for transitions between the ancestral mammalian karyotype, descendent ancestors, and extant species. For example, 94 inversions, 16 fissions, and 14 fusions that occurred over 53 My differentiated the therian from the descendent eutherian ancestor. The highest breakpoint rate was observed between the mammalian and therian ancestors (3.9 breakpoints/My). Reconstructed mammalian ancestor chromosomes were found to have distinct evolutionary histories reflected in their rates and types of rearrangements. The distributions of genes, repetitive elements, topologically associating domains, and actively transcribed regions in multispecies homologous synteny blocks and evolutionary breakpoint regions indicate that purifying selection acted over millions of years of vertebrate evolution to maintain syntenic relationships of developmentally important genes and regulatory landscapes of gene-dense chromosomes.},
}
@article {pmid36147678,
year = {2022},
author = {Chow, CN and Tseng, KC and Hou, PF and Wu, NY and Lee, TY and Chang, WC},
title = {Mysteries of gene regulation: Promoters are not the sole triggers of gene expression.},
journal = {Computational and structural biotechnology journal},
volume = {20},
number = {},
pages = {4910-4920},
pmid = {36147678},
issn = {2001-0370},
abstract = {Cis-regulatory elements of promoters are essential for gene regulation by transcription factors (TFs). However, the regulatory roles of nonpromoter regions, TFs, and epigenetic marks remain poorly understood in plants. In this study, we characterized the cis-regulatory regions of 53 TFs and 19 histone marks in 328 chromatin immunoprecipitation (ChIP-seq) datasets from Arabidopsis. The genome-wide maps indicated that both promoters and regions around the transcription termination sites of protein-coding genes recruit the most TFs. The maps also revealed a diverse of histone combinations. The analysis suggested that exons play critical roles in the regulation of non-coding genes. Additionally, comparative analysis between heat-stress-responsive and nonresponsive genes indicated that the genes with distinct functions also exhibited substantial differences in cis-regulatory regions, histone regulation, and topologically associating domain (TAD) boundary organization. By integrating multiple high-throughput sequencing datasets, this study generated regulatory models for protein-coding genes, non-coding genes, and TAD boundaries to explain the complexity of transcriptional regulation.},
}
@article {pmid36105358,
year = {2022},
author = {Doyle, EJ and Morey, L and Conway, E},
title = {Know when to fold 'em: Polycomb complexes in oncogenic 3D genome regulation.},
journal = {Frontiers in cell and developmental biology},
volume = {10},
number = {},
pages = {986319},
pmid = {36105358},
issn = {2296-634X},
support = {P30 CA240139/CA/NCI NIH HHS/United States ; R01 GM141349/GM/NIGMS NIH HHS/United States ; },
abstract = {Chromatin is spatially and temporally regulated through a series of orchestrated processes resulting in the formation of 3D chromatin structures such as topologically associating domains (TADs), loops and Polycomb Bodies. These structures are closely linked to transcriptional regulation, with loss of control of these processes a frequent feature of cancer and developmental syndromes. One such oncogenic disruption of the 3D genome is through recurrent dysregulation of Polycomb Group Complex (PcG) functions either through genetic mutations, amplification or deletion of genes that encode for PcG proteins. PcG complexes are evolutionarily conserved epigenetic complexes. They are key for early development and are essential transcriptional repressors. PcG complexes include PRC1, PRC2 and PR-DUB which are responsible for the control of the histone modifications H2AK119ub1 and H3K27me3. The spatial distribution of the complexes within the nuclear environment, and their associated modifications have profound effects on the regulation of gene transcription and the 3D genome. Nevertheless, how PcG complexes regulate 3D chromatin organization is still poorly understood. Here we glean insights into the role of PcG complexes in 3D genome regulation and compaction, how these processes go awry during tumorigenesis and the therapeutic implications that result from our insights into these mechanisms.},
}
@article {pmid36104317,
year = {2022},
author = {Götz, M and Messina, O and Espinola, S and Fiche, JB and Nollmann, M},
title = {Multiple parameters shape the 3D chromatin structure of single nuclei at the doc locus in Drosophila.},
journal = {Nature communications},
volume = {13},
number = {1},
pages = {5375},
pmid = {36104317},
issn = {2041-1723},
mesh = {Animals ; *Chromatin/genetics ; Chromatin Assembly and Disassembly ; DNA ; *Drosophila/genetics ; In Situ Hybridization, Fluorescence ; },
abstract = {The spatial organization of chromatin at the scale of topologically associating domains (TADs) and below displays large cell-to-cell variations. Up until now, how this heterogeneity in chromatin conformation is shaped by chromatin condensation, TAD insulation, and transcription has remained mostly elusive. Here, we used Hi-M, a multiplexed DNA-FISH imaging technique providing developmental timing and transcriptional status, to show that the emergence of TADs at the ensemble level partially segregates the conformational space explored by single nuclei during the early development of Drosophila embryos. Surprisingly, a substantial fraction of nuclei display strong insulation even before TADs emerge. Moreover, active transcription within a TAD leads to minor changes to the local inter- and intra-TAD chromatin conformation in single nuclei and only weakly affects insulation to the neighboring TAD. Overall, our results indicate that multiple parameters contribute to shaping the chromatin architecture of single nuclei at the TAD scale.},
}
@article {pmid36097291,
year = {2022},
author = {Kane, L and Williamson, I and Flyamer, IM and Kumar, Y and Hill, RE and Lettice, LA and Bickmore, WA},
title = {Cohesin is required for long-range enhancer action at the Shh locus.},
journal = {Nature structural &amp; molecular biology},
volume = {29},
number = {9},
pages = {891-897},
pmid = {36097291},
issn = {1545-9985},
support = {MC_UU_00007/2/MRC_/Medical Research Council/United Kingdom ; MC_UU_00007/8/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Animals ; CCCTC-Binding Factor/genetics/metabolism ; *Cell Cycle Proteins/genetics/metabolism ; Chromatin/genetics ; *Chromosomal Proteins, Non-Histone/genetics/metabolism ; Enhancer Elements, Genetic/genetics ; Hedgehog Proteins/genetics/metabolism ; Mammals/genetics ; Mice ; Transcription Factors/metabolism ; },
abstract = {The regulatory landscapes of developmental genes in mammals can be complex, with enhancers spread over many hundreds of kilobases. It has been suggested that three-dimensional genome organization, particularly topologically associating domains formed by cohesin-mediated loop extrusion, is important for enhancers to act over such large genomic distances. By coupling acute protein degradation with synthetic activation by targeted transcription factor recruitment, here we show that cohesin, but not CTCF, is required for activation of the target gene Shh by distant enhancers in mouse embryonic stem cells. Cohesin is not required for activation directly at the promoter or by an enhancer located closer to the Shh gene. Our findings support the hypothesis that chromatin compaction via cohesin-mediated loop extrusion allows for genes to be activated by enhancers that are located many hundreds of kilobases away in the linear genome and suggests that cohesin is dispensable for enhancers located more proximally.},
}
@article {pmid36075900,
year = {2022},
author = {Zheng, L and Wang, W},
title = {Regulation associated modules reflect 3D genome modularity associated with chromatin activity.},
journal = {Nature communications},
volume = {13},
number = {1},
pages = {5281},
pmid = {36075900},
issn = {2041-1723},
support = {R01 HG009626/HG/NHGRI NIH HHS/United States ; },
mesh = {*Chromatin/genetics ; Chromatin Assembly and Disassembly/genetics ; Chromosomes ; *Genome ; Promoter Regions, Genetic/genetics ; },
abstract = {The 3D genome has been shown to be organized into modules including topologically associating domains (TADs) and compartments that are primarily defined by spatial contacts from Hi-C. There exists a gap to investigate whether and how the spatial modularity of the chromatin is related to the functional modularity resulting from chromatin activity. Despite histone modifications reflecting chromatin activity, inferring spatial modularity of the genome directly from the histone modification patterns has not been well explored. Here, we report that histone modifications show a modular pattern (referred to as regulation associated modules, RAMs) that reflects spatial chromatin modularity. Enhancer-promoter interactions, loop anchors, super-enhancer clusters and extrachromosomal DNAs (ecDNAs) are found to occur more often within the same RAMs than within the same TADs. Consistently, compared to the TAD boundaries, deletions of RAM boundaries perturb the chromatin structure more severely (may even cause cell death) and somatic variants in cancer samples are more enriched in RAM boundaries. These observations suggest that RAMs reflect a modular organization of the 3D genome at a scale better aligned with chromatin activity, providing a bridge connecting the structural and functional modularity of the genome.},
}
@article {pmid36043052,
year = {2022},
author = {Sun, Y and Dotson, GA and Muir, LA and Ronquist, S and Oravecz-Wilson, K and Peltier, D and Seike, K and Li, L and Meixner, W and Rajapakse, I and Reddy, P},
title = {Rearrangement of T Cell genome architecture regulates GVHD.},
journal = {iScience},
volume = {25},
number = {9},
pages = {104846},
pmid = {36043052},
issn = {2589-0042},
abstract = {WAPL, cohesin's DNA release factor, regulates three-dimensional (3D) chromatin architecture. The 3D chromatin structure and its relevance to mature T cell functions is not well understood. We show that in vivo lymphopenic expansion, and alloantigen-driven proliferation, alters the 3D structure and function of the genome in mature T cells. Conditional deletion of WAPL, cohesin's DNA release factor, in T cells reduced long-range genomic interactions and altered chromatin A/B compartments and interactions within topologically associating domains (TADs) of the chromatin in T cells at baseline. WAPL deficiency in T cells reduced loop extensions, changed expression of cell cycling genes and reduced proliferation following in vitro and in vivo stimulation, and reduced severity of graft-versus-host disease (GVHD) following experimental allogeneic hematopoietic stem cell transplantation. These data collectively characterize 3D genomic architecture of T cells in vivo and demonstrate biological and clinical implications for its disruption by cohesin release factor WAPL.},
}
@article {pmid36039936,
year = {2022},
author = {Che, Y and Yang, X and Jia, P and Wang, T and Xu, D and Guo, T and Ye, K},
title = {D[2] Plot, a Matrix of DNA Density and Distance to Periphery, Reveals Functional Genome Regions.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {9},
number = {30},
pages = {e2202149},
pmid = {36039936},
issn = {2198-3844},
mesh = {*Histones/genetics ; *Chromatin/genetics ; Genome/genetics ; DNA/genetics ; Genomics ; },
abstract = {The execution of biological activities inside space-limited cell nuclei requires sophisticated organization. Current studies on the 3D genome focus on chromatin interactions and local structures, e.g., topologically associating domains (TADs). In this study, two global physical properties: DNA density and distance to nuclear periphery (DisTP), are introduced and a 2D matrix, D[2] plot, is constructed for mapping genetic and epigenetic markers. Distinct patterns of functional markers on the D[2] plot, indicating its ability to compartmentalize functional genome regions, are observed. Furthermore, enrichments of transcription-related markers are concatenated into a cross-species transcriptional activation model, where the nucleus is divided into four areas: active, intermediate, repress and histone, and repress and repeat. Based on the trajectories of the genomic regions on D[2] plot, the constantly active and newly activated genes are successfully identified during olfactory sensory neuron maturation. The analysis reveals that the D[2] plot effectively categorizes functional regions and provides a universal and transcription-related measurement for the 3D genome.},
}
@article {pmid36036457,
year = {2022},
author = {Schwartz, M},
title = {Can abnormal chromatin folding cause high-penetrance cancer predisposition?.},
journal = {Physiological genomics},
volume = {54},
number = {10},
pages = {380-388},
doi = {10.1152/physiolgenomics.00052.2022},
pmid = {36036457},
issn = {1531-2267},
mesh = {*Chromatin/genetics ; Genome ; Humans ; *Neoplasms/genetics ; Penetrance ; Promoter Regions, Genetic ; },
abstract = {Sequencing cancer predisposing genes (CPGs) in evocative patients (i.e., patients with personal and family history of multiple/early-onset/unusual cancers) allows follow-up in their relatives to be adapted when a causative pathogenic variant is identified. Unfortunately, many evocative families remain unexplained. Part of this "missing heritability" could be due to CPG dysregulations caused by remote noncoding genomic alterations. Transcription levels are regulated through the ability of promoters to physically interact with their distant cis-regulatory elements. Three-dimensional chromatin contacts, mediated by a dynamic loop extrusion process, are uncovered by chromosome conformation capture (3C) and 3C-derived techniques, which have enabled the discovery of new pathological mechanisms in developmental diseases and cancers. High-penetrance cancer predisposition is caused by germline hereditary alterations otherwise found at the somatic level in sporadic cancers. Thus, data from both developmental diseases and cancers provide information about possible unknown cancer predisposition mechanisms. This mini-review aims to deduce from these data whether abnormal chromatin folding can cause high-penetrance cancer predisposition.},
}
@article {pmid36031655,
year = {2022},
author = {Kulikova, T and Maslova, A and Starshova, P and Rodriguez Ramos, JS and Krasikova, A},
title = {Comparison of the somatic TADs and lampbrush chromomere-loop complexes in transcriptionally active prophase I oocytes.},
journal = {Chromosoma},
volume = {131},
number = {4},
pages = {207-223},
pmid = {36031655},
issn = {1432-0886},
mesh = {Animals ; Chick Embryo ; *Meiotic Prophase I ; *Oocytes ; Oogenesis/genetics ; Genomics ; Chickens/genetics ; Chromatin/genetics ; Mammals ; },
abstract = {In diplotene oocyte nuclei of all vertebrate species, except mammals, chromosomes lack interchromosomal contacts and chromatin is linearly compartmentalized into distinct chromomere-loop complexes forming lampbrush chromosomes. However, the mechanisms underlying the formation of chromomere-loop complexes remain unexplored. Here we aimed to compare somatic topologically associating domains (TADs), recently identified in chicken embryonic fibroblasts, with chromomere-loop complexes in lampbrush meiotic chromosomes. By measuring 3D-distances and colocalization between linear equidistantly located genomic loci, positioned within one TAD or separated by a TAD border, we confirmed the presence of predicted TADs in chicken embryonic fibroblast nuclei. Using three-colored FISH with BAC probes, we mapped equidistant genomic regions included in several sequential somatic TADs on isolated chicken lampbrush chromosomes. Eight genomic regions, each comprising two or three somatic TADs, were mapped to non-overlapping neighboring lampbrush chromatin domains - lateral loops, chromomeres, or chromomere-loop complexes. Genomic loci from the neighboring somatic TADs could localize in one lampbrush chromomere-loop complex, while genomic loci belonging to the same somatic TAD could be localized in neighboring lampbrush chromomere-loop domains. In addition, FISH-mapping of BAC probes to the nascent transcripts on the lateral loops indicates transcription of at least 17 protein-coding genes and 2 non-coding RNA genes during the lampbrush stage of chicken oogenesis, including genes involved in oocyte maturation and early embryo development.},
}
@article {pmid36003143,
year = {2022},
author = {Wang, X and Yan, J and Ye, Z and Zhang, Z and Wang, S and Hao, S and Shen, B and Wei, G},
title = {Reorganization of 3D chromatin architecture in doxorubicin-resistant breast cancer cells.},
journal = {Frontiers in cell and developmental biology},
volume = {10},
number = {},
pages = {974750},
pmid = {36003143},
issn = {2296-634X},
abstract = {Background: Doxorubicin resistance remains a major therapeutic challenge leading to poor survival prognosis and treatment failure in breast cancer. Although doxorubicin induces massive changes in the transcriptional landscape are well known, potential diagnostic or therapeutic targets associated with the reorganization of three-dimensional (3D) chromatin architecture have not yet been systematically investigated. Methods: Here we performed in situ high-throughput chromosome conformation capture (Hi-C) on parental and doxorubicin-resistant MCF7 (MCF7-DR) human breast cancer cells, followed by integrative analysis of HiC, ATAC-seq, RNA-seq and TCGA data. Results: It revealed that A/B compartment switching was positively correlated to genome-wide differential gene expression. The genome of MCF7-DR cells was spatially reorganized into smaller topologically associating domains (TADs) and chromatin loops. We also revealed the contribution of increased chromatin accessibility and potential transcription factor families, including CTCF, AP-1 and bHLH, to gained TADs or loops. Intriguingly, we observed two condensed genomic regions (∼20 kb) with decreased chromatin accessibility flanking TAD boundaries, which might play a critical role in the formation or maintenance of TADs. Finally, combining data from TCGA, we identified a number of gained and lost enhancer-promoter interactions and their corresponding differentially expressed genes involved in chromatin organization and breast cancer signaling pathways, including FA2H, FOXA1 and JRKL, which might serve as potential treatment targets for breast cancer. Conclusion: These data uncovered a close connection between 3D genome reorganization, chromatin accessibility as well as gene transcription and provide novel insights into the epigenomic mechanisms involving doxorubicin resistance in breast cancer.},
}
@article {pmid35980315,
year = {2022},
author = {Chen, M and Jia, L and Zheng, X and Han, M and Li, L and Zhang, L},
title = {Ancient Human Endogenous Retroviruses Contribute to Genetic Evolution and Regulate Cancer Cell Type-Specific Gene Expression.},
journal = {Cancer research},
volume = {82},
number = {19},
pages = {3457-3473},
doi = {10.1158/0008-5472.CAN-22-0290},
pmid = {35980315},
issn = {1538-7445},
mesh = {3' Untranslated Regions/genetics ; 5' Untranslated Regions/genetics ; Chromatin ; DNA Transposable Elements/genetics ; *Endogenous Retroviruses/genetics ; Evolution, Molecular ; Female ; Gene Expression ; Genome-Wide Association Study ; Humans ; *Neoplasms/genetics ; Placenta ; Pregnancy ; },
abstract = {UNLABELLED: Human endogenous retroviruses (HERV), a type of transposable elements (TE), play crucial roles in human placental morphogenesis, immune response, and cancer progression. Emerging evidence suggests that TEs have been a rich source of regulatory elements in the human genome, but little is known about the global impact of HERVs on transcriptional networks in cancer. Using genome-wide approaches, we show that HERVs are composed primarily of three ancient superfamilies: ERVL-MaLR, ERVL, and ERV1. This analysis suggests that the integration of exonic, intronic, and intergenic HERVs, as well as human or Hominidae gene-specific HERVs, contributes to human genomic innovation. HERVs exonized in genes are located mainly in the 3' untranslated region (UTR) or 3' end and participate in basic biological processes. Active HERVs are located mainly in intronic and intergenic regions and tend to function as enhancers and contribute to cancer cell type-specific gene expression. More importantly, HERVs may also define chromatin topologically associating domain (TAD) and loop boundaries in a cell type-specific manner. Taken together, these findings reveal that ancient HERV elements are a source of diverse regulatory sequences, including 3' UTRs, 5' UTRs, promoters, and enhancers, and they contribute to genetic innovation and cancer cell type-specific gene expression, highlighting the previously underestimated importance of these elements.<br><br>SIGNIFICANCE: Genome-wide analyses show that human endogenous retroviruses mediate cancer cell type-specific gene expression, epigenetic modification, and 3D chromatin architecture, elucidating the relationship between HERVs and diverse cancers.},
}
@article {pmid35969760,
year = {2022},
author = {Kurotaki, D and Kikuchi, K and Cui, K and Kawase, W and Saeki, K and Fukumoto, J and Nishiyama, A and Nagamune, K and Zhao, K and Ozato, K and Rocha, PP and Tamura, T},
title = {Chromatin structure undergoes global and local reorganization during murine dendritic cell development and activation.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {119},
number = {34},
pages = {e2207009119},
pmid = {35969760},
issn = {1091-6490},
mesh = {Animals ; Cell Differentiation/genetics ; Chromatin/genetics/metabolism ; *Chromatin Assembly and Disassembly ; *Dendritic Cells/cytology ; Gene Expression Regulation ; *Hematopoietic Stem Cells ; Mice ; },
abstract = {Classical dendritic cells (cDCs) are essential for immune responses and differentiate from hematopoietic stem cells via intermediate progenitors, such as monocyte-DC progenitors (MDPs) and common DC progenitors (CDPs). Upon infection, cDCs are activated and rapidly express host defense-related genes, such as those encoding cytokines and chemokines. Chromatin structures, including nuclear compartments and topologically associating domains (TADs), have been implicated in gene regulation. However, the extent and dynamics of their reorganization during cDC development and activation remain unknown. In this study, we comprehensively determined higher-order chromatin structures by Hi-C in DC progenitors and cDC subpopulations. During cDC differentiation, chromatin activation was initially induced at the MDP stage. Subsequently, a shift from inactive to active nuclear compartments occurred at the cDC gene loci in CDPs, which was followed by increased intra-TAD interactions and loop formation. Mechanistically, the transcription factor IRF8, indispensable for cDC differentiation, mediated chromatin activation and changes into the active compartments in DC progenitors, thereby possibly leading to cDC-specific gene induction. Using an infection model, we found that the chromatin structures of host defense-related gene loci were preestablished in unstimulated cDCs, indicating that the formation of higher-order chromatin structures prior to infection may contribute to the rapid responses to pathogens. Overall, these results suggest that chromatin structure reorganization is closely related to the establishment of cDC-specific gene expression and immune functions. This study advances the fundamental understanding of chromatin reorganization in cDC differentiation and activation.},
}
@article {pmid35966880,
year = {2022},
author = {Zhou, T and Feng, Q},
title = {Androgen receptor signaling and spatial chromatin organization in castration-resistant prostate cancer.},
journal = {Frontiers in medicine},
volume = {9},
number = {},
pages = {924087},
pmid = {35966880},
issn = {2296-858X},
abstract = {Prostate cancer is one of the leading causes of cancer death and affects millions of men in the world. The American Cancer Society estimated about 34,500 deaths from prostate cancer in the United States in year 2022. The Androgen receptor (AR) signaling is a major pathway that sustains local and metastatic prostate tumor growth. Androgen-deprivation therapy (ADT) is the standard of care for metastatic prostate cancer patient and can suppress the tumor growth for a median of 2-3 years. Unfortunately, the malignancy inevitably progresses to castration-resistant prostate cancer (CRPC) which is more aggressive and no longer responsive to ADT. Surprisingly, for most of the CPRC patients, cancer growth still depends on androgen receptor signaling. Accumulating evidence suggests that CRPC cells have rewired their transcriptional program to retain AR signaling in the absence of androgens. Besides AR, other transcription factors also contribute to the resistance mechanism through multiple pathways including enhancing AR signaling pathway and activating other complementary signaling pathways for the favor of AR downstream genes expression. More recent studies have shown the role of transcription factors in reconfiguring chromatin 3D structure and regulating topologically associating domains (TADs). Pioneer factors, transcription factors and coactivators form liquid-liquid phase separation compartment that can modulate transcriptional events along with configuring TADs. The role of AR and other transcription factors on chromatin structure change and formation of condensate compartment in prostate cancer cells has only been recently investigated and appreciated. This review intends to provide an overview of transcription factors that contribute to AR signaling through activation of gene expression, governing 3D chromatin structure and establishing phase to phase separation. A more detailed understanding of the spatial role of transcription factors in CRPC might provide novel therapeutic targets for the treatment of CRPC.},
}
@article {pmid35961952,
year = {2022},
author = {Giaimo, BD and Borggrefe, T},
title = {Enhancer-promoter communication: unraveling enhancer strength and positioning within a given topologically associating domain (TAD).},
journal = {Signal transduction and targeted therapy},
volume = {7},
number = {1},
pages = {281},
pmid = {35961952},
issn = {2059-3635},
mesh = {*Chromatin ; *Promoter Regions, Genetic/genetics ; },
}
@article {pmid35950186,
year = {2022},
author = {Fang, K and Wang, J and Liu, L and Jin, VX},
title = {Mapping nucleosome and chromatin architectures: A survey of computational methods.},
journal = {Computational and structural biotechnology journal},
volume = {20},
number = {},
pages = {3955-3962},
pmid = {35950186},
issn = {2001-0370},
support = {R01 GM114142/GM/NIGMS NIH HHS/United States ; U54 CA217297/CA/NCI NIH HHS/United States ; },
abstract = {With ever-growing genomic sequencing data, the data variabilities and the underlying biases of the sequencing technologies pose significant computational challenges ranging from the need for accurately detecting the nucleosome positioning or chromatin interaction to the need for developing normalization methods to eliminate systematic biases. This review mainly surveys the computational methods for mapping the higher-resolution nucleosome and higher-order chromatin architectures. While a detailed discussion of the underlying algorithms is beyond the scope of our survey, we have discussed the methods and tools that can detect the nucleosomes in the genome, then demonstrated the computational methods for identifying 3D chromatin domains and interactions. We further illustrated computational approaches for integrating multi-omics data with Hi-C data and the advance of single-cell (sc)Hi-C data analysis. Our survey provides a comprehensive and valuable resource for biomedical scientists interested in studying nucleosome organization and chromatin structures as well as for computational scientists who are interested in improving upon them.},
}
@article {pmid35938007,
year = {2022},
author = {Ahn, J and Lee, J and Kim, DH and Hwang, IS and Park, MR and Cho, IC and Hwang, S and Lee, K},
title = {Loss of Monoallelic Expression of IGF2 in the Adult Liver Via Alternative Promoter Usage and Chromatin Reorganization.},
journal = {Frontiers in genetics},
volume = {13},
number = {},
pages = {920641},
pmid = {35938007},
issn = {1664-8021},
abstract = {In mammals, genomic imprinting operates via gene silencing mechanisms. Although conservation of the imprinting mechanism at the H19/IGF2 locus has been generally described in pigs, tissue-specific imprinting at the transcript level, monoallelic-to-biallelic conversion, and spatio-temporal chromatin reorganization remain largely uninvestigated. Here, we delineate spatially regulated imprinting of IGF2 transcripts, age-dependent hepatic mono- to biallelic conversion, and reorganization of topologically associating domains at the porcine H19/IGF2 locus for better translation to human and animal research. Whole-genome bisulfite sequencing (WGBS) and RNA sequencing (RNA-seq) of normal and parthenogenetic porcine embryos revealed the paternally hypermethylated H19 differentially methylated region and paternal expression of IGF2. Using a polymorphism-based approach and omics datasets from chromatin immunoprecipitation sequencing (ChIP-seq), whole-genome sequencing (WGS), RNA-seq, and Hi-C, regulation of IGF2 during development was analyzed. Regulatory elements in the liver were distinguished from those in the muscle where the porcine IGF2 transcript was monoallelically expressed. The IGF2 transcript from the liver was biallelically expressed at later developmental stages in both pigs and humans. Chromatin interaction was less frequent in the adult liver compared to the fetal liver and skeletal muscle. The duration of genomic imprinting effects within the H19/IGF2 locus might be reduced in the liver with biallelic conversion through alternative promoter usage and chromatin remodeling. Our integrative omics analyses of genome, epigenome, and transcriptome provided a comprehensive view of imprinting status at the H19/IGF2 cluster.},
}
@article {pmid35933090,
year = {2022},
author = {Sun, Z and Wang, Y and Song, Z and Zhang, H and Wang, Y and Liu, K and Ma, M and Wang, P and Fang, Y and Cai, D and Li, G and Fang, Y},
title = {DNA methylation in transposable elements buffers the connection between three-dimensional chromatin organization and gene transcription upon rice genome duplication.},
journal = {Journal of advanced research},
volume = {42},
number = {},
pages = {41-53},
pmid = {35933090},
issn = {2090-1224},
mesh = {*DNA Transposable Elements/genetics ; *Oryza/genetics ; DNA Methylation ; Gene Duplication ; Chromatin/genetics ; Transcription, Genetic/genetics ; },
abstract = {INTRODUCTION: Polyploidy is a major force in plant evolution and the domestication of cultivated crops.<br><br>OBJECTIVES: The study aimed to explore the relationship and underlying mechanism between three-dimensional (3D) chromatin organization and gene transcription upon rice genome duplication.<br><br>METHODS: The 3D chromatin structures between diploid (2C) and autotetraploid (4C) rice were compared using high-throughput chromosome conformation capture (Hi-C) analysis. The study combined genetics, transcriptomics, whole-genome bisulfite sequencing (WGBS-seq) and 3D genomics approaches to uncover the mechanism for DNA methylation in modulating gene transcription through 3D chromatin architectures upon rice genome duplication.<br><br>RESULTS: We found that 4C rice presents weakened intra-chromosomal interactions compared to its 2C progenitor in some chromosomes. In addition, we found that changes of 3D chromatin organizations including chromatin compartments, topologically associating domains (TADs), and loops, are uncorrelated with gene transcription. Moreover, DNA methylations in the regulatory sequences of genes in compartment A/B switched regions and TAD boundaries are unrelated to their expression. Importantly, although there was no significant difference in the methylation levels in transposable elements (TEs) in differentially expressed gene (DEG) and non-DEG promoters between 2C and 4C rice, we found that the hypermethylated TEs across genes in compartment A/B switched regions and TAD boundaries may suppress the expression of these genes.<br><br>CONCLUSION: The study proposed that the rice genome doubling might modulate TE methylation to buffer the effects of chromatin architecture on gene transcription in compartment A/B switched regions and TAD boundaries, resulting in the disconnection between 3D chromatin structure alteration and gene transcription upon rice genome duplication.},
}
@article {pmid35932041,
year = {2022},
author = {Li, D and Strong, A and Hou, C and Downes, H and Pritchard, AB and Mazzeo, P and Zackai, EH and Conlin, LK and Hakonarson, H},
title = {Interstitial deletion 4p15.32p16.1 and complex chromoplexy in a female proband with severe neurodevelopmental delay, growth failure and dysmorphism.},
journal = {Molecular cytogenetics},
volume = {15},
number = {1},
pages = {33},
pmid = {35932041},
issn = {1755-8166},
abstract = {Complex chromosomal rearrangements involve the restructuring of genetic material within a single chromosome or across multiple chromosomes. These events can cause serious human disease by disrupting coding DNA and gene regulatory elements via deletions, duplications, and structural rearrangements. Here we describe a 5-year-old female with severe developmental delay, dysmorphic features, multi-suture craniosynostosis, and growth failure found to have a complex series of balanced intra- and inter-chromosomal rearrangements involving chromosomes 4, 11, 13, and X. Initial clinical studies were performed by karyotype, chromosomal microarray, and FISH with research-based short-read genome sequencing coupled with sanger sequencing to precisely map her breakpoints to the base pair resolution to understand the molecular basis of her phenotype. Genome analysis revealed two pathogenic deletions at 4p16.1-p15.32 and 4q31.1, accounting for her developmental delay and dysmorphism. We identified over 60 breakpoints, many with blunt ends and limited homology, supporting a role for non-homologous end joining in restructuring and resolution of the seminal chromoplexy event. We propose that the complexity of our patient's genomic rearrangements with a high number of breakpoints causes dysregulation of gene expression by three-dimensional chromatin interactions or topologically associating domains leading to growth failure and craniosynostosis. Our work supports an important role for genome sequencing in understanding the molecular basis of complex chromosomal rearrangements in human disease.},
}
@article {pmid35867573,
year = {2022},
author = {Campbell, M and Chantarasrivong, C and Yanagihashi, Y and Inagaki, T and Davis, RR and Nakano, K and Kumar, A and Tepper, CG and Izumiya, Y},
title = {KSHV Topologically Associating Domains in Latent and Reactivated Viral Chromatin.},
journal = {Journal of virology},
volume = {96},
number = {14},
pages = {e0056522},
pmid = {35867573},
issn = {1098-5514},
support = {P30 CA093373/CA/NCI NIH HHS/United States ; },
mesh = {*Chromatin/genetics ; Gene Expression Regulation, Viral ; Genome, Viral ; *Herpesvirus 8, Human/genetics ; Humans ; Trans-Activators/genetics ; Virus Latency/genetics ; },
abstract = {Eukaryotic genomes are structurally organized via the formation of multiple loops that create gene expression regulatory units called topologically associating domains (TADs). Here we revealed the KSHV TAD structure at 500 bp resolution and constructed a 3D KSHV genomic structural model with 2 kb binning. The latent KSHV genome formed very similar genomic architectures in three different naturally infected PEL cell lines and in an experimentally infected epithelial cell line. The majority of the TAD boundaries were occupied by structural maintenance of chromosomes (SMC1) cohesin complex and CCCTC-binding factor (CTCF), and the KSHV transactivator was recruited to those sites during reactivation. Triggering KSHV gene expression decreased prewired genomic loops within the regulatory unit, while contacts extending outside of regulatory borders increased, leading to formation of a larger regulatory unit with a shift from repressive to active compartments (B to A). The 3D genomic structural model proposes that the immediate early promoter region is localized on the periphery of the 3D viral genome during latency, while highly inducible noncoding RNA regions moved toward the inner space of the structure, resembling the configuration of a "bird cage" during reactivation. The compartment-like properties of viral episomal chromatin structure and its reorganization during the transition from latency may help facilitate viral gene transcription. IMPORTANCE The 3D architecture of chromatin allows for efficient arrangement, expression, and replication of genetic material. The genomes of all organisms studied to date have been found to be organized through some form of tiered domain structures. However, the architectural framework of the genomes of large double-stranded DNA viruses such as the herpesvirus family has not been reported. Prior studies with Kaposi's sarcoma-associated herpesvirus (KSHV) have indicated that the viral chromatin shares many biological properties exhibited by the host cell genome, essentially behaving as a mini human chromosome. Thus, we hypothesized that the KSHV genome may be organized in a similar manner. In this report, we describe the domain structure of the latent and lytic KSHV genome at 500 bp resolution and present a 3D genomic structural model for KSHV under each condition. These results add new insights into the complex regulation of the viral life cycle.},
}
@article {pmid35867254,
year = {2022},
author = {Sabaté, T and Zimmer, C and Bertrand, E},
title = {Versatile CRISPR-Based Method for Site-Specific Insertion of Repeat Arrays to Visualize Chromatin Loci in Living Cells.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {2532},
number = {},
pages = {275-290},
pmid = {35867254},
issn = {1940-6029},
mesh = {*Chromatin/genetics ; Chromatin Assembly and Disassembly ; *Chromosomes ; DNA ; Genome, Human ; Humans ; },
abstract = {Hi-C and related sequencing-based techniques have brought a detailed understanding of the 3D genome architecture and the discovery of novel structures such as topologically associating domains (TADs) and chromatin loops, which emerge from cohesin-mediated DNA extrusion. However, these techniques require cell fixation, which precludes assessment of chromatin structure dynamics, and are generally restricted to population averages, thus masking cell-to-cell heterogeneity. By contrast, live-cell imaging allows to characterize and quantify the temporal dynamics of chromatin, potentially including TADs and loops in single cells. Specific chromatin loci can be visualized at high temporal and spatial resolution by inserting a repeat array from bacterial operator sequences bound by fluorescent tags. Using two different types of repeats allows to tag both anchors of a loop in different colors, thus enabling to track them separately even when they are in close vicinity. Here, we describe a versatile cloning method for generating many repeat array repair cassettes in parallel and inserting them by CRISPR-Cas9 into the human genome. This method should be instrumental to studying chromatin loop dynamics in single human cells.},
}
@article {pmid35867243,
year = {2022},
author = {Miranda, M and Noordermeer, D and Moindrot, B},
title = {Detection of Allele-Specific 3D Chromatin Interactions Using High-Resolution In-Nucleus 4C-seq.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {2532},
number = {},
pages = {15-33},
pmid = {35867243},
issn = {1940-6029},
mesh = {Alleles ; Animals ; *Chromatin/genetics ; *Chromosomes ; Genomics/methods ; High-Throughput Nucleotide Sequencing/methods ; Mammals/genetics ; },
abstract = {Chromosome conformation capture techniques are a set of methods used to determine 3D genome organization through the capture and identification of physical contacts between pairs of genomic loci. Among them, 4C-seq (circular chromosome conformation capture coupled to high-throughput sequencing) allows for the identification and quantification of the sequences interacting with a preselected locus of interest. 4C-seq has been widely used in the literature, mainly to study chromatin loops between enhancers and promoters or between CTCF binding sites and to identify chromatin domain boundaries. As 3D-contacts may be established in an allele-specific manner, we describe an up-to-date allele-specific 4C-seq protocol, starting from the selection of allele-specific viewpoints to Illumina sequencing. This protocol has mainly been optimized for cultured mammalian cells, but can be adapted for other cell types with relatively minor changes in initial steps.},
}
@article {pmid35860407,
year = {2022},
author = {Sengupta, K and Denkiewicz, M and Chiliński, M and Szczepińska, T and Mollah, AF and Korsak, S and D'Souza, R and Ruan, Y and Plewczynski, D},
title = {Multi-scale phase separation by explosive percolation with single-chromatin loop resolution.},
journal = {Computational and structural biotechnology journal},
volume = {20},
number = {},
pages = {3591-3603},
pmid = {35860407},
issn = {2001-0370},
abstract = {The 2 m-long human DNA is tightly intertwined into the cell nucleus of the size of 10 μm. The DNA packing is explained by folding of chromatin fiber. This folding leads to the formation of such hierarchical structures as: chromosomal territories, compartments; densely-packed genomic regions known as Topologically Associating Domains (TADs), or Chromatin Contact Domains (CCDs), and loops. We propose models of dynamical human genome folding into hierarchical components in human lymphoblastoid, stem cell, and fibroblast cell lines. Our models are based on explosive percolation theory. The chromosomes are modeled as graphs where CTCF chromatin loops are represented as edges. The folding trajectory is simulated by gradually introducing loops to the graph following various edge addition strategies that are based on topological network properties, chromatin loop frequencies, compartmentalization, or epigenomic features. Finally, we propose the genome folding model - a biophysical pseudo-time process guided by a single scalar order parameter. The parameter is calculated by Linear Discriminant Analysis of chromatin features. We also include dynamics of loop formation by using Loop Extrusion Model (LEM) while adding them to the system. The chromatin phase separation, where fiber folds in 3D space into topological domains and compartments, is observed when the critical number of contacts is reached. We also observe that at least 80% of the loops are needed for chromatin fiber to condense in 3D space, and this is constant through various cell lines. Overall, our in-silico model integrates the high-throughput 3D genome interaction experimental data with the novel theoretical concept of phase separation, which allows us to model event-based time dynamics of chromatin loop formation and folding trajectories.},
}
@article {pmid35832633,
year = {2022},
author = {Lamberti, WF and Zang, C},
title = {Extracting physical characteristics of higher-order chromatin structures from 3D image data.},
journal = {Computational and structural biotechnology journal},
volume = {20},
number = {},
pages = {3387-3398},
pmid = {35832633},
issn = {2001-0370},
abstract = {Higher-order chromatin structures have functional impacts on gene regulation and cell identity determination. Using high-throughput sequencing (HTS)-based methods like Hi-C, active or inactive compartments and open or closed topologically associating domain (TAD) structures can be identified on a cell population level. Recently developed high-resolution three-dimensional (3D) molecular imaging techniques such as 3D electron microscopy with in situ hybridization (3D-EMSIH) and 3D structured illumination microscopy (3D-SIM) enable direct detection of physical representations of chromatin structures in a single cell. However, computational analysis of 3D image data with explainability and interpretability on functional characteristics of chromatin structures is still challenging. We developed Extracting Physical-Characteristics from Images of Chromatin Structures (EPICS), a machine-learning based computational method for processing high-resolution chromatin 3D image data. Using EPICS on images produced by 3D-EMISH or 3D-SIM techniques, we generated more direct 3D representations of higher-order chromatin structures, identified major chromatin domains, and determined the open or closed status of each domain. We identified several high-contributing features from the model as the major physical characteristics that define the open or closed chromatin domains, demonstrating the explainability and interpretability of EPICS. EPICS can be applied to the analysis of other high-resolution 3D molecular imaging data for spatial genomics studies. The R and Python codes of EPICS are available at https://github.com/zang-lab/epics.},
}
@article {pmid35821502,
year = {2022},
author = {Ballarino, R and Bouwman, BAM and Agostini, F and Harbers, L and Diekmann, C and Wernersson, E and Bienko, M and Crosetto, N},
title = {An atlas of endogenous DNA double-strand breaks arising during human neural cell fate determination.},
journal = {Scientific data},
volume = {9},
number = {1},
pages = {400},
pmid = {35821502},
issn = {2052-4463},
mesh = {Cell Line, Tumor ; DNA/metabolism ; *DNA Breaks, Double-Stranded ; Genomics ; Humans ; *Neurogenesis ; },
abstract = {Endogenous DNA double-strand breaks (DSBs) occurring in neural cells have been implicated in the pathogenesis of neurodevelopmental disorders (NDDs). Currently, a genomic map of endogenous DSBs arising during human neurogenesis is missing. Here, we applied in-suspension Breaks Labeling In Situ and Sequencing (sBLISS), RNA-Seq, and Hi-C to chart the genomic landscape of DSBs and relate it to gene expression and genome architecture in 2D cultures of human neuroepithelial stem cells (NES), neural progenitor cells (NPC), and post-mitotic neural cells (NEU). Endogenous DSBs were enriched at the promoter and along the gene body of transcriptionally active genes, at the borders of topologically associating domains (TADs), and around chromatin loop anchors. NDD risk genes harbored significantly more DSBs in comparison to other protein-coding genes, especially in NEU cells. We provide sBLISS, RNA-Seq, and Hi-C datasets for each differentiation stage, and all the scripts needed to reproduce our analyses. Our datasets and tools represent a unique resource that can be harnessed to investigate the role of genome fragility in the pathogenesis of NDDs.},
}
@article {pmid35817979,
year = {2022},
author = {Anania, C and Acemel, RD and Jedamzick, J and Bolondi, A and Cova, G and Brieske, N and Kühn, R and Wittler, L and Real, FM and Lupiáñez, DG},
title = {In vivo dissection of a clustered-CTCF domain boundary reveals developmental principles of regulatory insulation.},
journal = {Nature genetics},
volume = {54},
number = {7},
pages = {1026-1036},
pmid = {35817979},
issn = {1546-1718},
mesh = {Animals ; Binding Sites/genetics ; CCCTC-Binding Factor/genetics/metabolism ; *Chromatin/genetics ; Chromosomes/metabolism ; Genome/genetics ; *Genome-Wide Association Study ; Mice ; },
abstract = {Vertebrate genomes organize into topologically associating domains, delimited by boundaries that insulate regulatory elements from nontarget genes. However, how boundary function is established is not well understood. Here, we combine genome-wide analyses and transgenic mouse assays to dissect the regulatory logic of clustered-CCCTC-binding factor (CTCF) boundaries in vivo, interrogating their function at multiple levels: chromatin interactions, transcription and phenotypes. Individual CTCF binding site (CBS) deletions revealed that the characteristics of specific sites can outweigh other factors such as CBS number and orientation. Combined deletions demonstrated that CBSs cooperate redundantly and provide boundary robustness. We show that divergent CBS signatures are not strictly required for effective insulation and that chromatin loops formed by nonconvergently oriented sites could be mediated by a loop interference mechanism. Further, we observe that insulation strength constitutes a quantitative modulator of gene expression and phenotypes. Our results highlight the modular nature of boundaries and their control over developmental processes.},
}
@article {pmid35812944,
year = {2022},
author = {Wu, H and Song, X and Lyu, S and Ren, Y and Liu, T and Hou, X and Li, Y and Zhang, C},
title = {Integrated Analysis of Hi-C and RNA-Seq Reveals the Molecular Mechanism of Autopolyploid Growth Advantages in Pak Choi (Brassica rapa ssp. chinensis).},
journal = {Frontiers in plant science},
volume = {13},
number = {},
pages = {905202},
pmid = {35812944},
issn = {1664-462X},
abstract = {Polyploids generated by the replication of a single genome (autopolyploid) or synthesis of two or more distinct genomes (allopolyploid) usually show significant advantages over their diploid progenitors in biological characteristics, including growth and development, nutrient accumulation, and plant resistance. Whereas, the impacts of genomic replication on transcription regulation and chromatin structure in pak choi have not been explored fully. In this study, we observed the transcriptional and genomic structural alterations between diploid B. rapa (AA) and artificial autotetraploid B. rapa (AAAA) using RNA-seq and Hi-C. RNA-seq revealed 1,786 differentially expressed genes (DEGs) between the diploids and autotetraploids, including 717 down-regulated and 1,069 up-regulated genes in autotetraploids. Of all the 1,786 DEGs, 23 DEGs (10 down-regulated DEGs in autotetraploids) were involved in Compartment A-B shifts, while 28 DEGs (20 up-regulated DEGs in autotetraploids) participated in Compartment B-A shifts. Moreover, there were 15 DEGs in activated topologically associating domains (TADs) (9 up-regulated DEGs in diploids) and 80 DEGs in repressed TADs (49 down-regulated DEGs in diploids). Subsequently, eight DEGs with genomic structural variants were selected as potential candidate genes, including four DEGs involved in photosynthesis (BraA01003143, BraA09002798, BraA04002224, and BraA08000594), three DEGs related to chloroplast (BraA05002974, BraA05001662, and BraA04001148), and one DEG associated with disease resistance (BraA09004451), which all showed high expression in autotetraploids. Overall, our results demonstrated that integrative RNA-seq and Hi-C analysis can identify related genes to phenotypic traits and also provided new insights into the molecular mechanism of the growth advantage of polyploids.},
}
@article {pmid35777365,
year = {2022},
author = {Fujita, Y and Pather, SR and Ming, GL and Song, H},
title = {3D spatial genome organization in the nervous system: From development and plasticity to disease.},
journal = {Neuron},
volume = {110},
number = {18},
pages = {2902-2915},
pmid = {35777365},
issn = {1097-4199},
support = {R01 AG057497/AG/NIA NIH HHS/United States ; R35 NS097370/NS/NINDS NIH HHS/United States ; P30 ES013508/ES/NIEHS NIH HHS/United States ; R01 MH125528/MH/NIMH NIH HHS/United States ; R35 NS116843/NS/NINDS NIH HHS/United States ; },
mesh = {*Chromatin/genetics ; *Genome ; Nervous System ; },
abstract = {Chromatin is organized into multiscale three-dimensional structures, including chromosome territories, A/B compartments, topologically associating domains, and chromatin loops. This hierarchically organized genomic architecture regulates gene transcription, which, in turn, is essential for various biological processes during brain development and adult plasticity. Here, we review different aspects of spatial genome organization and their functions in regulating gene expression in the nervous system, as well as their dysregulation in brain disorders. We also highlight new technologies to probe and manipulate chromatin architecture and discuss how investigating spatial genome organization can lead to a better understanding of the nervous system and associated disorders.},
}
@article {pmid35768498,
year = {2022},
author = {Wei, C and Jia, L and Huang, X and Tan, J and Wang, M and Niu, J and Hou, Y and Sun, J and Zeng, P and Wang, J and Qing, L and Ma, L and Liu, X and Tang, X and Li, F and Jiang, S and Liu, J and Li, T and Fan, L and Sun, Y and Gao, J and Li, C and Ding, J},
title = {CTCF organizes inter-A compartment interactions through RYBP-dependent phase separation.},
journal = {Cell research},
volume = {32},
number = {8},
pages = {744-760},
pmid = {35768498},
issn = {1748-7838},
mesh = {CCCTC-Binding Factor/metabolism ; Cell Differentiation ; *Chromatin ; Chromatin Assembly and Disassembly ; Embryonic Stem Cells/metabolism ; *Neural Stem Cells/metabolism ; },
abstract = {Chromatin is spatially organized into three-dimensional structures at different levels including A/B compartments, topologically associating domains and loops. The canonical CTCF-mediated loop extrusion model can explain the formation of loops. However, the organization mechanisms underlying long-range chromatin interactions such as interactions between A-A compartments are still poorly understood. Here we show that different from the canonical loop extrusion model, RYBP-mediated phase separation of CTCF organizes inter-A compartment interactions. Based on this model, we designed and verified an induced CTCF phase separation system in embryonic stem cells (ESCs), which facilitated inter-A compartment interactions, improved self-renewal of ESCs and inhibited their differentiation toward neural progenitor cells. These findings support a novel and non-canonical role of CTCF in organizing long-range chromatin interactions via phase separation.},
}
@article {pmid35759905,
year = {2022},
author = {Sawh, AN and Mango, SE},
title = {Chromosome organization in 4D: insights from C. elegans development.},
journal = {Current opinion in genetics &amp; development},
volume = {75},
number = {},
pages = {101939},
doi = {10.1016/j.gde.2022.101939},
pmid = {35759905},
issn = {1879-0380},
mesh = {Animals ; *Caenorhabditis elegans/genetics ; *Chromatin/genetics ; Genome/genetics ; Nucleosomes/genetics ; Promoter Regions, Genetic ; },
abstract = {Eukaryotic genome organization is ordered and multilayered, from the nucleosome to chromosomal scales. These layers are not static during development, but are remodeled over time and between tissues. Thus, animal model studies with high spatiotemporal resolution are necessary to understand the various forms and functions of genome organization in vivo. In C. elegans, sequencing- and imaging-based advances have provided insight on how histone modifications, regulatory elements, and large-scale chromosome conformations are established and changed. Recent observations include unexpected physiological roles for topologically associating domains, different roles for the nuclear lamina at different chromatin scales, cell-type-specific enhancer and promoter regulatory grammars, and prevalent compartment variability in early development. Here, we summarize these and other recent findings in C. elegans, and suggest future avenues of research to enrich our in vivo knowledge of the forms and functions of nuclear organization.},
}
@article {pmid35741810,
year = {2022},
author = {Liu, T and Wang, Z},
title = {scHiCEmbed: Bin-Specific Embeddings of Single-Cell Hi-C Data Using Graph Auto-Encoders.},
journal = {Genes},
volume = {13},
number = {6},
pages = {},
pmid = {35741810},
issn = {2073-4425},
support = {R35 GM137974/GM/NIGMS NIH HHS/United States ; },
mesh = {*Chromatin ; Cluster Analysis ; *Genome ; Software ; },
abstract = {Most publicly accessible single-cell Hi-C data are sparse and cannot reach a higher resolution. Therefore, learning latent representations (bin-specific embeddings) of sparse single-cell Hi-C matrices would provide us with a novel way of mining valuable information hidden in the limited number of single-cell Hi-C contacts. We present scHiCEmbed, an unsupervised computational method for learning bin-specific embeddings of single-cell Hi-C data, and the computational system is applied to the tasks of 3D structure reconstruction of whole genomes and detection of topologically associating domains (TAD). The only input of scHiCEmbed is a raw or scHiCluster-imputed single-cell Hi-C matrix. The main process of scHiCEmbed is to embed each node/bin in a higher dimensional space using graph auto-encoders. The learned n-by-3 bin-specific embedding/latent matrix is considered the final reconstructed 3D genome structure. For TAD detection, we use constrained hierarchical clustering on the latent matrix to classify bins: S_Dbw is used to determine the optimal number of clusters, and each cluster is considered as one potential TAD. Our reconstructed 3D structures for individual chromatins at different cell stages reveal the expanding process of chromatins during the cell cycle. We observe that the TADs called from single-cell Hi-C data are not shared across individual cells and that the TAD boundaries called from raw or imputed single-cell Hi-C are significantly different from those called from bulk Hi-C, confirming the cell-to-cell variability in terms of TAD definitions. The source code for scHiCEmbed is publicly available, and the URL can be found in the conclusion section.},
}
@article {pmid35730671,
year = {2022},
author = {Tian, GG and Hou, C and Li, J and Wu, J},
title = {Three-dimensional genome structure shapes the recombination landscape of chromatin features during female germline stem cell development.},
journal = {Clinical and translational medicine},
volume = {12},
number = {6},
pages = {e927},
pmid = {35730671},
issn = {2001-1326},
mesh = {Animals ; *Chromatin/genetics ; Chromosomes ; Genome/genetics ; Male ; Mammals/genetics ; Mice ; *Oogonial Stem Cells ; Recombination, Genetic ; },
abstract = {BACKGROUND: During meiosis of mammalian cells, chromatin undergoes drastic reorganization. However, the dynamics of the three-dimensional (3D) chromatin structure during the development of female germline stem cells (FGSCs) are poorly understood.<br><br>METHODS: The high-throughput chromosome conformation capture technique was used to probe the 3D structure of chromatin in mouse germ cells at each stage of FGSC development.<br><br>RESULTS: The global 3D genome was dramatically reorganized during FGSC development. In topologically associating domains, the chromatin structure was weakened in germinal vesicle stage oocytes and still present in meiosis I stage oocytes but had vanished in meiosis II oocytes. This switch between topologically associating domains was related to the biological process of FGSC development. Moreover, we constructed a landscape of chromosome X organization, which showed that the X chromosome occupied a smaller proportion of the active (A) compartment than the autosome during FGSC development. By comparing the high-order chromatin structure between female and male germline development, we found that 3D genome organization was remodelled by two different potential mechanisms during gamete development, in which interchromosomal interactions, compartments, and topologically associating domain were decreased during FGSC development but reorganized and recovered during spermatogenesis. Finally, we identified conserved chromatin structures between FGSC development and early embryonic development.<br><br>CONCLUSIONS: These results provide a valuable resource to characterize chromatin organization and for further studies of FGSC development.},
}
@article {pmid35726060,
year = {2022},
author = {Wang, W and Chandra, A and Goldman, N and Yoon, S and Ferrari, EK and Nguyen, SC and Joyce, EF and Vahedi, G},
title = {TCF-1 promotes chromatin interactions across topologically associating domains in T cell progenitors.},
journal = {Nature immunology},
volume = {23},
number = {7},
pages = {1052-1062},
pmid = {35726060},
issn = {1529-2916},
support = {U01 DK127768/DK/NIDDK NIH HHS/United States ; UC4 DK112217/DK/NIDDK NIH HHS/United States ; U01 DA052715/DA/NIDA NIH HHS/United States ; U01 DK112217/DK/NIDDK NIH HHS/United States ; R01 HL145754/HL/NHLBI NIH HHS/United States ; },
mesh = {CCCTC-Binding Factor/genetics/metabolism ; Cell Cycle Proteins/metabolism ; *Chromatin ; *Enhancer Elements, Genetic/genetics ; Gene Expression Regulation ; T-Lymphocytes/metabolism ; },
abstract = {The high mobility group (HMG) transcription factor TCF-1 is essential for early T cell development. Although in vitro biochemical assays suggest that HMG proteins can serve as architectural elements in the assembly of higher-order nuclear organization, the contribution of TCF-1 on the control of three-dimensional (3D) genome structures during T cell development remains unknown. Here, we investigated the role of TCF-1 in 3D genome reconfiguration. Using gain- and loss-of-function experiments, we discovered that the co-occupancy of TCF-1 and the architectural protein CTCF altered the structure of topologically associating domains in T cell progenitors, leading to interactions between previously insulated regulatory elements and target genes at late stages of T cell development. The TCF-1-dependent gain in long-range interactions was linked to deposition of active enhancer mark H3K27ac and recruitment of the cohesin-loading factor NIPBL at active enhancers. These data indicate that TCF-1 has a role in controlling global genome organization during T cell development.},
}
@article {pmid35725901,
year = {2022},
author = {Liu, E and Lyu, H and Peng, Q and Liu, Y and Wang, T and Han, J},
title = {TADfit is a multivariate linear regression model for profiling hierarchical chromatin domains on replicate Hi-C data.},
journal = {Communications biology},
volume = {5},
number = {1},
pages = {608},
pmid = {35725901},
issn = {2399-3642},
mesh = {*Chromatin/genetics ; *Chromosomes ; Genome ; Linear Models ; Reproducibility of Results ; },
abstract = {Topologically associating domains (TADs) are fundamental building blocks of three dimensional genome, and organized into complex hierarchies. Identifying hierarchical TADs on Hi-C data helps to understand the relationship between genome architectures and gene regulation. Herein we propose TADfit, a multivariate linear regression model for profiling hierarchical chromatin domains, which tries to fit the interaction frequencies in Hi-C contact matrix with and without replicates using all-possible hierarchical TADs, and the significant ones can be determined by the regression coefficients obtained with the help of an online learning solver called Follow-The-Regularized-Leader (FTRL). Beyond the existing methods, TADfit has an ability to handle multiple contact matrix replicates and find partially overlapping TADs on them, which helps to find the comprehensive underlying TADs across replicates from different experiments. The comparative results tell that TADfit has better accuracy and reproducibility, and the hierarchical TADs called by it exhibit a reasonable biological relevance.},
}
@article {pmid35715427,
year = {2022},
author = {Bolt, CC and Lopez-Delisle, L and Hintermann, A and Mascrez, B and Rauseo, A and Andrey, G and Duboule, D},
title = {Context-dependent enhancer function revealed by targeted inter-TAD relocation.},
journal = {Nature communications},
volume = {13},
number = {1},
pages = {3488},
pmid = {35715427},
issn = {2041-1723},
support = {F32 HD093555/HD/NICHD NIH HHS/United States ; },
mesh = {*Chromatin/genetics ; Chromosomes ; *Enhancer Elements, Genetic/genetics ; Extremities ; Transcription Factors/genetics ; },
abstract = {The expression of some genes depends on large, adjacent regions of the genome that contain multiple enhancers. These regulatory landscapes frequently align with Topologically Associating Domains (TADs), where they integrate the function of multiple similar enhancers to produce a global, TAD-specific regulation. We asked if an individual enhancer could overcome the influence of one of these landscapes, to drive gene transcription. To test this, we transferred an enhancer from its native location, into a nearby TAD with a related yet different functional specificity. We used the biphasic regulation of Hoxd genes during limb development as a paradigm. These genes are first activated in proximal limb cells by enhancers located in one TAD, which is then silenced when the neighboring TAD activates its enhancers in distal limb cells. We transferred a distal limb enhancer into the proximal limb TAD and found that its new context suppresses its normal distal specificity, even though it is bound by HOX13 transcription factors, which are responsible for the distal activity. This activity can be rescued only when a large portion of the surrounding environment is removed. These results indicate that, at least in some cases, the functioning of enhancer elements is subordinated to the host chromatin context, which can exert a dominant control over its activity.},
}
@article {pmid35714583,
year = {2022},
author = {Michieletto, D and Bickmore, WA},
title = {TADs do not stay in the loop.},
journal = {Molecular cell},
volume = {82},
number = {12},
pages = {2188-2189},
doi = {10.1016/j.molcel.2022.05.033},
pmid = {35714583},
issn = {1097-4164},
support = {MC_UU_00007/2/MRC_/Medical Research Council/United Kingdom ; 212203/WT_/Wellcome Trust/United Kingdom ; },
mesh = {CCCTC-Binding Factor/genetics ; *Chromatin ; },
abstract = {In a recent issue of Science, Gabriele et al. have, for the first time, quantified the dynamics of a topologically associating domain (TAD) in live cells by coupling super-resolution imaging and computational modelling, concluding that a TAD spends most of its life in a "partially extruded state" and that CTCF-CTCF loops are rare.},
}
@article {pmid35710139,
year = {2022},
author = {Sudarshan, D and Avvakumov, N and Lalonde, ME and Alerasool, N and Joly-Beauparlant, C and Jacquet, K and Mameri, A and Lambert, JP and Rousseau, J and Lachance, C and Paquet, E and Herrmann, L and Thonta Setty, S and Loehr, J and Bernardini, MQ and Rouzbahman, M and Gingras, AC and Coulombe, B and Droit, A and Taipale, M and Doyon, Y and Côté, J},
title = {Recurrent chromosomal translocations in sarcomas create a megacomplex that mislocalizes NuA4/TIP60 to Polycomb target loci.},
journal = {Genes &amp; development},
volume = {36},
number = {11-12},
pages = {664-683},
pmid = {35710139},
issn = {1549-5477},
support = {FDN-143314//CIHR/Canada ; },
mesh = {Chromatin ; DNA-Binding Proteins/metabolism ; *Endometrial Neoplasms/genetics/metabolism/pathology ; Female ; Histones/metabolism ; Humans ; Polycomb Repressive Complex 2/genetics/metabolism ; Polycomb-Group Proteins/genetics/metabolism ; *Sarcoma/genetics ; *Sarcoma, Endometrial Stromal/genetics/metabolism/pathology ; Translocation, Genetic/genetics ; },
abstract = {Chromosomal translocations frequently promote carcinogenesis by producing gain-of-function fusion proteins. Recent studies have identified highly recurrent chromosomal translocations in patients with endometrial stromal sarcomas (ESSs) and ossifying fibromyxoid tumors (OFMTs), leading to an in-frame fusion of PHF1 (PCL1) to six different subunits of the NuA4/TIP60 complex. While NuA4/TIP60 is a coactivator that acetylates chromatin and loads the H2A.Z histone variant, PHF1 is part of the Polycomb repressive complex 2 (PRC2) linked to transcriptional repression of key developmental genes through methylation of histone H3 on lysine 27. In this study, we characterize the fusion protein produced by the EPC1-PHF1 translocation. The chimeric protein assembles a megacomplex harboring both NuA4/TIP60 and PRC2 activities and leads to mislocalization of chromatin marks in the genome, in particular over an entire topologically associating domain including part of the HOXD cluster. This is linked to aberrant gene expression-most notably increased expression of PRC2 target genes. Furthermore, we show that JAZF1-implicated with a PRC2 component in the most frequent translocation in ESSs, JAZF1-SUZ12-is a potent transcription activator that physically associates with NuA4/TIP60, its fusion creating outcomes similar to those of EPC1-PHF1 Importantly, the specific increased expression of PRC2 targets/HOX genes was also confirmed with ESS patient samples. Altogether, these results indicate that most chromosomal translocations linked to these sarcomas use the same molecular oncogenic mechanism through a physical merge of NuA4/TIP60 and PRC2 complexes, leading to mislocalization of histone marks and aberrant Polycomb target gene expression.},
}
@article {pmid35710138,
year = {2022},
author = {Taylor, T and Sikorska, N and Shchuka, VM and Chahar, S and Ji, C and Macpherson, NN and Moorthy, SD and de Kort, MAC and Mullany, S and Khader, N and Gillespie, ZE and Langroudi, L and Tobias, IC and Lenstra, TL and Mitchell, JA and Sexton, T},
title = {Transcriptional regulation and chromatin architecture maintenance are decoupled functions at the Sox2 locus.},
journal = {Genes &amp; development},
volume = {36},
number = {11-12},
pages = {699-717},
pmid = {35710138},
issn = {1549-5477},
support = {R01 HG010045/HG/NHGRI NIH HHS/United States ; FRN 153186//CIHR/Canada ; },
mesh = {Animals ; Chromatin ; *Enhancer Elements, Genetic ; Gene Expression Regulation, Developmental ; Mice ; *Promoter Regions, Genetic ; SOXB1 Transcription Factors/*genetics ; Transcription Factors/metabolism ; },
abstract = {How distal regulatory elements control gene transcription and chromatin topology is not clearly defined, yet these processes are closely linked in lineage specification during development. Through allele-specific genome editing and chromatin interaction analyses of the Sox2 locus in mouse embryonic stem cells, we found a striking disconnection between transcriptional control and chromatin architecture. We traced nearly all Sox2 transcriptional activation to a small number of key transcription factor binding sites, whose deletions have no effect on promoter-enhancer interaction frequencies or topological domain organization. Local chromatin architecture maintenance, including at the topologically associating domain (TAD) boundary downstream from the Sox2 enhancer, is widely distributed over multiple transcription factor-bound regions and maintained in a CTCF-independent manner. Furthermore, partial disruption of promoter-enhancer interactions by ectopic chromatin loop formation has no effect on Sox2 transcription. These findings indicate that many transcription factors are involved in modulating chromatin architecture independently of CTCF.},
}
@article {pmid35688654,
year = {2022},
author = {Shukla, V and Cetnarowska, A and Hyldahl, M and Mandrup, S},
title = {Interplay between regulatory elements and chromatin topology in cellular lineage determination.},
journal = {Trends in genetics : TIG},
volume = {38},
number = {10},
pages = {1048-1061},
doi = {10.1016/j.tig.2022.05.011},
pmid = {35688654},
issn = {0168-9525},
mesh = {Cell Lineage/genetics ; *Chromatin/genetics ; DNA ; *Enhancer Elements, Genetic ; Transcription Factors/genetics/metabolism ; },
abstract = {Cellular lineage determination is controlled by combinations of lineage-selective transcription factors (TFs) and associated coregulators that bind to cis-regulatory elements in DNA and regulate gene expression. The ability of these factors to regulate transcription is determined not only by their cooperativity, but also by biochemical and structural properties of the chromatin, sculpting higher-order genome organization. Here, we review recent advances in the understanding of the interplay between chromatin topology and transcription. Studies from many different fields, including adipocyte lineage determination, indicate that lineage determination and differentiation are dependent on elaborate crosstalk between cis-regulatory elements, leading to the formation of transcriptional hubs. Chromatin topology appears to provide a dynamic and supportive, rather than a deterministic, scaffold for this crosstalk.},
}
@article {pmid35687908,
year = {2022},
author = {Tsujikawa, LM and Kharenko, OA and Stotz, SC and Rakai, BD and Sarsons, CD and Gilham, D and Wasiak, S and Fu, L and Sweeney, M and Johansson, JO and Wong, NCW and Kulikowski, E},
title = {Breaking boundaries: Pan BETi disrupt 3D chromatin structure, BD2-selective BETi are strictly epigenetic transcriptional regulators.},
journal = {Biomedicine &amp; pharmacotherapy = Biomedecine &amp; pharmacotherapie},
volume = {152},
number = {},
pages = {113230},
doi = {10.1016/j.biopha.2022.113230},
pmid = {35687908},
issn = {1950-6007},
mesh = {*COVID-19 ; Cell Cycle Proteins/metabolism ; Chromatin ; Endothelial Cells/metabolism ; Epigenesis, Genetic ; Humans ; Nuclear Proteins/genetics/metabolism ; *Transcription Factors/metabolism ; },
abstract = {BACKGROUND: Bromodomain and extraterminal proteins (BETs) are more than just epigenetic regulators of transcription. Here we highlight a new role for the BET protein BRD4 in the maintenance of higher order chromatin structure at Topologically Associating Domain Boundaries (TADBs). BD2-selective and pan (non-selective) BET inhibitors (BETi) differentially support chromatin structure, selectively affecting transcription and cell viability.<br><br>METHODS: Using RNA-seq and BRD4 ChIP-seq, the differential effect of BETi treatment on the transcriptome and BRD4 chromatin occupancy of human aortic endothelial cells from diabetic patients (dHAECs) stimulated with TNF&#x3b1; was evaluated. Chromatin decondensation and DNA fragmentation was assessed by immunofluorescence imaging and quantification. Key dHAEC findings were verified in proliferating monocyte-like THP-1 cells using real time-PCR, BRD4 co-immunoprecipitation studies, western blots, proliferation and apoptosis assays.<br><br>FINDINGS: We discovered that 1) BRD4 co-localizes with Ying-Yang 1 (YY1) at TADBs, critical chromatin structure complexes proximal to many DNA repair genes. 2) BD2-selective BETi enrich BRD4/YY1 associations, while pan-BETi do not. 3) Failure to support chromatin structures through BRD4/YY1 enrichment inhibits DNA repair gene transcription, which induces DNA damage responses, and causes widespread chromatin decondensation, DNA fragmentation, and apoptosis. 4) BD2-selective BETi maintain high order chromatin structure and cell viability, while reducing deleterious pro-inflammatory transcription.<br><br>INTERPRETATION: BRD4 plays a previously unrecognized role at TADBs. BETi differentially impact TADB stability. Our results provide translational insight for the development of BETi as therapeutics for a range of diseases including CVD, chronic kidney disease, cancer, and COVID-19.},
}
@article {pmid35685367,
year = {2022},
author = {Segueni, J and Noordermeer, D},
title = {CTCF: A misguided jack-of-all-trades in cancer cells.},
journal = {Computational and structural biotechnology journal},
volume = {20},
number = {},
pages = {2685-2698},
pmid = {35685367},
issn = {2001-0370},
abstract = {The emergence and progression of cancers is accompanied by a dysregulation of transcriptional programs. The three-dimensional (3D) organization of the human genome has emerged as an important multi-level mediator of gene transcription and regulation. In cancer cells, this organization can be restructured, providing a framework for the deregulation of gene activity. The CTCF protein, initially identified as the product from a tumor suppressor gene, is a jack-of-all-trades for the formation of 3D genome organization in normal cells. Here, we summarize how CTCF is involved in the multi-level organization of the human genome and we discuss emerging insights into how perturbed CTCF function and DNA binding causes the activation of oncogenes in cancer cells, mostly through a process of enhancer hijacking. Moreover, we highlight non-canonical functions of CTCF that can be relevant for the emergence of cancers as well. Finally, we provide guidelines for the computational identification of perturbed CTCF binding and reorganized 3D genome structure in cancer cells.},
}
@article {pmid35676475,
year = {2022},
author = {Emerson, DJ and Zhao, PA and Cook, AL and Barnett, RJ and Klein, KN and Saulebekova, D and Ge, C and Zhou, L and Simandi, Z and Minsk, MK and Titus, KR and Wang, W and Gong, W and Zhang, D and Yang, L and Venev, SV and Gibcus, JH and Yang, H and Sasaki, T and Kanemaki, MT and Yue, F and Dekker, J and Chen, CL and Gilbert, DM and Phillips-Cremins, JE},
title = {Cohesin-mediated loop anchors confine the locations of human replication origins.},
journal = {Nature},
volume = {606},
number = {7915},
pages = {812-819},
pmid = {35676475},
issn = {1476-4687},
support = {R01 MH120269/MH/NIMH NIH HHS/United States ; UM1 HG011536/HG/NHGRI NIH HHS/United States ; R01 HG010658/HG/NHGRI NIH HHS/United States ; DP1 MH129957/MH/NIMH NIH HHS/United States ; U01 DA052715/DA/NIDA NIH HHS/United States ; U54 DK107965/DK/NIDDK NIH HHS/United States ; U01 DK127405/DK/NIDDK NIH HHS/United States ; U01 HL129998/HL/NHLBI NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; U54 DK107980/DK/NIDDK NIH HHS/United States ; },
mesh = {*Cell Cycle Proteins/metabolism ; *Chromatin/genetics ; *Chromosomal Proteins, Non-Histone/metabolism ; DNA Replication ; Humans ; *Replication Origin/genetics ; S Phase ; },
abstract = {DNA replication occurs through an intricately regulated series of molecular events and is fundamental for genome stability[1,2]. At present, it is unknown how the locations of replication origins are determined in the human genome. Here we dissect the role of topologically associating domains (TADs)[3-6], subTADs[7] and loops[8] in the positioning of replication initiation zones (IZs). We stratify TADs and subTADs by the presence of corner-dots indicative of loops and the orientation of CTCF motifs. We find that high-efficiency, early replicating IZs localize to boundaries between adjacent corner-dot TADs anchored by high-density arrays of divergently and convergently oriented CTCF motifs. By contrast, low-efficiency IZs localize to weaker dotless boundaries. Following ablation of cohesin-mediated loop extrusion during G1, high-efficiency IZs become diffuse and delocalized at boundaries with complex CTCF motif orientations. Moreover, G1 knockdown of the cohesin unloading factor WAPL results in gained long-range loops and narrowed localization of IZs at the same boundaries. Finally, targeted deletion or insertion of specific boundaries causes local replication timing shifts consistent with IZ loss or gain, respectively. Our data support a model in which cohesin-mediated loop extrusion and stalling at a subset of genetically encoded TAD and subTAD boundaries is an essential determinant of the locations of replication origins in human S phase.},
}
@article {pmid35664233,
year = {2022},
author = {Zhang, S and Tao, W and Han, JJ},
title = {3D chromatin structure changes during spermatogenesis and oogenesis.},
journal = {Computational and structural biotechnology journal},
volume = {20},
number = {},
pages = {2434-2441},
pmid = {35664233},
issn = {2001-0370},
abstract = {Gametogenesis, including spermatogenesis and oogenesis, are unique differentiation processes involving extraordinarily complex and precise regulatory mechanisms that require the interactions of multiple cell types, hormones, paracrine factors, genes and epigenetic regulators, and extensive chromatin 3D structure re-organization. In recent years, the development of 3D genome technology represented by Hi-C, enabled mapping of the 3D re-organization of chromosomes during zygogenesis at an unprecedented resolution. The 3D remodeling is achieved by folding chromatin into loops, topologically associating domains (TADs), and compartments (A and B), which ultimately affect transcriptional activity. In this review, we summarize the research progresses and findings on chromatin 3D structure changes during spermatogenesis and oogenesis.},
}
@article {pmid35633286,
year = {2022},
author = {Zhang, Y and Tian, GG and Wang, X and Hou, C and Hu, X and Wu, J},
title = {Retinoic acid induced meiosis initiation in female germline stem cells by remodelling three-dimensional chromatin structure.},
journal = {Cell proliferation},
volume = {55},
number = {7},
pages = {e13242},
pmid = {35633286},
issn = {1365-2184},
mesh = {Adaptor Proteins, Signal Transducing/genetics/metabolism ; Chromatin ; Meiosis ; *Oogonial Stem Cells/metabolism ; *Tretinoin/pharmacology ; },
abstract = {OBJECTIVES: This study aimed to clarify the regulation and mechanism of meiotic initiation in FGSC development.<br><br>MATERIALS AND METHODS: FGSCs were induced to differentiate into meiosis in differentiation medium. RNA sequencing was performed to analysis the difference of transcription level. High-through chromosome conformation capture sequencing (Hi-C) was performed to analysis changes of three-dimensional chromatin structure. Chromosome conformation capture further confirmed a spatial chromatin loop. ChIP-qPCR and dual luciferase reporter were used to test the interaction between Stimulated by retinoic acid gene 8 (STRA8) protein and Trip13 promoter.<br><br>RESULTS: Compared with FGSCs, the average diameter of STRA8-positive germ cells increased from 13&#x2009;&#x3bc;m to 16.8&#xa0;&#x3bc;m. Furthermore, there were 4788 differentially expressed genes between the two cell stages; Meiosis and chromatin structure-associated terms were significantly enriched. Additionally, Hi-C results showed that FGSCs underwent A/B compartment switching (switch rate was 29.81%), the number of topologically associating domains (TADs) increasing, the average size of TADs decreasing, and chromatin loop changes at genome region of Trip13 from undifferentiated stage to meiosis-initiation stage. Furthermore, we validated that Trip13 promoter contacted distal enhancer to form spatial chromatin loop and STRA8 could bind Trip13 promoter to promote gene expression.<br><br>CONCLUSION: FGSCs underwent chromatin structure remodelling from undifferentiated stage to meiosis-initiation stage, which facilitated STRA8 binding to Trip13 promoter and promoting its expression.},
}
@article {pmid35588541,
year = {2022},
author = {Bin Akhtar, G and Buist, M and Rastegar, M},
title = {MeCP2 and transcriptional control of eukaryotic gene expression.},
journal = {European journal of cell biology},
volume = {101},
number = {3},
pages = {151237},
doi = {10.1016/j.ejcb.2022.151237},
pmid = {35588541},
issn = {1618-1298},
mesh = {DNA Methylation ; *Eukaryota/genetics/metabolism ; Eukaryotic Cells/metabolism ; Gene Expression ; Gene Expression Regulation ; *Methyl-CpG-Binding Protein 2/genetics/metabolism ; RNA/metabolism ; },
abstract = {Eukaryotic gene expression is controlled at multiple steps that work in harmony to ensure proper maintenance of cellular morphology and function. Such regulatory mechanisms would include transcriptional gene regulation, which is in turn controlled by chromatin remodeling, distinct topologically associating domains of the chromatin structure, cis-regulatory elements such as enhancers and promoters, action of trans-acting factors, DNA methylation, RNA modifications, and post-translational modification of histones. These guiding mechanisms of gene expression play critical roles in the epigenetic setting of individual cells within the eukaryotic systems. Some epigenetic factors may play multiple functional roles in guarding the accurate gene expression program of the eukaryotic cells, especially within the central nervous system. A well-studied example of such multi-functional factors is the methyl-CpG-binding protein 2 (MeCP2), a nuclear protein that is encoded by the X-linked MECP2 gene. Here, we aim to provide an overview of eukaryotic gene regulation, the three-dimensional chromatin organization, standard techniques to study newly synthesized RNA transcripts, and the role of MeCP2 as an important transcriptional regulator in eukaryotes.},
}
@article {pmid35585235,
year = {2022},
author = {Dequeker, BJH and Scherr, MJ and Brandão, HB and Gassler, J and Powell, S and Gaspar, I and Flyamer, IM and Lalic, A and Tang, W and Stocsits, R and Davidson, IF and Peters, JM and Duderstadt, KE and Mirny, LA and Tachibana, K},
title = {MCM complexes are barriers that restrict cohesin-mediated loop extrusion.},
journal = {Nature},
volume = {606},
number = {7912},
pages = {197-203},
pmid = {35585235},
issn = {1476-4687},
support = {DK107980/NH/NIH HHS/United States ; },
mesh = {Animals ; CCCTC-Binding Factor/metabolism ; *Cell Cycle Proteins/metabolism ; Chromatids/chemistry/metabolism ; *Chromosomal Proteins, Non-Histone/metabolism ; *DNA/chemistry/metabolism ; G1 Phase ; HCT116 Cells ; Humans ; Mice ; Minichromosome Maintenance Complex Component 3/chemistry/metabolism ; *Minichromosome Maintenance Proteins/chemistry/metabolism ; Multienzyme Complexes/chemistry/metabolism ; Nucleic Acid Conformation ; Saccharomyces cerevisiae ; Saccharomyces cerevisiae Proteins/metabolism ; },
abstract = {Eukaryotic genomes are compacted into loops and topologically associating domains (TADs)[1-3], which contribute to transcription, recombination and genomic stability[4,5]. Cohesin extrudes DNA into loops that are thought to lengthen until CTCF boundaries are encountered[6-12]. Little is known about whether loop extrusion is impeded by DNA-bound machines. Here we show that the minichromosome maintenance (MCM) complex is a barrier that restricts loop extrusion in G1 phase. Single-nucleus Hi-C (high-resolution chromosome conformation capture) of mouse zygotes reveals that MCM loading reduces CTCF-anchored loops and decreases TAD boundary insulation, which suggests that loop extrusion is impeded before reaching CTCF. This effect extends to HCT116 cells, in which MCMs affect the number of CTCF-anchored loops and gene expression. Simulations suggest that MCMs are abundant, randomly positioned and partially permeable barriers. Single-molecule imaging shows that MCMs are physical barriers that frequently constrain cohesin translocation in vitro. Notably, chimeric yeast MCMs that contain a cohesin-interaction motif from human MCM3 induce cohesin pausing, indicating that MCMs are 'active' barriers with binding sites. These findings raise the possibility that cohesin can arrive by loop extrusion at MCMs, which determine the genomic sites at which sister chromatid cohesion is established. On the basis of in vivo, in silico and in vitro data, we conclude that distinct loop extrusion barriers shape the three-dimensional genome.},
}
@article {pmid35551512,
year = {2022},
author = {Lei, Z and Meng, H and Liu, L and Zhao, H and Rao, X and Yan, Y and Wu, H and Liu, M and He, A and Yi, C},
title = {Mitochondrial base editor induces substantial nuclear off-target mutations.},
journal = {Nature},
volume = {606},
number = {7915},
pages = {804-811},
pmid = {35551512},
issn = {1476-4687},
mesh = {*Cell Nucleus/genetics ; *Cytosine/metabolism ; DNA, Mitochondrial/genetics ; *Gene Editing ; *Mitochondria/genetics/metabolism ; *Mutation ; },
abstract = {DddA-derived cytosine base editors (DdCBEs)-which are fusions of split DddA halves and transcription activator-like effector (TALE) array proteins from bacteria-enable targeted C•G-to-T•A conversions in mitochondrial DNA[1]. However, their genome-wide specificity is poorly understood. Here we show that the mitochondrial base editor induces extensive off-target editing in the nuclear genome. Genome-wide, unbiased analysis of its editome reveals hundreds of off-target sites that are TALE array sequence (TAS)-dependent or TAS-independent. TAS-dependent off-target sites in the nuclear DNA are often specified by only one of the two TALE repeats, challenging the principle that DdCBEs are guided by paired TALE proteins positioned in close proximity. TAS-independent off-target sites on nuclear DNA are frequently shared among DdCBEs with distinct TALE arrays. Notably, they co-localize strongly with binding sites for the transcription factor CTCF and are enriched in topologically associating domain boundaries. We engineered DdCBE to alleviate such off-target effects. Collectively, our results have implications for the use of DdCBEs in basic research and therapeutic applications, and suggest the need to thoroughly define and evaluate the off-target effects of base-editing tools.},
}
@article {pmid35551308,
year = {2022},
author = {Zhou, J},
title = {Sequence-based modeling of three-dimensional genome architecture from kilobase to chromosome scale.},
journal = {Nature genetics},
volume = {54},
number = {5},
pages = {725-734},
pmid = {35551308},
issn = {1546-1718},
support = {DP2 GM146336/GM/NIGMS NIH HHS/United States ; },
mesh = {*Chromatin/genetics ; *Chromosomes/genetics ; Genome/genetics ; Polycomb-Group Proteins/genetics ; Promoter Regions, Genetic/genetics ; Transcription Factors/genetics ; },
abstract = {To learn how genomic sequence influences multiscale three-dimensional (3D) genome architecture, this manuscript presents a sequence-based deep-learning approach, Orca, that predicts directly from sequence the 3D genome architecture from kilobase to whole-chromosome scale. Orca captures the sequence dependencies of structures including chromatin compartments and topologically associating domains, as well as diverse types of interactions from CTCF-mediated to enhancer-promoter interactions and Polycomb-mediated interactions with cell-type specificity. Orca enables various applications including predicting structural variant effects on multiscale genome organization and it recapitulated effects of experimentally studied variants at varying sizes (300 bp to 90 Mb). Moreover, Orca enables in silico virtual screens to probe the sequence basis of 3D genome organization at different scales. At the submegabase scale, it predicted specific transcription factor motifs underlying cell-type-specific genome interactions. At the compartment scale, virtual screens of sequence activities suggest a model for the sequence basis of chromatin compartments with a prominent role of transcription start sites.},
}
@article {pmid35530130,
year = {2022},
author = {Fan, Z and Wu, C and Chen, M and Jiang, Y and Wu, Y and Mao, R and Fan, Y},
title = {The generation of PD-L1 and PD-L2 in cancer cells: From nuclear chromatin reorganization to extracellular presentation.},
journal = {Acta pharmaceutica Sinica. B},
volume = {12},
number = {3},
pages = {1041-1053},
pmid = {35530130},
issn = {2211-3835},
abstract = {The immune checkpoint blockade (ICB) targeting on PD-1/PD-L1 has shown remarkable promise in treating cancers. However, the low response rate and frequently observed severe side effects limit its broad benefits. It is partially due to less understanding of the biological regulation of PD-L1. Here, we systematically and comprehensively summarized the regulation of PD-L1 from nuclear chromatin reorganization to extracellular presentation. In PD-L1 and PD-L2 highly expressed cancer cells, a new TAD (topologically associating domain) (chr9: 5,400,000-5,600,000) around CD274 and CD273 was discovered, which includes a reported super-enhancer to drive synchronous transcription of PD-L1 and PD-L2. The re-shaped TAD allows transcription factors such as STAT3 and IRF1 recruit to PD-L1 locus in order to guide the expression of PD-L1. After transcription, the PD-L1 is tightly regulated by miRNAs and RNA-binding proteins via the long 3'UTR. At translational level, PD-L1 protein and its membrane presentation are tightly regulated by post-translational modification such as glycosylation and ubiquitination. In addition, PD-L1 can be secreted via exosome to systematically inhibit immune response. Therefore, fully dissecting the regulation of PD-L1/PD-L2 and thoroughly detecting PD-L1/PD-L2 as well as their regulatory networks will bring more insights in ICB and ICB-based combinational therapy.},
}
@article {pmid35524567,
year = {2022},
author = {Poszewiecka, B and Pienkowski, VM and Nowosad, K and Robin, JD and Gogolewski, K and Gambin, A},
title = {TADeus2: a web server facilitating the clinical diagnosis by pathogenicity assessment of structural variations disarranging 3D chromatin structure.},
journal = {Nucleic acids research},
volume = {50},
number = {W1},
pages = {W744-52},
pmid = {35524567},
issn = {1362-4962},
abstract = {In recent years great progress has been made in identification of structural variants (SV) in the human genome. However, the interpretation of SVs, especially located in non-coding DNA, remains challenging. One of the reasons stems in the lack of tools exclusively designed for clinical SVs evaluation acknowledging the 3D chromatin architecture. Therefore, we present TADeus2 a web server dedicated for a quick investigation of chromatin conformation changes, providing a visual framework for the interpretation of SVs affecting topologically associating domains (TADs). This tool provides a convenient visual inspection of SVs, both in a continuous genome view as well as from a rearrangement's breakpoint perspective. Additionally, TADeus2 allows the user to assess the influence of analyzed SVs within flaking coding/non-coding regions based on the Hi-C matrix. Importantly, the SVs pathogenicity is quantified and ranked using TADA, ClassifyCNV tools and sampling-based P-value. TADeus2 is publicly available at https://tadeus2.mimuw.edu.pl.},
}
@article {pmid35524220,
year = {2022},
author = {Li, D and He, M and Tang, Q and Tian, S and Zhang, J and Li, Y and Wang, D and Jin, L and Ning, C and Zhu, W and Hu, S and Long, K and Ma, J and Liu, J and Zhang, Z and Li, M},
title = {Comparative 3D genome architecture in vertebrates.},
journal = {BMC biology},
volume = {20},
number = {1},
pages = {99},
pmid = {35524220},
issn = {1741-7007},
mesh = {Animals ; Chickens/genetics ; *Chromatin ; DNA Transposable Elements ; Euchromatin/genetics ; *Heterochromatin/genetics ; Mammals/genetics ; Vertebrates/genetics ; },
abstract = {BACKGROUND: The three-dimensional (3D) architecture of the genome has a highly ordered and hierarchical nature, which influences the regulation of essential nuclear processes at the basis of gene expression, such as gene transcription. While the hierarchical organization of heterochromatin and euchromatin can underlie differences in gene expression that determine evolutionary differences among species, the way 3D genome architecture is affected by evolutionary forces within major lineages remains unclear. Here, we report a comprehensive comparison of 3D genomes, using high resolution Hi-C data in fibroblast cells of fish, chickens, and 10 mammalian species.<br><br>RESULTS: This analysis shows a correlation between genome size and chromosome length that affects chromosome territory (CT) organization in the upper hierarchy of genome architecture, whereas lower hierarchical features, including local transcriptional availability of DNA, are selected through the evolution of vertebrates. Furthermore, conservation of topologically associating domains (TADs) appears strongly associated with the modularity of expression profiles across species. Additionally, LINE and SINE transposable elements likely contribute to heterochromatin and euchromatin organization, respectively, during the evolution of genome architecture.<br><br>CONCLUSIONS: Our analysis uncovers organizational features that appear to determine the conservation and transcriptional regulation of functional genes across species. These findings can guide ongoing investigations of genome evolution by extending our understanding of the mechanisms shaping genome architecture.},
}
@article {pmid35509102,
year = {2022},
author = {Deng, S and Feng, Y and Pauklin, S},
title = {3D chromatin architecture and transcription regulation in cancer.},
journal = {Journal of hematology &amp; oncology},
volume = {15},
number = {1},
pages = {49},
pmid = {35509102},
issn = {1756-8722},
mesh = {*Chromatin ; DNA-Binding Proteins ; Gene Expression Regulation ; Humans ; *Neoplasms/genetics ; Promoter Regions, Genetic ; },
abstract = {Chromatin has distinct three-dimensional (3D) architectures important in key biological processes, such as cell cycle, replication, differentiation, and transcription regulation. In turn, aberrant 3D structures play a vital role in developing abnormalities and diseases such as cancer. This review discusses key 3D chromatin structures (topologically associating domain, lamina-associated domain, and enhancer-promoter interactions) and corresponding structural protein elements mediating 3D chromatin interactions [CCCTC-binding factor, polycomb group protein, cohesin, and Brother of the Regulator of Imprinted Sites (BORIS) protein] with a highlight of their associations with cancer. We also summarise the recent development of technologies and bioinformatics approaches to study the 3D chromatin interactions in gene expression regulation, including crosslinking and proximity ligation methods in the bulk cell population (ChIA-PET and HiChIP) or single-molecule resolution (ChIA-drop), and methods other than proximity ligation, such as GAM, SPRITE, and super-resolution microscopy techniques.},
}
@article {pmid35508135,
year = {2022},
author = {Gilbertson, SE and Walter, HC and Gardner, K and Wren, SN and Vahedi, G and Weinmann, AS},
title = {Topologically associating domains are disrupted by evolutionary genome rearrangements forming species-specific enhancer connections in mice and humans.},
journal = {Cell reports},
volume = {39},
number = {5},
pages = {110769},
pmid = {35508135},
issn = {2211-1247},
support = {R01 AI061061/AI/NIAID NIH HHS/United States ; R01 HL145754/HL/NHLBI NIH HHS/United States ; R56 AI061061/AI/NIAID NIH HHS/United States ; },
mesh = {Animals ; *Chromatin ; Enhancer Elements, Genetic/genetics ; Evolution, Molecular ; Gene Rearrangement/genetics ; *Genome, Human ; Genomics ; Humans ; Mice ; },
abstract = {Distinguishing between conserved and divergent regulatory mechanisms is essential for translating preclinical research from mice to humans, yet there is a lack of information about how evolutionary genome rearrangements affect the regulation of the immune response, a rapidly evolving system. The current model is topologically associating domains (TADs) are conserved between species, buffering evolutionary rearrangements and conserving long-range interactions within a TAD. However, we find that TADs frequently span evolutionary translocation and inversion breakpoints near genes with species-specific expression in immune cells, creating unique enhancer-promoter interactions exclusive to the mouse or human genomes. This includes TADs encompassing immune-related transcription factors, cytokines, and receptors. For example, we uncover an evolutionary rearrangement that created a shared LPS-inducible regulatory module between OASL and P2RX7 in human macrophages that is absent in mice. Therefore, evolutionary genome rearrangements disrupt TAD boundaries, enabling sequence-conserved enhancer elements from divergent genomic locations between species to create unique regulatory modules.},
}
@article {pmid35502750,
year = {2022},
author = {Galupa, R and Picard, C and Servant, N and Nora, EP and Zhan, Y and van Bemmel, JG and El Marjou, F and Johanneau, C and Borensztein, M and Ancelin, K and Giorgetti, L and Heard, E},
title = {Inversion of a topological domain leads to restricted changes in its gene expression and affects interdomain communication.},
journal = {Development (Cambridge, England)},
volume = {149},
number = {9},
pages = {},
pmid = {35502750},
issn = {1477-9129},
mesh = {Animals ; CCCTC-Binding Factor/genetics/metabolism ; Chromatin ; Communication ; Gene Expression ; Genome ; Mice ; *RNA, Long Noncoding/genetics ; *X Chromosome Inactivation/genetics ; },
abstract = {The interplay between the topological organization of the genome and the regulation of gene expression remains unclear. Depletion of molecular factors (e.g. CTCF) underlying topologically associating domains (TADs) leads to modest alterations in gene expression, whereas genomic rearrangements involving TAD boundaries disrupt normal gene expression and can lead to pathological phenotypes. Here, we targeted the TAD neighboring that of the noncoding transcript Xist, which controls X-chromosome inactivation. Inverting 245 kb within the TAD led to expected rearrangement of CTCF-based contacts but revealed heterogeneity in the 'contact' potential of different CTCF sites. Expression of most genes therein remained unaffected in mouse embryonic stem cells and during differentiation. Interestingly, expression of Xist was ectopically upregulated. The same inversion in mouse embryos led to biased Xist expression. Smaller inversions and deletions of CTCF clusters led to similar results: rearrangement of contacts and limited changes in local gene expression, but significant changes in Xist expression in embryos. Our study suggests that the wiring of regulatory interactions within a TAD can influence the expression of genes in neighboring TADs, highlighting the existence of mechanisms of inter-TAD communication.},
}
@article {pmid35476527,
year = {2022},
author = {Panarotto, M and Davidson, IF and Litos, G and Schleiffer, A and Peters, JM},
title = {Cornelia de Lange syndrome mutations in NIPBL can impair cohesin-mediated DNA loop extrusion.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {119},
number = {18},
pages = {e2201029119},
pmid = {35476527},
issn = {1091-6490},
mesh = {Cell Cycle Proteins/genetics ; Chromosomal Proteins, Non-Histone/genetics ; DNA/genetics ; *De Lange Syndrome/genetics ; Humans ; Mutation ; },
abstract = {Cornelia de Lange syndrome (CdLS) is a developmental multisystem disorder frequently associated with mutations in NIPBL. CdLS is thought to arise from developmental gene regulation defects, but how NIPBL mutations cause these is unknown. Here we show that several NIPBL mutations impair the DNA loop extrusion activity of cohesin. Because this activity is required for the formation of chromatin loops and topologically associating domains, which have important roles in gene regulation, our results suggest that defects in cohesin-mediated loop extrusion contribute to the etiology of CdLS by altering interactions between developmental genes and their enhancers.},
}
@article {pmid35470444,
year = {2022},
author = {Jouret, G and Heide, S and Sorlin, A and Faivre, L and Chantot-Bastaraud, S and Beneteau, C and Denis-Musquer, M and Turnpenny, PD and Coutton, C and Vieville, G and Thevenon, J and Larson, A and Petit, F and Boudry, E and Smol, T and Delobel, B and Duban-Bedu, B and Fallerini, C and Mari, F and Lo Rizzo, C and Renieri, A and Caberg, JH and Denommé-Pichon, AS and Tran Mau-Them, F and Maystadt, I and Courtin, T and Keren, B and Mouthon, L and Charles, P and Cuinat, S and Isidor, B and Theis, P and Müller, C and Kulisic, M and Türkmen, S and Stieber, D and Bourgeois, D and Scalais, E and Klink, B},
title = {Understanding the new BRD4-related syndrome: Clinical and genomic delineation with an international cohort study.},
journal = {Clinical genetics},
volume = {102},
number = {2},
pages = {117-122},
doi = {10.1111/cge.14141},
pmid = {35470444},
issn = {1399-0004},
mesh = {Cell Cycle Proteins/genetics ; Child ; *De Lange Syndrome/diagnosis/genetics/pathology ; Female ; Genomics ; Humans ; Mutation ; *Nuclear Proteins/genetics ; Phenotype ; Pregnancy ; Transcription Factors/genetics ; },
abstract = {BRD4 is part of a multiprotein complex involved in loading the cohesin complex onto DNA, a fundamental process required for cohesin-mediated loop extrusion and formation of Topologically Associating Domains. Pathogenic variations in this complex have been associated with a growing number of syndromes, collectively known as cohesinopathies, the most classic being Cornelia de Lange syndrome. However, no cohort study has been conducted to delineate the clinical and molecular spectrum of BRD4-related disorder. We formed an international collaborative study, and collected 14 new patients, including two fetuses. We performed phenotype and genotype analysis, integrated prenatal findings from fetopathological examinations, phenotypes of pediatric patients and adults. We report the first cohort of patients with BRD4-related disorder and delineate the dysmorphic features at different ages. This work extends the phenotypic spectrum of cohesinopathies and characterize a new clinically relevant and recognizable pattern, distinguishable from the other cohesinopathies.},
}
@article {pmid35462859,
year = {2022},
author = {Habash, NW and Sehrawat, TS and Shah, VH and Cao, S},
title = {Epigenetics of alcohol-related liver diseases.},
journal = {JHEP reports : innovation in hepatology},
volume = {4},
number = {5},
pages = {100466},
pmid = {35462859},
issn = {2589-5559},
support = {R01 AA021171/AA/NIAAA NIH HHS/United States ; R01 DK059615/DK/NIDDK NIH HHS/United States ; R37 AA021171/AA/NIAAA NIH HHS/United States ; },
abstract = {Alcohol-related liver disease (ARLD) is a primary cause of chronic liver disease in the United States. Despite advances in the diagnosis and management of ARLD, it remains a major public health problem associated with significant morbidity and mortality, emphasising the need to adopt novel approaches to the study of ARLD and its complications. Epigenetic changes are increasingly being recognised as contributing to the pathogenesis of multiple disease states. Harnessing the power of innovative technologies for the study of epigenetics (e.g., next-generation sequencing, DNA methylation assays, histone modification profiling and computational techniques like machine learning) has resulted in a seismic shift in our understanding of the pathophysiology of ARLD. Knowledge of these techniques and advances is of paramount importance for the practicing hepatologist and researchers alike. Accordingly, in this review article we will summarise the current knowledge about alcohol-induced epigenetic alterations in the context of ARLD, including but not limited to, DNA hyper/hypo methylation, histone modifications, changes in non-coding RNA, 3D chromatin architecture and enhancer-promoter interactions. Additionally, we will discuss the state-of-the-art techniques used in the study of ARLD (e.g. single-cell sequencing). We will also highlight the epigenetic regulation of chemokines and their proinflammatory role in the context of ARLD. Lastly, we will examine the clinical applications of epigenetics in the diagnosis and management of ARLD.},
}
@article {pmid35456393,
year = {2022},
author = {Liu, W and Zhong, W and Chen, J and Huang, B and Hu, M and Li, Y},
title = {Understanding Regulatory Mechanisms of Brain Function and Disease through 3D Genome Organization.},
journal = {Genes},
volume = {13},
number = {4},
pages = {},
pmid = {35456393},
issn = {2073-4425},
support = {R35HG011922/NH/NIH HHS/United States ; R01NR019245/NH/NIH HHS/United States ; U01DA052713/NH/NIH HHS/United States ; U01 DK127421/DK/NIDDK NIH HHS/United States ; R01MH123724/NH/NIH HHS/United States ; P50HD103573/NH/NIH HHS/United States ; },
mesh = {Brain ; *Chromatin ; *Chromosomes ; Gene Expression Regulation ; Genome, Human ; Humans ; },
abstract = {The human genome has a complex and dynamic three-dimensional (3D) organization, which plays a critical role for gene regulation and genome function. The importance of 3D genome organization in brain development and function has been well characterized in a region- and cell-type-specific fashion. Recent technological advances in chromosome conformation capture (3C)-based techniques, imaging approaches, and ligation-free methods, along with computational methods to analyze the data generated, have revealed 3D genome features at different scales in the brain that contribute to our understanding of genetic mechanisms underlying neuropsychiatric diseases and other brain-related traits. In this review, we discuss how these advances aid in the genetic dissection of brain-related traits.},
}
@article {pmid35440598,
year = {2022},
author = {Aljahani, A and Hua, P and Karpinska, MA and Quililan, K and Davies, JOJ and Oudelaar, AM},
title = {Analysis of sub-kilobase chromatin topology reveals nano-scale regulatory interactions with variable dependence on cohesin and CTCF.},
journal = {Nature communications},
volume = {13},
number = {1},
pages = {2139},
pmid = {35440598},
issn = {2041-1723},
support = {MR/R008108/MRC_/Medical Research Council/United Kingdom ; },
mesh = {CCCTC-Binding Factor/genetics/metabolism ; Cell Cycle Proteins/genetics/metabolism ; *Chromatin/genetics ; *Chromosomal Proteins, Non-Histone/genetics/metabolism ; Chromosomes/metabolism ; },
abstract = {Enhancers and promoters predominantly interact within large-scale topologically associating domains (TADs), which are formed by loop extrusion mediated by cohesin and CTCF. However, it is unclear whether complex chromatin structures exist at sub-kilobase-scale and to what extent fine-scale regulatory interactions depend on loop extrusion. To address these questions, we present an MNase-based chromosome conformation capture (3C) approach, which has enabled us to generate the most detailed local interaction data to date (20 bp resolution) and precisely investigate the effects of cohesin and CTCF depletion on chromatin architecture. Our data reveal that cis-regulatory elements have distinct internal nano-scale structures, within which local insulation is dependent on CTCF, but which are independent of cohesin. In contrast, we find that depletion of cohesin causes a subtle reduction in longer-range enhancer-promoter interactions and that CTCF depletion can cause rewiring of regulatory contacts. Together, our data show that loop extrusion is not essential for enhancer-promoter interactions, but contributes to their robustness and specificity and to precise regulation of gene expression.},
}
@article {pmid35420890,
year = {2022},
author = {Gabriele, M and Brandão, HB and Grosse-Holz, S and Jha, A and Dailey, GM and Cattoglio, C and Hsieh, TS and Mirny, L and Zechner, C and Hansen, AS},
title = {Dynamics of CTCF- and cohesin-mediated chromatin looping revealed by live-cell imaging.},
journal = {Science (New York, N.Y.)},
volume = {376},
number = {6592},
pages = {496-501},
pmid = {35420890},
issn = {1095-9203},
support = {DP2 GM140938/GM/NIGMS NIH HHS/United States ; R33 CA257878/CA/NCI NIH HHS/United States ; UM1 HG011536/HG/NHGRI NIH HHS/United States ; R00 GM130896/GM/NIGMS NIH HHS/United States ; R01 GM114190/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Bayes Theorem ; CCCTC-Binding Factor ; Cell Cycle Proteins/metabolism ; *Chromatin ; *Chromosomal Proteins, Non-Histone/metabolism ; Mice ; },
abstract = {Animal genomes are folded into loops and topologically associating domains (TADs) by CTCF and loop-extruding cohesins, but the live dynamics of loop formation and stability remain unknown. Here, we directly visualized chromatin looping at the Fbn2 TAD in mouse embryonic stem cells using super-resolution live-cell imaging and quantified looping dynamics by Bayesian inference. Unexpectedly, the Fbn2 loop was both rare and dynamic, with a looped fraction of approximately 3 to 6.5% and a median loop lifetime of approximately 10 to 30 minutes. Our results establish that the Fbn2 TAD is highly dynamic, and about 92% of the time, cohesin-extruded loops exist within the TAD without bridging both CTCF boundaries. This suggests that single CTCF boundaries, rather than the fully CTCF-CTCF looped state, may be the primary regulators of functional interactions.},
}
@article {pmid35418676,
year = {2022},
author = {Zuin, J and Roth, G and Zhan, Y and Cramard, J and Redolfi, J and Piskadlo, E and Mach, P and Kryzhanovska, M and Tihanyi, G and Kohler, H and Eder, M and Leemans, C and van Steensel, B and Meister, P and Smallwood, S and Giorgetti, L},
title = {Nonlinear control of transcription through enhancer-promoter interactions.},
journal = {Nature},
volume = {604},
number = {7906},
pages = {571-577},
pmid = {35418676},
issn = {1476-4687},
support = {759366/ERC_/European Research Council/International ; },
mesh = {Animals ; Chromatin/genetics ; *Chromosomes ; *Enhancer Elements, Genetic/genetics ; Gene Expression Regulation ; Genomics ; Mammals/genetics ; Promoter Regions, Genetic/genetics ; },
abstract = {Chromosome structure in mammals is thought to regulate transcription by modulating three-dimensional interactions between enhancers and promoters, notably through CTCF-mediated loops and topologically associating domains (TADs)[1-4]. However, how chromosome interactions are actually translated into transcriptional outputs remains unclear. Here, to address this question, we use an assay to position an enhancer at large numbers of densely spaced chromosomal locations relative to a fixed promoter, and measure promoter output and interactions within a genomic region with minimal regulatory and structural complexity. A quantitative analysis of hundreds of cell lines reveals that the transcriptional effect of an enhancer depends on its contact probabilities with the promoter through a nonlinear relationship. Mathematical modelling suggests that nonlinearity might arise from transient enhancer-promoter interactions being translated into slower promoter bursting dynamics in individual cells, therefore uncoupling the temporal dynamics of interactions from those of transcription. This uncovers a potential mechanism of how distal enhancers act from large genomic distances, and of how topologically associating domain boundaries block distal enhancers. Finally, we show that enhancer strength also determines absolute transcription levels as well as the sensitivity of a promoter to CTCF-mediated transcriptional insulation. Our measurements establish general principles for the context-dependent role of chromosome structure in long-range transcriptional regulation.},
}
@article {pmid35413815,
year = {2022},
author = {Sefer, E},
title = {A comparison of topologically associating domain callers over mammals at high resolution.},
journal = {BMC bioinformatics},
volume = {23},
number = {1},
pages = {127},
pmid = {35413815},
issn = {1471-2105},
mesh = {Animals ; *Chromatin/genetics ; *Mammals/genetics ; },
abstract = {BACKGROUND: Topologically associating domains (TADs) are locally highly-interacting genome regions, which also play a critical role in regulating gene expression in the cell. TADs have been first identified while investigating the 3D genome structure over High-throughput Chromosome Conformation Capture (Hi-C) interaction dataset. Substantial degree of efforts have been devoted to develop techniques for inferring TADs from Hi-C interaction dataset. Many TAD-calling methods have been developed which differ in their criteria and assumptions in TAD inference. Correspondingly, TADs inferred via these callers vary in terms of both similarities and biological features they are enriched in.<br><br>RESULT: We have carried out a systematic comparison of 27 TAD-calling methods over mammals. We use Micro-C, a recent high-resolution variant of Hi-C, to compare TADs at a very high resolution, and classify the methods into 3 categories: feature-based methods, Clustering methods, Graph-partitioning methods. We have evaluated TAD boundaries, gaps between adjacent TADs, and quality of TADs across various criteria. We also found particularly CTCF and Cohesin proteins to be effective in formation of TADs with corner dots. We have also assessed the callers performance on simulated datasets since a gold standard for TADs is missing. TAD sizes and numbers change remarkably between TAD callers and dataset resolutions, indicating that TADs are hierarchically-organized domains, instead of disjoint regions. A core subset of feature-based TAD callers regularly perform the best while inferring reproducible domains, which are also enriched for TAD related biological properties.<br><br>CONCLUSION: We have analyzed the fundamental principles of TAD-calling methods, and identified the existing situation in TAD inference across high resolution Micro-C interaction datasets over mammals. We come up with a systematic, comprehensive, and concise framework to evaluate the TAD-calling methods performance across Micro-C datasets. Our research will be useful in selecting appropriate methods for TAD inference and evaluation based on available data, experimental design, and biological question of interest. We also introduce our analysis as a benchmarking tool with publicly available source code.},
}
@article {pmid35410381,
year = {2022},
author = {Xie, L and Dong, P and Qi, Y and Hsieh, TS and English, BP and Jung, S and Chen, X and De Marzio, M and Casellas, R and Chang, HY and Zhang, B and Tjian, R and Liu, Z},
title = {BRD2 compartmentalizes the accessible genome.},
journal = {Nature genetics},
volume = {54},
number = {4},
pages = {481-491},
pmid = {35410381},
issn = {1546-1718},
support = {/HHMI/Howard Hughes Medical Institute/United States ; },
mesh = {Animals ; Cell Cycle Proteins/genetics/metabolism ; Chromatin/genetics ; Chromosomes/genetics/metabolism ; Mammals/genetics ; *Nuclear Proteins/genetics/metabolism ; Protein Binding ; Protein Domains ; *Transcription Factors/genetics/metabolism ; },
abstract = {Mammalian chromosomes are organized into megabase-sized compartments that are further subdivided into topologically associating domains (TADs). While the formation of TADs is dependent on cohesin, the mechanism behind compartmentalization remains enigmatic. Here, we show that the bromodomain and extraterminal (BET) family scaffold protein BRD2 promotes spatial mixing and compartmentalization of active chromatin after cohesin loss. This activity is independent of transcription but requires BRD2 to recognize acetylated targets through its double bromodomain and interact with binding partners with its low-complexity domain. Notably, genome compartmentalization mediated by BRD2 is antagonized on the one hand by cohesin and on the other hand by the BET homolog protein BRD4, both of which inhibit BRD2 binding to chromatin. Polymer simulation of our data supports a BRD2-cohesin interplay model of nuclear topology, in which genome compartmentalization results from a competition between loop extrusion and chromatin-state-specific affinity interactions.},
}
@article {pmid35400201,
year = {2022},
author = {Feng, Y and Cai, L and Hong, W and Zhang, C and Tan, N and Wang, M and Wang, C and Liu, F and Wang, X and Ma, J and Gao, C and Kumar, M and Mo, Y and Geng, Q and Luo, C and Lin, Y and Chen, H and Wang, SY and Watson, MJ and Jegga, AG and Pedersen, RA and Fu, JD and Wang, ZV and Fan, GC and Sadayappan, S and Wang, Y and Pauklin, S and Huang, F and Huang, W and Jiang, L},
title = {Rewiring of 3D Chromatin Topology Orchestrates Transcriptional Reprogramming and the Development of Human Dilated Cardiomyopathy.},
journal = {Circulation},
volume = {145},
number = {22},
pages = {1663-1683},
pmid = {35400201},
issn = {1524-4539},
support = {R01 HL160811/HL/NHLBI NIH HHS/United States ; R01 HL157456/HL/NHLBI NIH HHS/United States ; R01 GM132149/GM/NIGMS NIH HHS/United States ; R01 AR078001/AR/NIAMS NIH HHS/United States ; R01 HL143490/HL/NHLBI NIH HHS/United States ; R38 HL155775/HL/NHLBI NIH HHS/United States ; R01 HL139006/HL/NHLBI NIH HHS/United States ; R01 HL130356/HL/NHLBI NIH HHS/United States ; R01 HL105826/HL/NHLBI NIH HHS/United States ; C59392/A25064/CRUK_/Cancer Research UK/United Kingdom ; R01 HL136025/HL/NHLBI NIH HHS/United States ; },
mesh = {Animals ; *Cardiomyopathy, Dilated/metabolism ; Chromatin/genetics/metabolism ; Histones/metabolism ; Humans ; *Induced Pluripotent Stem Cells/metabolism ; Mice ; Transcription Factors/genetics ; },
abstract = {BACKGROUND: Transcriptional reconfiguration is central to heart failure, the most common cause of which is dilated cardiomyopathy (DCM). The effect of 3-dimensional chromatin topology on transcriptional dysregulation and pathogenesis in human DCM remains elusive.<br><br>METHODS: We generated a compendium of 3-dimensional epigenome and transcriptome maps from 101 biobanked human DCM and nonfailing heart tissues through highly integrative chromatin immunoprecipitation (H3K27ac [acetylation of lysine 27 on histone H3]), in situ high-throughput chromosome conformation capture, chromatin immunoprecipitation sequencing, assay for transposase-accessible chromatin using sequencing, and RNA sequencing. We used human induced pluripotent stem cell-derived cardiomyocytes and mouse models to interrogate the key transcription factor implicated in 3-dimensional chromatin organization and transcriptional regulation in DCM pathogenesis.<br><br>RESULTS: We discovered that the active regulatory elements (H3K27ac peaks) and their connectome (H3K27ac loops) were extensively reprogrammed in DCM hearts and contributed to transcriptional dysregulation implicated in DCM development. For example, we identified that nontranscribing NPPA-AS1 (natriuretic peptide A antisense RNA 1) promoter functions as an enhancer and physically interacts with the NPPA (natriuretic peptide A) and NPPB (natriuretic peptide B) promoters, leading to the cotranscription of NPPA and NPPB in DCM hearts. We revealed that DCM-enriched H3K27ac loops largely resided in conserved high-order chromatin architectures (compartments, topologically associating domains) and their anchors unexpectedly had equivalent chromatin accessibility. We discovered that the DCM-enriched H3K27ac loop anchors exhibited a strong enrichment for HAND1 (heart and neural crest derivatives expressed 1), a key transcription factor involved in early cardiogenesis. In line with this, its protein expression was upregulated in human DCM and mouse failing hearts. To further validate whether HAND1 is a causal driver for the reprogramming of enhancer-promoter connectome in DCM hearts, we performed comprehensive 3-dimensional epigenome mappings in human induced pluripotent stem cell-derived cardiomyocytes. We found that forced overexpression of HAND1 in human induced pluripotent stem cell-derived cardiomyocytes induced a distinct gain of enhancer-promoter connectivity and correspondingly increased the expression of their connected genes implicated in DCM pathogenesis, thus recapitulating the transcriptional signature in human DCM hearts. Electrophysiology analysis demonstrated that forced overexpression of HAND1 in human induced pluripotent stem cell-derived cardiomyocytes induced abnormal calcium handling. Furthermore, cardiomyocyte-specific overexpression of Hand1 in the mouse hearts resulted in dilated cardiac remodeling with impaired contractility/Ca[2+] handling in cardiomyocytes, increased ratio of heart weight/body weight, and compromised cardiac function, which were ascribed to recapitulation of transcriptional reprogramming in DCM.<br><br>CONCLUSIONS: This study provided novel chromatin topology insights into DCM pathogenesis and illustrated a model whereby a single transcription factor (HAND1) reprograms the genome-wide enhancer-promoter connectome to drive DCM pathogenesis.},
}
@article {pmid35388001,
year = {2022},
author = {Chu, Z and Gu, L and Hu, Y and Zhang, X and Li, M and Chen, J and Teng, D and Huang, M and Shen, CH and Cai, L and Yoshida, T and Qi, Y and Niu, Z and Feng, A and Geng, S and Frederick, DT and Specht, E and Piris, A and Sullivan, RJ and Flaherty, KT and Boland, GM and Georgopoulos, K and Liu, D and Shi, Y and Zheng, B},
title = {STAG2 regulates interferon signaling in melanoma via enhancer loop reprogramming.},
journal = {Nature communications},
volume = {13},
number = {1},
pages = {1859},
pmid = {35388001},
issn = {2041-1723},
support = {R01 CA219814/CA/NCI NIH HHS/United States ; R01 HL140622/HL/NHLBI NIH HHS/United States ; R35 CA210104/CA/NCI NIH HHS/United States ; },
mesh = {Cell Cycle Proteins/genetics/metabolism ; *Chromosomal Proteins, Non-Histone/genetics/metabolism ; Genome ; Humans ; Interferons/genetics ; *Melanoma/genetics ; },
abstract = {The cohesin complex participates in the organization of 3D genome through generating and maintaining DNA loops. Stromal antigen 2 (STAG2), a core subunit of the cohesin complex, is frequently mutated in various cancers. However, the impact of STAG2 inactivation on 3D genome organization, especially the long-range enhancer-promoter contacts and subsequent gene expression control in cancer, remains poorly understood. Here we show that depletion of STAG2 in melanoma cells leads to expansion of topologically associating domains (TADs) and enhances the formation of acetylated histone H3 lysine 27 (H3K27ac)-associated DNA loops at sites where binding of STAG2 is switched to its paralog STAG1. We further identify Interferon Regulatory Factor 9 (IRF9) as a major direct target of STAG2 in melanoma cells via integrated RNA-seq, STAG2 ChIP-seq and H3K27ac HiChIP analyses. We demonstrate that loss of STAG2 activates IRF9 through modulating the 3D genome organization, which in turn enhances type I interferon signaling and increases the expression of PD-L1. Our findings not only establish a previously unknown role of the STAG2 to STAG1 switch in 3D genome organization, but also reveal a functional link between STAG2 and interferon signaling in cancer cells, which may enhance the immune evasion potential in STAG2-mutant cancer.},
}
@article {pmid35380694,
year = {2022},
author = {Serna-Pujol, N and Salinas-Pena, M and Mugianesi, F and Le Dily, F and Marti-Renom, MA and Jordan, A},
title = {Coordinated changes in gene expression, H1 variant distribution and genome 3D conformation in response to H1 depletion.},
journal = {Nucleic acids research},
volume = {50},
number = {7},
pages = {3892-3910},
pmid = {35380694},
issn = {1362-4962},
mesh = {Base Composition ; *Chromatin/genetics ; Chromatin Assembly and Disassembly ; Gene Expression ; *Histones/genetics/metabolism ; Humans ; },
abstract = {Up to seven members of the histone H1 family may contribute to chromatin compaction and its regulation in human somatic cells. In breast cancer cells, knock-down of multiple H1 variants deregulates many genes, promotes the appearance of genome-wide accessibility sites and triggers an interferon response via activation of heterochromatic repeats. However, how these changes in the expression profile relate to the re-distribution of H1 variants as well as to genome conformational changes have not been yet studied. Here, we combined ChIP-seq of five endogenous H1 variants with Chromosome Conformation Capture analysis in wild-type and H1.2/H1.4 knock-down T47D cells. The results indicate that H1 variants coexist in the genome in two large groups depending on the local GC content and that their distribution is robust with respect to H1 depletion. Despite the small changes in H1 variants distribution, knock-down of H1 translated into more isolated but de-compacted chromatin structures at the scale of topologically associating domains (TADs). Such changes in TAD structure correlated with a coordinated gene expression response of their resident genes. This is the first report describing simultaneous profiling of five endogenous H1 variants and giving functional evidence of genome topology alterations upon H1 depletion in human cancer cells.},
}
@article {pmid35379945,
year = {2022},
author = {Brown, JM and De Ornellas, S and Parisi, E and Schermelleh, L and Buckle, VJ},
title = {RASER-FISH: non-denaturing fluorescence in situ hybridization for preservation of three-dimensional interphase chromatin structure.},
journal = {Nature protocols},
volume = {17},
number = {5},
pages = {1306-1331},
pmid = {35379945},
issn = {1750-2799},
support = {MC_UU_00016/1/MRC_/Medical Research Council/United Kingdom ; MR/N00969X/1/MRC_/Medical Research Council/United Kingdom ; MR/K015777X/1/MRC_/Medical Research Council/United Kingdom ; BB/L01811X/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; 104924/Z/14/Z/WT_/Wellcome Trust/United Kingdom ; 091911/WT_/Wellcome Trust/United Kingdom ; 107457/Z/15/Z/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Animals ; *Cell Nucleus/genetics/metabolism ; *Chromatin/metabolism ; DNA/genetics/metabolism ; Exonucleases/metabolism ; In Situ Hybridization, Fluorescence/methods ; Interphase ; Mammals ; },
abstract = {DNA fluorescence in situ hybridization (FISH) has been a central technique in advancing our understanding of how chromatin is organized within the nucleus. With the increasing resolution offered by super-resolution microscopy, the optimal maintenance of chromatin structure within the nucleus is essential for accuracy in measurements and interpretation of data. However, standard 3D-FISH requires potentially destructive heat denaturation in the presence of chaotropic agents such as formamide to allow access to the DNA strands for labeled FISH probes. To avoid the need to heat-denature, we developed Resolution After Single-strand Exonuclease Resection (RASER)-FISH, which uses exonuclease digestion to generate single-stranded target DNA for efficient probe binding over a 2 d process. Furthermore, RASER-FISH is easily combined with immunostaining of nuclear proteins or the detection of RNAs. Here, we provide detailed procedures for RASER-FISH in mammalian cultured cells to detect single loci, chromatin tracks and topologically associating domains with conventional and super-resolution 3D structured illumination microscopy. Moreover, we provide a validation and characterization of our method, demonstrating excellent preservation of chromatin structure and nuclear integrity, together with improved hybridization efficiency, compared with classic 3D-FISH protocols.},
}
@article {pmid35354608,
year = {2022},
author = {Chathoth, KT and Mikheeva, LA and Crevel, G and Wolfe, JC and Hunter, I and Beckett-Doyle, S and Cotterill, S and Dai, H and Harrison, A and Zabet, NR},
title = {The role of insulators and transcription in 3D chromatin organization of flies.},
journal = {Genome research},
volume = {32},
number = {4},
pages = {682-698},
pmid = {35354608},
issn = {1549-5469},
support = {/WT_/Wellcome Trust/United Kingdom ; 202012/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Animals ; *Chromatin/genetics ; Chromosomes/metabolism ; DNA-Binding Proteins/genetics ; Drosophila/genetics/metabolism ; *Drosophila Proteins/genetics/metabolism ; Drosophila melanogaster/genetics/metabolism ; Eye Proteins/genetics ; Microtubule-Associated Proteins/genetics ; Nuclear Proteins/genetics ; Transcription Factors/metabolism ; },
abstract = {The DNA in many organisms, including humans, is shown to be organized in topologically associating domains (TADs). In Drosophila, several architectural proteins are enriched at TAD borders, but it is still unclear whether these proteins play a functional role in the formation and maintenance of TADs. Here, we show that depletion of BEAF-32, Cp190, Chro, and Dref leads to changes in TAD organization and chromatin loops. Their depletion predominantly affects TAD borders located in regions moderately enriched in repressive modifications and depleted in active ones, whereas TAD borders located in euchromatin are resilient to these knockdowns. Furthermore, transcriptomic data has revealed hundreds of genes displaying differential expression in these knockdowns and showed that the majority of differentially expressed genes are located within reorganized TADs. Our work identifies a novel and functional role for architectural proteins at TAD borders in Drosophila and a link between TAD reorganization and subsequent changes in gene expression.},
}
@article {pmid35346781,
year = {2022},
author = {Yin, S and NandyMazumdar, M and Paranjapye, A and Harris, A},
title = {Cross-talk between enhancers, structural elements and activating transcription factors maintains the 3D architecture and expression of the CFTR gene.},
journal = {Genomics},
volume = {114},
number = {3},
pages = {110350},
pmid = {35346781},
issn = {1089-8646},
support = {R01 HD068901/HD/NICHD NIH HHS/United States ; R01 HL094585/HL/NHLBI NIH HHS/United States ; T32 GM008056/GM/NIGMS NIH HHS/United States ; },
mesh = {*Cystic Fibrosis Transmembrane Conductance Regulator/genetics ; *Enhancer Elements, Genetic ; Chromatin ; Gene Expression Regulation ; Activating Transcription Factors/genetics/metabolism ; },
abstract = {Robust protocols to examine 3D chromatin structure have greatly advanced knowledge of gene regulatory mechanisms. Here we focus on the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which provides a paradigm for validating models of gene regulation built upon genome-wide analysis. We examine the mechanisms by which multiple cis-regulatory elements (CREs) at the CFTR gene coordinate its expression in intestinal epithelial cells. Using CRISPR/Cas9 to remove CREs, individually and in tandem, followed by assays of gene expression and higher-order chromatin structure (4C-seq), we reveal the cross-talk and dependency of two cell-specific intronic enhancers. The results suggest a mechanism whereby the locus responds when CREs are lost, which may involve activating transcription factors such as FOXA2. Also, by removing the 5' topologically-associating domain (TAD) boundary, we illustrate its impact on CFTR gene expression and architecture. These data suggest a multi-layered regulatory hierarchy that is highly sensitive to perturbations.},
}
@article {pmid35341742,
year = {2022},
author = {Paranjapye, A and NandyMazumdar, M and Harris, A},
title = {Krüppel-Like Factor 5 Regulates CFTR Expression Through Repression by Maintaining Chromatin Architecture Coupled with Direct Enhancer Activation.},
journal = {Journal of molecular biology},
volume = {434},
number = {10},
pages = {167561},
pmid = {35341742},
issn = {1089-8638},
support = {R01 HD068901/HD/NICHD NIH HHS/United States ; R01 HL094585/HL/NHLBI NIH HHS/United States ; R01 HL117843/HL/NHLBI NIH HHS/United States ; },
mesh = {*Chromatin/metabolism ; *Cystic Fibrosis Transmembrane Conductance Regulator/genetics ; *Enhancer Elements, Genetic ; Epithelial Cells/metabolism ; Humans ; *Kruppel-Like Transcription Factors/genetics/metabolism ; *Transcriptional Activation ; },
abstract = {Single cell RNA-sequencing has accurately identified cell types within the human airway that express the Cystic Fibrosis Transmembrane Conductance regulator (CFTR) gene. Low abundance CFTR transcripts are seen in many secretory cells, while high levels are restricted to rare pulmonary ionocytes. Here we focus on the mechanisms coordinating basal CFTR expression in the secretory compartment. Cell-selective regulation of CFTR is achieved within its invariant topologically associating domain by the recruitment of cis-regulatory elements (CREs). CRE activity is coordinated by cell-type-selective transcription factors. One such factor, Krüppel-Like Factor 5 (KLF5), profoundly represses CFTR transcript and protein in primary human airway epithelial cells and airway cell lines. Here we reveal the mechanism of action of KLF5 upon the CFTR gene. We find that depletion or ablation of KLF5 from airway epithelial cells changes higher order chromatin structure at the CFTR locus. Critical looping interactions that are required for normal gene expression are altered, the H3K27ac active chromatin mark is redistributed, and CTCF occupancy is modified. However, mutation of a single KLF5 binding site within a pivotal airway cell CRE abolishes CFTR expression. Hence, KLF5 has both direct activating and indirect repressive effects, which together coordinate CFTR expression in the airway.},
}
@article {pmid35332326,
year = {2022},
author = {Girdhar, K and Hoffman, GE and Bendl, J and Rahman, S and Dong, P and Liao, W and Hauberg, ME and Sloofman, L and Brown, L and Devillers, O and Kassim, BS and Wiseman, JR and Park, R and Zharovsky, E and Jacobov, R and Flatow, E and Kozlenkov, A and Gilgenast, T and Johnson, JS and Couto, L and Peters, MA and Phillips-Cremins, JE and Hahn, CG and Gur, RE and Tamminga, CA and Lewis, DA and Haroutunian, V and , and Dracheva, S and Lipska, BK and Marenco, S and Kundakovic, M and Fullard, JF and Jiang, Y and Roussos, P and Akbarian, S},
title = {Chromatin domain alterations linked to 3D genome organization in a large cohort of schizophrenia and bipolar disorder brains.},
journal = {Nature neuroscience},
volume = {25},
number = {4},
pages = {474-483},
pmid = {35332326},
issn = {1546-1726},
support = {R01 MH094714/MH/NIMH NIH HHS/United States ; R21 MH103877/MH/NIMH NIH HHS/United States ; U01 MH103365/MH/NIMH NIH HHS/United States ; U01 MH103392/MH/NIMH NIH HHS/United States ; DP1 MH129957/MH/NIMH NIH HHS/United States ; U01 MH103346/MH/NIMH NIH HHS/United States ; U01 MH103340/MH/NIMH NIH HHS/United States ; U01 MH103339/MH/NIMH NIH HHS/United States ; U01 DA048279/DA/NIDA NIH HHS/United States ; P50 MH096890/MH/NIMH NIH HHS/United States ; R21 MH105881/MH/NIMH NIH HHS/United States ; R01 NS114226/NS/NINDS NIH HHS/United States ; P50 MH106934/MH/NIMH NIH HHS/United States ; R01 MH105472/MH/NIMH NIH HHS/United States ; R01 MH106056/MH/NIMH NIH HHS/United States ; ZIC MH002903/ImNIH/Intramural NIH HHS/United States ; R21 MH102791/MH/NIMH NIH HHS/United States ; R01 MH105898/MH/NIMH NIH HHS/United States ; },
mesh = {Adult ; *Bipolar Disorder/genetics ; Brain ; Chromatin ; Humans ; Lysine/genetics ; *Schizophrenia/genetics ; },
abstract = {Chromosomal organization, scaling from the 147-base pair (bp) nucleosome to megabase-ranging domains encompassing multiple transcriptional units, including heritability loci for psychiatric traits, remains largely unexplored in the human brain. In this study, we constructed promoter- and enhancer-enriched nucleosomal histone modification landscapes for adult prefrontal cortex from H3-lysine 27 acetylation and H3-lysine 4 trimethylation profiles, generated from 388 controls and 351 individuals diagnosed with schizophrenia (SCZ) or bipolar disorder (BD) (n = 739). We mapped thousands of cis-regulatory domains (CRDs), revealing fine-grained, 10[4]-10[6]-bp chromosomal organization, firmly integrated into Hi-C topologically associating domain stratification by open/repressive chromosomal environments and nuclear topography. Large clusters of hyper-acetylated CRDs were enriched for SCZ heritability, with prominent representation of regulatory sequences governing fetal development and glutamatergic neuron signaling. Therefore, SCZ and BD brains show coordinated dysregulation of risk-associated regulatory sequences assembled into kilobase- to megabase-scaling chromosomal domains.},
}
@article {pmid35328034,
year = {2022},
author = {Zhao, C and Liu, T and Wang, Z},
title = {Functional Similarities of Protein-Coding Genes in Topologically Associating Domains and Spatially-Proximate Genomic Regions.},
journal = {Genes},
volume = {13},
number = {3},
pages = {},
pmid = {35328034},
issn = {2073-4425},
support = {R35 GM137974/GM/NIGMS NIH HHS/United States ; },
mesh = {*Genome/genetics ; *Genomics ; },
abstract = {Topologically associating domains (TADs) are the structural and functional units of the genome. However, the functions of protein-coding genes existing in the same or different TADs have not been fully investigated. We compared the functional similarities of protein-coding genes existing in the same TAD and between different TADs, and also in the same gap region (the region between two consecutive TADs) and between different gap regions. We found that the protein-coding genes from the same TAD or gap region are more likely to share similar protein functions, and this trend is more obvious with TADs than the gap regions. We further created two types of gene-gene spatial interaction networks: the first type is based on Hi-C contacts, whereas the second type is based on both Hi-C contacts and the relationship of being in the same TAD. A graph auto-encoder was applied to learn the network topology, reconstruct the two types of networks, and predict the functions of the central genes/nodes based on the functions of the neighboring genes/nodes. It was found that better performance was achieved with the second type of network. Furthermore, we detected long-range spatially-interactive regions based on Hi-C contacts and calculated the functional similarities of the gene pairs from these regions.},
}
@article {pmid35309301,
year = {2022},
author = {Xia, Y and Liu, X and Mu, W and Ma, C and Wang, L and Jiao, Y and Cui, B and Hu, S and Gao, Y and Liu, T and Sun, H and Zong, S and Liu, X and Zhao, Y},
title = {Capturing 3D Chromatin Maps of Human Primary Monocytes: Insights From High-Resolution Hi-C.},
journal = {Frontiers in immunology},
volume = {13},
number = {},
pages = {837336},
pmid = {35309301},
issn = {1664-3224},
mesh = {*Chromatin/genetics ; Chromatin Immunoprecipitation Sequencing ; Chromosomes ; Epigenesis, Genetic ; Humans ; *Monocytes ; },
abstract = {Although the variation in chromatin architecture during adaptive immune responses has been thoroughly investigated, the 3D landscape of innate immunity is still unknown. Herein, chromatin regulation and heterogeneity among human primary monocytes were investigated. Peripheral blood was collected from two healthy persons and two patients with systemic lupus erythematosus (SLE), and CD14[+] monocytes were selected to perform Hi-C, RNA-seq, ATAC-seq and ChIP-seq analyses. Raw data from the THP1 cell line Hi-C library were used for comparison. For each sample, we constructed three Hi-C libraries and obtained approximately 3 billion paired-end reads in total. Resolution analysis showed that more than 80% of bins presented depths greater than 1000 at a 5 kb resolution. The constructed high-resolution chromatin interaction maps presented similar landscapes in the four individuals, which showed significant divergence from the THP1 cell line chromatin structure. The variability in chromatin interactions around HLA-D genes in the HLA complex region was notable within individuals. We further found that the CD16-encoding gene (FCGR3A) is located at a variable topologically associating domain (TAD) boundary and that chromatin loop dynamics might modulate CD16 expression. Our results indicate both the stability and variability of high-resolution chromatin interaction maps among human primary monocytes. This work sheds light on the potential mechanisms by which the complex interplay of epigenetics and spatial 3D architecture regulates chromatin in innate immunity.},
}
@article {pmid35304523,
year = {2022},
author = {Sanders, JT and Golloshi, R and Das, P and Xu, Y and Terry, PH and Nash, DG and Dekker, J and McCord, RP},
title = {Loops, topologically associating domains, compartments, and territories are elastic and robust to dramatic nuclear volume swelling.},
journal = {Scientific reports},
volume = {12},
number = {1},
pages = {4721},
pmid = {35304523},
issn = {2045-2322},
support = {F32 GM100617/GM/NIGMS NIH HHS/United States ; R01 HG003143/HG/NHGRI NIH HHS/United States ; R35 GM133557/GM/NIGMS NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; },
mesh = {Cell Nucleus/metabolism ; *Chromatin/metabolism ; Chromatin Assembly and Disassembly ; *Chromosomes ; Genome ; },
abstract = {Layers of genome organization are becoming increasingly better characterized, but less is known about how these structures respond to perturbation or shape changes. Low-salt swelling of isolated chromatin fibers or nuclei has been used for decades to investigate the structural properties of chromatin. But, visible changes in chromatin appearance have not been linked to known building blocks of genome structure or features along the genome sequence. We combine low-salt swelling of isolated nuclei with genome-wide chromosome conformation capture (Hi-C) and imaging approaches to probe the effects of chromatin extension genome-wide. Photoconverted patterns on nuclei during expansion and contraction indicate that global genome structure is preserved after dramatic nuclear volume swelling, suggesting a highly elastic chromosome topology. Hi-C experiments before, during, and after nuclear swelling show changes in average contact probabilities at short length scales, reflecting the extension of the local chromatin fiber. But, surprisingly, during this large increase in nuclear volume, there is a striking maintenance of loops, TADs, active and inactive compartments, and chromosome territories. Subtle differences after expansion are observed, suggesting that the local chromatin state, protein interactions, and location in the nucleus can affect how strongly a given structure is maintained under stress. From these observations, we propose that genome topology is robust to extension of the chromatin fiber and isotropic shape change, and that this elasticity may be beneficial in physiological circumstances of changes in nuclear size and volume.},
}
@article {pmid35277200,
year = {2022},
author = {Zhang, J and Liu, P and He, M and Wang, Y and Kui, H and Jin, L and Li, D and Li, M},
title = {Reorganization of 3D genome architecture across wild boar and Bama pig adipose tissues.},
journal = {Journal of animal science and biotechnology},
volume = {13},
number = {1},
pages = {32},
pmid = {35277200},
issn = {1674-9782},
abstract = {BACKGROUND: A growing body of evidence has revealed that the mammalian genome is organized into hierarchical layers that are closely correlated with and may even be causally linked with variations in gene expression. Recent studies have characterized chromatin organization in various porcine tissues and cell types and compared them among species and during the early development of pigs. However, how chromatin organization differs among pig breeds is poorly understood.<br><br>RESULTS: In this study, we investigated the 3D genome organization and performed transcriptome characterization of two adipose depots (upper layer of backfat [ULB] and greater omentum [GOM]) in wild boars and Bama pigs; the latter is a typical indigenous pig in China. We found that over 95% of the A/B compartments and topologically associating domains (TADs) are stable between wild boars and Bama pigs. In contrast, more than 70% of promoter-enhancer interactions (PEIs) are dynamic and widespread, involving over a thousand genes. Alterations in chromatin structure are associated with changes in the expression of genes that are involved in widespread biological functions such as basic cellular functions, endocrine function, energy metabolism and the immune response. Approximately 95% and 97% of the genes associated with reorganized A/B compartments and PEIs in the two pig breeds differed between GOM and ULB, respectively.<br><br>CONCLUSIONS: We reported 3D genome organization in adipose depots from different pig breeds. In a comparison of Bama pigs and wild boar, large-scale compartments and TADs were mostly conserved, while fine-scale PEIs were extensively reorganized. The chromatin architecture in these two pig breeds was reorganized in an adipose depot-specific manner. These results contribute to determining the regulatory mechanism of phenotypic differences between Bama pigs and wild boar.},
}
@article {pmid35274679,
year = {2022},
author = {Hicks, P and Oluwadare, O},
title = {HiCARN: resolution enhancement of Hi-C data using cascading residual networks.},
journal = {Bioinformatics (Oxford, England)},
volume = {38},
number = {9},
pages = {2414-2421},
pmid = {35274679},
issn = {1367-4811},
mesh = {Humans ; Mice ; Animals ; Reproducibility of Results ; *Software ; *Chromatin ; Chromosomes ; Molecular Conformation ; },
abstract = {MOTIVATION: High throughput chromosome conformation capture (Hi-C) contact matrices are used to predict 3D chromatin structures in eukaryotic cells. High-resolution Hi-C data are less available than low-resolution Hi-C data due to sequencing costs but provide greater insight into the intricate details of 3D chromatin structures such as enhancer-promoter interactions and sub-domains. To provide a cost-effective solution to high-resolution Hi-C data collection, deep learning models are used to predict high-resolution Hi-C matrices from existing low-resolution matrices across multiple cell types.<br><br>RESULTS: Here, we present two Cascading Residual Networks called HiCARN-1 and HiCARN-2, a convolutional neural network and a generative adversarial network, that use a novel framework of cascading connections throughout the network for Hi-C contact matrix prediction from low-resolution data. Shown by image evaluation and Hi-C reproducibility metrics, both HiCARN models, overall, outperform state-of-the-art Hi-C resolution enhancement algorithms in predictive accuracy for both human and mouse 1/16, 1/32, 1/64 and 1/100 downsampled high-resolution Hi-C data. Also, validation by extracting topologically associating domains, chromosome 3D structure and chromatin loop predictions from the enhanced data shows that HiCARN can proficiently reconstruct biologically significant regions.<br><br>HiCARN can be accessed and utilized as an open-sourced software at: https://github.com/OluwadareLab/HiCARN and is also available as a containerized application that can be run on any platform.<br><br>SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},
}
@article {pmid35274099,
year = {2022},
author = {Galan, S and Serra, F and Marti-Renom, MA},
title = {Identification of chromatin loops from Hi-C interaction matrices by CTCF-CTCF topology classification.},
journal = {NAR genomics and bioinformatics},
volume = {4},
number = {1},
pages = {lqac021},
pmid = {35274099},
issn = {2631-9268},
support = {609989/ERC_/European Research Council/International ; },
abstract = {Genome-wide profiling of long-range interactions has revealed that the CCCTC-Binding factor (CTCF) often anchors chromatin loops and is enriched at boundaries of the so-called Topologically Associating Domains, which suggests that CTCF is essential in the 3D organization of chromatin. However, the systematic topological classification of pairwise CTCF-CTCF interactions has not been yet explored. Here, we developed a computational pipeline able to classify all CTCF-CTCF pairs according to their chromatin interactions from Hi-C experiments. The interaction profiles of all CTCF-CTCF pairs were further structurally clustered using self-organizing feature maps and their functionality characterized by their epigenetic states. The resulting clusters were then input to a convolutional neural network aiming at the de novo detecting chromatin loops from Hi-C interaction matrices. Our new method, called LOOPbit, is able to automatically detect significant interactions with a higher proportion of enhancer-promoter loops compared to other callers. Our highly specific loop caller adds a new layer of detail to the link between chromatin structure and function.},
}
@article {pmid35236295,
year = {2022},
author = {Mourad, R},
title = {TADreg: a versatile regression framework for TAD identification, differential analysis and rearranged 3D genome prediction.},
journal = {BMC bioinformatics},
volume = {23},
number = {1},
pages = {82},
pmid = {35236295},
issn = {1471-2105},
mesh = {Chromatin ; *Genome ; *Transcription Factors/genetics ; },
abstract = {BACKGROUND/AIM: In higher eukaryotes, the three-dimensional (3D) organization of the genome is intimately related to numerous key biological functions including gene expression, DNA repair and DNA replication regulations. Alteration of 3D organization, in particular topologically associating domains (TADs), is detrimental to the organism and can give rise to a broad range of diseases such as cancers.<br><br>METHODS: Here, we propose a versatile regression framework which not only identifies TADs in a fast and accurate manner, but also detects differential TAD borders across conditions for which few methods exist, and predicts 3D genome reorganization after chromosomal rearrangement. Moreover, the framework is biologically meaningful, has an intuitive interpretation and is easy to visualize.<br><br>RESULT AND CONCLUSION: The novel regression ranks among top TAD callers. Moreover, it identifies new features of the genome we called TAD facilitators, and that are enriched with specific transcription factors. It also unveils the importance of cell-type specific transcription factors in establishing novel TAD borders during neuronal differentiation. Lastly, it compares favorably with the state-of-the-art method for predicting rearranged 3D genome.},
}
@article {pmid35228717,
year = {2022},
author = {Pommier, Y and Nussenzweig, A and Takeda, S and Austin, C},
title = {Human topoisomerases and their roles in genome stability and organization.},
journal = {Nature reviews. Molecular cell biology},
volume = {23},
number = {6},
pages = {407-427},
pmid = {35228717},
issn = {1471-0080},
support = {Z01 BC006150/ImNIH/Intramural NIH HHS/United States ; Z01 BC006161/ImNIH/Intramural NIH HHS/United States ; },
mesh = {DNA Damage/genetics ; DNA Replication/genetics ; *Genomic Instability ; Humans ; Mitochondria/genetics ; *Neoplasms/genetics ; },
abstract = {Human topoisomerases comprise a family of six enzymes: two type IB (TOP1 and mitochondrial TOP1 (TOP1MT), two type IIA (TOP2A and TOP2B) and two type IA (TOP3A and TOP3B) topoisomerases. In this Review, we discuss their biochemistry and their roles in transcription, DNA replication and chromatin remodelling, and highlight the recent progress made in understanding TOP3A and TOP3B. Because of recent advances in elucidating the high-order organization of the genome through chromatin loops and topologically associating domains (TADs), we integrate the functions of topoisomerases with genome organization. We also discuss the physiological and pathological formation of irreversible topoisomerase cleavage complexes (TOPccs) as they generate topoisomerase DNA-protein crosslinks (TOP-DPCs) coupled with DNA breaks. We discuss the expanding number of redundant pathways that repair TOP-DPCs, and the defects in those pathways, which are increasingly recognized as source of genomic damage leading to neurological diseases and cancer.},
}
@article {pmid35202564,
year = {2022},
author = {Franke, M and Daly, AF and Palmeira, L and Tirosh, A and Stigliano, A and Trifan, E and Faucz, FR and Abboud, D and Petrossians, P and Tena, JJ and Vitali, E and Lania, AG and Gómez-Skarmeta, JL and Beckers, A and Stratakis, CA and Trivellin, G},
title = {Duplications disrupt chromatin architecture and rewire GPR101-enhancer communication in X-linked acrogigantism.},
journal = {American journal of human genetics},
volume = {109},
number = {4},
pages = {553-570},
pmid = {35202564},
issn = {1537-6605},
support = {Z01 HD008720/ImNIH/Intramural NIH HHS/United States ; },
mesh = {*Acromegaly/complications/genetics/pathology ; Child, Preschool ; Chromatin/genetics ; Communication ; DNA-Binding Proteins/genetics ; *Genetic Diseases, X-Linked/genetics ; *Gigantism/complications/genetics/pathology ; Humans ; *Pituitary Neoplasms/genetics ; Receptors, G-Protein-Coupled/genetics ; Transcription Factors/genetics ; },
abstract = {X-linked acrogigantism (X-LAG) is the most severe form of pituitary gigantism and is characterized by aggressive growth hormone (GH)-secreting pituitary tumors that occur in early childhood. X-LAG is associated with chromosome Xq26.3 duplications (the X-LAG locus typically includes VGLL1, CD40LG, ARHGEF6, RBMX, and GPR101) that lead to massive pituitary tumoral expression of GPR101, a novel regulator of GH secretion. The mechanism by which the duplications lead to marked pituitary misexpression of GPR101 alone was previously unclear. Using Hi-C and 4C-seq, we characterized the normal chromatin structure at the X-LAG locus. We showed that GPR101 is located within a topologically associating domain (TAD) delineated by a tissue-invariant border that separates it from centromeric genes and regulatory sequences. Next, using 4C-seq with GPR101, RBMX, and VGLL1 viewpoints, we showed that the duplications in multiple X-LAG-affected individuals led to ectopic interactions that crossed the invariant TAD border, indicating the existence of a similar and consistent mechanism of neo-TAD formation in X-LAG. We then identified several pituitary active cis-regulatory elements (CREs) within the neo-TAD and demonstrated in vitro that one of them significantly enhanced reporter gene expression. At the same time, we showed that the GPR101 promoter permits the incorporation of new regulatory information. Our results indicate that X-LAG is a TADopathy of the endocrine system in which Xq26.3 duplications disrupt the local chromatin architecture forming a neo-TAD. Rewiring GPR101-enhancer interaction within the new regulatory unit is likely to cause the high levels of aberrant expression of GPR101 in pituitary tumors caused by X-LAG.},
}
@article {pmid35181793,
year = {2022},
author = {Wu, H and Zhang, P and Ai, Z and Wei, L and Zhang, H and Yang, F and Cui, L},
title = {StackTADB: a stacking-based ensemble learning model for predicting the boundaries of topologically associating domains (TADs) accurately in fruit flies.},
journal = {Briefings in bioinformatics},
volume = {23},
number = {2},
pages = {},
doi = {10.1093/bib/bbac023},
pmid = {35181793},
issn = {1477-4054},
mesh = {Animals ; *Chromatin ; Chromosomes ; DNA-Binding Proteins/genetics ; Drosophila/genetics ; *Drosophila Proteins/genetics ; Eye Proteins/genetics ; Machine Learning ; Software ; },
abstract = {Chromosome is composed of many distinct chromatin domains, referred to variably as topological domains or topologically associating domains (TADs). The domains are stable across different cell types and highly conserved across species, thus these chromatin domains have been considered as the basic units of chromosome folding and regarded as an important secondary structure in chromosome organization. However, the identification of TAD boundaries is still a great challenge due to the high cost and low resolution of Hi-C data or experiments. In this study, we propose a novel ensemble learning framework, termed as StackTADB, for predicting the boundaries of TADs. StackTADB integrates four base classifiers including Random Forest, Logistic Regression, K-NearestNeighbor and Support Vector Machine. From the analysis of a series of examinations on the data set in the previous study, it is concluded that StackTADB has optimal performance in six metrics, AUC, Accuracy, MCC, Precision, Recall and F1 score, and it is superior to the existing methods. In addition, the comparison of the performance of multiple features shows that Kmers-based features play an essential role in predicting TADs boundaries of fruit flies, and we also apply the SHapley Additive exPlanations (SHAP) framework to interpret the predictions of StackTADB to identify the reason why Kmers-based features are vital. The experimental results show that the subsequences matching the BEAF-32 motif play a crucial role in predicting the boundaries of TADs. The source code is freely available at https://github.com/HaoWuLab-Bioinformatics/StackTADB and the webserver of StackTADB is freely available at http://hwtad.sdu.edu.cn:8002/StackTADB.},
}
@article {pmid35176995,
year = {2022},
author = {Osman, N and Shawky, AE and Brylinski, M},
title = {Exploring the effects of genetic variation on gene regulation in cancer in the context of 3D genome structure.},
journal = {BMC genomic data},
volume = {23},
number = {1},
pages = {13},
pmid = {35176995},
issn = {2730-6844},
support = {R35 GM119524/GM/NIGMS NIH HHS/United States ; },
mesh = {*Breast Neoplasms/genetics ; Chromatin/genetics ; Female ; Gene Expression Regulation, Neoplastic ; Genome, Human ; *Genome-Wide Association Study ; Humans ; Male ; Polymorphism, Single Nucleotide ; *Prostatic Neoplasms/genetics ; },
abstract = {BACKGROUND: Numerous genome-wide association studies (GWAS) conducted to date revealed genetic variants associated with various diseases, including breast and prostate cancers. Despite the availability of these large-scale data, relatively few variants have been functionally characterized, mainly because the majority of single-nucleotide polymorphisms (SNPs) map to the non-coding regions of the human genome. The functional characterization of these non-coding variants and the identification of their target genes remain challenging.<br><br>RESULTS: In this communication, we explore the potential functional mechanisms of non-coding SNPs by integrating GWAS with the high-resolution chromosome conformation capture (Hi-C) data for breast and prostate cancers. We show that more genetic variants map to regulatory elements through the 3D genome structure than the 1D linear genome lacking physical chromatin interactions. Importantly, the association of enhancers, transcription factors, and their target genes with breast and prostate cancers tends to be higher when these regulatory elements are mapped to high-risk SNPs through spatial interactions compared to simply using a linear proximity. Finally, we demonstrate that topologically associating domains (TADs) carrying high-risk SNPs also contain gene regulatory elements whose association with cancer is generally higher than those belonging to control TADs containing no high-risk variants.<br><br>CONCLUSIONS: Our results suggest that many SNPs may contribute to the cancer development by affecting the expression of certain tumor-related genes through long-range chromatin interactions with gene regulatory elements. Integrating large-scale genetic datasets with the 3D genome structure offers an attractive and unique approach to systematically investigate the functional mechanisms of genetic variants in disease risk and progression.},
}
@article {pmid35166842,
year = {2022},
author = {Ilyin, AA and Kononkova, AD and Golova, AV and Shloma, VV and Olenkina, OM and Nenasheva, VV and Abramov, YA and Kotov, AA and Maksimov, DA and Laktionov, PP and Pindyurin, AV and Galitsyna, AA and Ulianov, SV and Khrameeva, EE and Gelfand, MS and Belyakin, SN and Razin, SV and Shevelyov, YY},
title = {Comparison of genome architecture at two stages of male germline cell differentiation in Drosophila.},
journal = {Nucleic acids research},
volume = {50},
number = {6},
pages = {3203-3225},
pmid = {35166842},
issn = {1362-4962},
mesh = {Animals ; Cell Differentiation/genetics ; *Chromatin/genetics ; Dosage Compensation, Genetic ; *Drosophila/genetics ; Germ Cells ; Male ; },
abstract = {Eukaryotic chromosomes are spatially segregated into topologically associating domains (TADs). Some TADs are attached to the nuclear lamina (NL) through lamina-associated domains (LADs). Here, we identified LADs and TADs at two stages of Drosophila spermatogenesis - in bamΔ86 mutant testes which is the commonly used model of spermatogonia (SpG) and in larval testes mainly filled with spermatocytes (SpCs). We found that initiation of SpC-specific transcription correlates with promoters' detachment from the NL and with local spatial insulation of adjacent regions. However, this insulation does not result in the partitioning of inactive TADs into sub-TADs. We also revealed an increased contact frequency between SpC-specific genes in SpCs implying their de novo gathering into transcription factories. In addition, we uncovered the specific X chromosome organization in the male germline. In SpG and SpCs, a single X chromosome is stronger associated with the NL than autosomes. Nevertheless, active chromatin regions in the X chromosome interact with each other more frequently than in autosomes. Moreover, despite the absence of dosage compensation complex in the male germline, randomly inserted SpG-specific reporter is expressed higher in the X chromosome than in autosomes, thus evidencing that non-canonical dosage compensation operates in SpG.},
}
@article {pmid35145304,
year = {2022},
author = {Ortabozkoyun, H and Huang, PY and Cho, H and Narendra, V and LeRoy, G and Gonzalez-Buendia, E and Skok, JA and Tsirigos, A and Mazzoni, EO and Reinberg, D},
title = {CRISPR and biochemical screens identify MAZ as a cofactor in CTCF-mediated insulation at Hox clusters.},
journal = {Nature genetics},
volume = {54},
number = {2},
pages = {202-212},
pmid = {35145304},
issn = {1546-1718},
support = {P01 CA229086/CA/NCI NIH HHS/United States ; P30 CA016087/CA/NCI NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; P30 CA008748/CA/NCI NIH HHS/United States ; F31 HD090892/HD/NICHD NIH HHS/United States ; R01 NS100897/NS/NINDS NIH HHS/United States ; R01 CA229235/CA/NCI NIH HHS/United States ; R35 GM122515/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; CCCTC-Binding Factor/chemistry/genetics/*metabolism ; CRISPR-Cas Systems ; Cell Cycle Proteins/metabolism ; Cell Differentiation ; Cell Line ; Chromatin/metabolism ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Embryonic Stem Cells/cytology/*metabolism ; Gene Editing ; Gene Expression ; Gene Expression Regulation, Developmental ; *Genes, Homeobox ; Homeodomain Proteins/*genetics ; Mice ; Transcription Factors/chemistry/genetics/*metabolism ; },
abstract = {CCCTC-binding factor (CTCF) is critical to three-dimensional genome organization. Upon differentiation, CTCF insulates active and repressed genes within Hox gene clusters. We conducted a genome-wide CRISPR knockout (KO) screen to identify genes required for CTCF-boundary activity at the HoxA cluster, complemented by biochemical approaches. Among the candidates, we identified Myc-associated zinc-finger protein (MAZ) as a cofactor in CTCF insulation. MAZ colocalizes with CTCF at chromatin borders and, similar to CTCF, interacts with the cohesin subunit RAD21. MAZ KO disrupts gene expression and local contacts within topologically associating domains. Similar to CTCF motif deletions, MAZ motif deletions lead to derepression of posterior Hox genes immediately after CTCF boundaries upon differentiation, giving rise to homeotic transformations in mouse. Thus, MAZ is a factor contributing to appropriate insulation, gene expression and genomic architecture during development.},
}
@article {pmid35144531,
year = {2022},
author = {Chang, JM and Weng, YF and Chang, WT and Lin, FA and Cavalli, G},
title = {HiCmapTools: a tool to access HiC contact maps.},
journal = {BMC bioinformatics},
volume = {23},
number = {1},
pages = {64},
pmid = {35144531},
issn = {1471-2105},
support = {Advanced Grant 3DEpi/ERC_/European Research Council/International ; 788972/ERC_/European Research Council/International ; },
mesh = {*Chromatin ; *Genomics ; },
abstract = {BACKGROUND: With the development of HiC technology, more and more HiC sequencing data have been produced. Although there are dozens of packages that can turn sequencing data into contact maps, there is no appropriate tool to query contact maps in order to extract biological information from HiC datasets.<br><br>RESULTS: We present HiCmapTools, a tool for biologists to efficiently calculate and analyze HiC maps. The complete program provides multi-query modes and analysis tools. We have validated its utility on two real biological questions: TAD loop and TAD intra-density.<br><br>CONCLUSIONS: HiCmapTools supports seven access options so that biologists can quantify contact frequency of the interest sites. The tool has been implemented in C++&#x2009;and R and is freely available at https://github.com/changlabtw/hicmaptools and documented at https://hicmaptools.readthedocs.io/ .},
}
@article {pmid35140205,
year = {2022},
author = {Owens, DDG and Anselmi, G and Oudelaar, AM and Downes, DJ and Cavallo, A and Harman, JR and Schwessinger, R and Bucakci, A and Greder, L and de Ornellas, S and Jeziorska, D and Telenius, J and Hughes, JR and de Bruijn, MFTR},
title = {Dynamic Runx1 chromatin boundaries affect gene expression in hematopoietic development.},
journal = {Nature communications},
volume = {13},
number = {1},
pages = {773},
pmid = {35140205},
issn = {2041-1723},
support = {G0902418/MRC_/Medical Research Council/United Kingdom ; 105281/Z/14/Z/WT_/Wellcome Trust/United Kingdom ; MC_UU_00016/2/MRC_/Medical Research Council/United Kingdom ; 108870/Z/15/Z/WT_/Wellcome Trust/United Kingdom ; 106130/Z/14/Z/WT_/Wellcome Trust/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; MC_UU_00016/14/MRC_/Medical Research Council/United Kingdom ; 203728/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; MC_UU_12009/2/MRC_/Medical Research Council/United Kingdom ; MR/N00969X/1/MRC_/Medical Research Council/United Kingdom ; MR/K015777X/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Animals ; Cell Cycle Proteins/metabolism ; Cell Differentiation ; Chromatin/*metabolism ; Core Binding Factor Alpha 2 Subunit/*genetics/*metabolism ; DNA/chemistry ; *Gene Expression ; Gene Expression Regulation, Developmental ; Hematopoietic Stem Cells/metabolism ; Mesoderm/metabolism ; Mice ; Nucleic Acid Conformation ; Promoter Regions, Genetic ; },
abstract = {The transcription factor RUNX1 is a critical regulator of developmental hematopoiesis and is frequently disrupted in leukemia. Runx1 is a large, complex gene that is expressed from two alternative promoters under the spatiotemporal control of multiple hematopoietic enhancers. To dissect the dynamic regulation of Runx1 in hematopoietic development, we analyzed its three-dimensional chromatin conformation in mouse embryonic stem cell (ESC) differentiation cultures. Runx1 resides in a 1.1 Mb topologically associating domain (TAD) demarcated by convergent CTCF motifs. As ESCs differentiate to mesoderm, chromatin accessibility, Runx1 enhancer-promoter (E-P) interactions, and CTCF-CTCF interactions increase in the TAD, along with initiation of Runx1 expression from the P2 promoter. Differentiation to hematopoietic progenitor cells is associated with the formation of tissue-specific sub-TADs over Runx1, a shift in E-P interactions, P1 promoter demethylation, and robust expression from both Runx1 promoters. Deletion of promoter-proximal CTCF sites at the sub-TAD boundaries has no obvious effects on E-P interactions but leads to partial loss of domain structure, mildly affects gene expression, and delays hematopoietic development. Together, our analysis of gene regulation at a large multi-promoter developmental gene reveals that dynamic sub-TAD chromatin boundaries play a role in establishing TAD structure and coordinated gene expression.},
}
@article {pmid35115029,
year = {2022},
author = {Pei, L and Huang, X and Liu, Z and Tian, X and You, J and Li, J and Fang, DD and Lindsey, K and Zhu, L and Zhang, X and Wang, M},
title = {Dynamic 3D genome architecture of cotton fiber reveals subgenome-coordinated chromatin topology for 4-staged single-cell differentiation.},
journal = {Genome biology},
volume = {23},
number = {1},
pages = {45},
pmid = {35115029},
issn = {1474-760X},
mesh = {Cell Differentiation ; *Chromatin ; *Cotton Fiber ; Genome ; },
abstract = {BACKGROUND: Despite remarkable advances in our knowledge of epigenetically mediated transcriptional programming of cell differentiation in plants, little is known about chromatin topology and its functional implications in this process.<br><br>RESULTS: To interrogate its significance, we establish the dynamic three-dimensional (3D) genome architecture of the allotetraploid cotton fiber, representing a typical single cell undergoing staged development in plants. We show that the subgenome-relayed switching of the chromatin compartment from active to inactive is coupled with the silencing of developmentally repressed genes, pinpointing subgenome-coordinated contribution to fiber development. We identify 10,571 topologically associating domain-like (TAD-like) structures, of which 25.6% are specifically organized in different stages and 75.23% are subject to partition or fusion between two subgenomes. Notably, dissolution of intricate TAD-like structure cliques showing long-range interactions represents a prominent characteristic at the later developmental stage. Dynamic chromatin loops are found to mediate the rewiring of gene regulatory networks that exhibit a significant difference between the two subgenomes, implicating expression bias of homologous genes.<br><br>CONCLUSIONS: This study sheds light on the spatial-temporal asymmetric chromatin structures of two subgenomes in the cotton fiber and offers a new insight into the regulatory orchestration of cell differentiation in plants.},
}
@article {pmid35113722,
year = {2022},
author = {Batut, PJ and Bing, XY and Sisco, Z and Raimundo, J and Levo, M and Levine, MS},
title = {Genome organization controls transcriptional dynamics during development.},
journal = {Science (New York, N.Y.)},
volume = {375},
number = {6580},
pages = {566-570},
doi = {10.1126/science.abi7178},
pmid = {35113722},
issn = {1095-9203},
support = {R35 GM118147/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Chromatin/chemistry/genetics ; Chromosomes, Insect/chemistry/genetics ; Drosophila/embryology/*genetics ; Enhancer Elements, Genetic ; *Gene Expression Regulation, Developmental ; *Genes, Homeobox ; Genes, Insect ; *Genome, Insect ; Promoter Regions, Genetic ; Regulatory Sequences, Nucleic Acid ; Single-Cell Analysis ; *Transcription, Genetic ; },
abstract = {Past studies offer contradictory claims for the role of genome organization in the regulation of gene activity. Here, we show through high-resolution chromosome conformation analysis that the Drosophila genome is organized by two independent classes of regulatory sequences, tethering elements and insulators. Quantitative live imaging and targeted genome editing demonstrate that this two-tiered organization is critical for the precise temporal dynamics of Hox gene transcription during development. Tethering elements mediate long-range enhancer-promoter interactions and foster fast activation kinetics. Conversely, the boundaries of topologically associating domains (TADs) prevent spurious interactions with enhancers and silencers located in neighboring TADs. These two levels of genome organization operate independently of one another to ensure precision of transcriptional dynamics and the reliability of complex patterning processes.},
}
@article {pmid35104223,
year = {2022},
author = {Liu, K and Li, H and Li, Y and Wang, J and Wang, J},
title = {A comparison of topologically associating domain callers based on Hi-C data.},
journal = {IEEE/ACM transactions on computational biology and bioinformatics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TCBB.2022.3147805},
pmid = {35104223},
issn = {1557-9964},
abstract = {Topologically associating domains (TADs) are local chromatin interaction domains, which have been shown to play an important role in gene expression regulation. TADs were originally discovered in the investigation of 3D genome organization based on High-throughput Chromosome Conformation Capture (Hi-C) data. Continuous considerable efforts have been dedicated to developing methods for detecting TADs from Hi-C data. Different computational methods for TADs identification vary in their assumptions and criteria in calling TADs. As a consequence, the TADs called by these methods differ in their similarities and biological features they are enriched in. In this work, we performed a systematic comparison of twenty-four TAD callers. We first compared the TADs and gaps between adjacent TADs across different methods, resolutions, and sequencing depths. We then assessed the quality of TADs and TAD boundaries according to three criteria: the decay of contact frequencies over the genomic distance, enrichment and depletion of regulatory elements around TAD boundaries, and reproducibility of TADs and TAD boundaries in replicate samples. Last, due to the lack of a gold standard for TADs, we also evaluated the performance of the methods on synthetic datasets.},
}
@article {pmid35098228,
year = {2022},
author = {Chu, X and Wang, J},
title = {Dynamics and Pathways of Chromosome Structural Organizations during Cell Transdifferentiation.},
journal = {JACS Au},
volume = {2},
number = {1},
pages = {116-127},
pmid = {35098228},
issn = {2691-3704},
abstract = {Direct conversion of one differentiated cell type into another is defined as cell transdifferentiation. In avoidance of forming pluripotency, cell transdifferentiation can reduce the potential risk of tumorigenicity, thus offering significant advantages over cell reprogramming in clinical applications. Until now, the mechanism of cell transdifferentiation is still largely unknown. It has been well recognized that cell transdifferentiation is determined by the underlying gene expression regulation, which relies on the accurate adaptation of the chromosome structure. To dissect the transdifferentiation at the molecular level, we develop a nonequilibrium landscape-switching model to investigate the chromosome structural dynamics during the state transitions between the human fibroblast and neuron cells. We uncover the high irreversibility of the transdifferentiation at the local chromosome structural ranges, where the topologically associating domains form. In contrast, the pathways in the two opposite directions of the transdifferentiation projected onto the chromosome compartment profiles are highly overlapped, indicating that the reversibility vanishes at the long-range chromosome structures. By calculating the contact strengths in the chromosome at the states along the paths, we observe strengthening contacts in compartment A concomitant with weakening contacts in compartment B at the early stages of the transdifferentiation. This further leads to adapting contacts toward the ones at the embryonic stem cell. In light of the intimate structure-function relationship at the chromosomal level, we suggest an increase of "stemness" during the transdifferentiation. In addition, we find that the neuron progenitor cell (NPC), a cell developmental state, is located on the transdifferentiation pathways projected onto the long-range chromosome contacts. The findings are consistent with the previous single-cell RNA sequencing experiment, where the NPC-like cell states were observed during the direct conversion of the fibroblast to neuron cells. Thus, we offer a promising microscopic and physical approach to study the cell transdifferentiation mechanism from the chromosome structural perspective.},
}
@article {pmid35090532,
year = {2022},
author = {Long, HS and Greenaway, S and Powell, G and Mallon, AM and Lindgren, CM and Simon, MM},
title = {Making sense of the linear genome, gene function and TADs.},
journal = {Epigenetics &amp; chromatin},
volume = {15},
number = {1},
pages = {4},
pmid = {35090532},
issn = {1756-8935},
support = {UM1 HG006370/HG/NHGRI NIH HHS/United States ; 203141/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; MC_U142684171/MRC_/Medical Research Council/United Kingdom ; },
mesh = {CCCTC-Binding Factor/genetics/metabolism ; *Chromatin/genetics ; Chromatin Assembly and Disassembly ; Chromatin Immunoprecipitation Sequencing ; *Genome ; },
abstract = {BACKGROUND: Topologically associating domains (TADs) are thought to act as functional units in the genome. TADs co-localise genes and their regulatory elements as well as forming the unit of genome switching between active and inactive compartments. This has led to the speculation that genes which are required for similar processes may fall within the same TADs, allowing them to share regulatory programs and efficiently switch between chromatin compartments. However, evidence to link genes within TADs to the same regulatory program is limited.<br><br>RESULTS: We investigated the functional similarity of genes which fall within the same TAD. To do this we developed a TAD randomisation algorithm to generate sets of "random TADs" to act as null distributions. We found that while pairs of paralogous genes are enriched in TADs overall, they are largely depleted in TADs with CCCTC-binding factor (CTCF) ChIP-seq peaks at both boundaries. By assessing gene constraint as a proxy for functional importance we found that genes which singly occupy a TAD have greater functional importance than genes which share a TAD, and these genes are enriched for developmental processes. We found little evidence that pairs of genes in CTCF bound TADs are more likely to be co-expressed or share functional annotations than can be explained by their linear proximity alone.<br><br>CONCLUSIONS: These results suggest that algorithmically defined TADs consist of two functionally different groups, those which are bound by CTCF and those which are not. We detected no association between genes sharing the same CTCF TADs and increased co-expression or functional similarity, other than that explained by linear genome proximity. We do, however, find that functionally important genes are more likely to fall within a TAD on their own suggesting that TADs play an important role in the insulation of these genes.},
}
@article {pmid35088940,
year = {2022},
author = {Lybaek, H and Robson, M and de Leeuw, N and Hehir-Kwa, JY and Jeffries, A and Haukanes, BI and Berland, S and de Bruijn, D and Mundlos, S and Spielmann, M and Houge, G},
title = {LRFN5 locus structure is associated with autism and influenced by the sex of the individual and locus conversions.},
journal = {Autism research : official journal of the International Society for Autism Research},
volume = {15},
number = {3},
pages = {421-433},
pmid = {35088940},
issn = {1939-3806},
mesh = {Animals ; *Autism Spectrum Disorder/genetics ; *Autistic Disorder/genetics ; Cell Adhesion Molecules, Neuronal/*genetics ; Female ; Haplotypes ; Humans ; Male ; Mammals ; Polymorphism, Genetic ; },
abstract = {LRFN5 is a regulator of synaptic development and the only gene in a 5.4 Mb mammalian-specific conserved topologically associating domain (TAD); the LRFN5 locus. An association between locus structural changes and developmental delay (DD) and/or autism was suggested by several cases in DECIPHER and own records. More significantly, we found that maternal inheritance of a specific LRFN5 locus haplotype segregated with an identical type of autism in distantly related males. This autism-susceptibility haplotype had a specific TAD pattern. We also found a male/female quantitative difference in the amount histone-3-lysine-9-associated chromatin around the LRFN5 gene itself (p < 0.01), possibly related to the male-restricted autism susceptibility. To better understand locus behavior, the prevalence of a 60 kb deletion polymorphism was investigated. Surprisingly, in three cohorts of individuals with DD (n = 8757), the number of deletion heterozygotes was 20%-26% lower than expected from Hardy-Weinberg equilibrium. This suggests allelic interaction, also because the conversions from heterozygosity to wild-type or deletion homozygosity were of equal magnitudes. Remarkably, in a control group of medical students (n = 1416), such conversions were three times more common (p = 0.00001), suggesting a regulatory role of this allelic interaction. Taken together, LRFN5 regulation appears unusually complex, and LRFN5 dysregulation could be an epigenetic cause of autism. LAY SUMMARY: LRFN5 is involved with communication between brain cells. The gene sits alone in a huge genomic niche, called the LRFN5 locus, of complex structure and high mammalian conservation. We have found that a specific locus structure increases autism susceptibility in males, but we do not yet know how common this epigenetic cause of autism is. It is, however, a cause that potentially could explain why higher-functioning autism is more common in males than females.},
}
@article {pmid35087776,
year = {2021},
author = {Wang, H and Cui, B and Sun, H and Zhang, F and Rao, J and Wang, R and Zhao, S and Shen, S and Liu, Y},
title = {Aberrant GATA2 Activation in Pediatric B-Cell Acute Lymphoblastic Leukemia.},
journal = {Frontiers in pediatrics},
volume = {9},
number = {},
pages = {795529},
pmid = {35087776},
issn = {2296-2360},
abstract = {GATA2 is a transcription factor that is critical for the generation and survival of hematopoietic stem cells (HSCs). It also plays an important role in the regulation of myeloid differentiation. Accordingly, GATA2 expression is restricted to HSCs and hematopoietic progenitors as well as early erythroid cells and megakaryocytic cells. Here we identified aberrant GATA2 expression in B-cell acute lymphoblastic leukemia (B-ALL) by analyzing transcriptome sequencing data obtained from St. Jude Cloud. Differentially expressed genes upon GATA2 activation showed significantly myeloid-like transcription signature. Further analysis identified several tumor-associated genes as targets of GATA2 activation including BAG3 and EPOR. In addition, the correlation between KMT2A-USP2 fusion and GATA2 activation not only indicates a potential trans-activating mechanism of GATA2 but also suggests that GATA2 is a target of KMT2A-USP2. Furthermore, by integrating whole-genome and transcriptome sequencing data, we showed that GATA2 is also cis activated. A somatic focal deletion located in the GATA2 neighborhood that disrupts the boundaries of topologically associating domains was identified in one B-ALL patient with GATA2 activation. These evidences support the hypothesis that GATA2 could be involved in leukemogenesis of B-ALL and can be transcriptionally activated through multiple mechanisms. The findings of aberrant activation of GATA2 and its molecular function extend our understanding of transcriptional factor dysregulation in B-ALL.},
}
@article {pmid35065445,
year = {2022},
author = {Ing-Simmons, E and Rigau, M and Vaquerizas, JM},
title = {Emerging mechanisms and dynamics of three-dimensional genome organisation at zygotic genome activation.},
journal = {Current opinion in cell biology},
volume = {74},
number = {},
pages = {37-46},
doi = {10.1016/j.ceb.2021.12.004},
pmid = {35065445},
issn = {1879-0410},
support = {MC_UP_1605/10/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Animals ; Chromatin/genetics ; Drosophila/metabolism ; *Drosophila Proteins/metabolism ; Gene Expression Regulation, Developmental ; Genome ; Mice ; Zebrafish ; *Zygote/metabolism ; },
abstract = {The genome of an early embryo undergoes significant remodelling at the epigenetic, transcriptional, and structural levels. New technological developments have made it possible to study 3D genome organisation in the zygote and early embryo of many different species. Recent studies in human embryos, zebrafish, medaka, and Xenopus have revealed that, similar to previous results in mouse and Drosophila, the zygotic genome is unstructured prior to zygotic genome activation. While these studies show that topologically associating domains are established coincident with zygotic genome activation across species, other 3D genome structures have more varied timing. Here, we review recent studies examining the timing and mechanisms of establishment of 3D genome organisation in the early embryo, and discuss similarities and differences between species. Investigating the establishment of 3D chromatin conformation in early embryos has the potential to reveal novel mechanisms of 3D genome organisation.},
}
@article {pmid35047813,
year = {2022},
author = {Tsagiopoulou, M and Pechlivanis, N and Maniou, MC and Psomopoulos, F},
title = {InterTADs: integration of multi-omics data on topologically associated domains, application to chronic lymphocytic leukemia.},
journal = {NAR genomics and bioinformatics},
volume = {4},
number = {1},
pages = {lqab121},
pmid = {35047813},
issn = {2631-9268},
abstract = {The integration of multi-omics data can greatly facilitate the advancement of research in Life Sciences by highlighting new interactions. However, there is currently no widespread procedure for meaningful multi-omics data integration. Here, we present a robust framework, called InterTADs, for integrating multi-omics data derived from the same sample, and considering the chromatin configuration of the genome, i.e. the topologically associating domains (TADs). Following the integration process, statistical analysis highlights the differences between the groups of interest (normal versus cancer cells) relating to (i) independent and (ii) integrated events through TADs. Finally, enrichment analysis using KEGG database, Gene Ontology and transcription factor binding sites and visualization approaches are available. We applied InterTADs to multi-omics datasets from 135 patients with chronic lymphocytic leukemia (CLL) and found that the integration through TADs resulted in a dramatic reduction of heterogeneity compared to individual events. Significant differences for individual events and on TADs level were identified between patients differing in the somatic hypermutation status of the clonotypic immunoglobulin genes, the core biological stratifier in CLL, attesting to the biomedical relevance of InterTADs. In conclusion, our approach suggests a new perspective towards analyzing multi-omics data, by offering reasonable execution time, biological benchmarking and potentially contributing to pattern discovery through TADs.},
}
@article {pmid35039499,
year = {2022},
author = {Li, CC and Zhang, G and Du, J and Liu, D and Li, Z and Ni, Y and Zhou, J and Li, Y and Hou, S and Zheng, X and Lan, Y and Liu, B and He, A},
title = {Pre-configuring chromatin architecture with histone modifications guides hematopoietic stem cell formation in mouse embryos.},
journal = {Nature communications},
volume = {13},
number = {1},
pages = {346},
pmid = {35039499},
issn = {2041-1723},
mesh = {Animals ; Chromatin/*chemistry ; Cluster Analysis ; Core Binding Factor Alpha 2 Subunit/metabolism ; Embryo, Mammalian/*cytology ; Enhancer Elements, Genetic/genetics ; Genome ; Hematopoietic Stem Cells/*cytology ; *Histone Code ; Mice, Inbred C57BL ; Molecular Sequence Annotation ; Promoter Regions, Genetic/genetics ; Transcription Factors/metabolism ; },
abstract = {The gene activity underlying cell differentiation is regulated by a diverse set of transcription factors (TFs), histone modifications, chromatin structures and more. Although definitive hematopoietic stem cells (HSCs) are known to emerge via endothelial-to-hematopoietic transition (EHT), how the multi-layered epigenome is sequentially unfolded in a small portion of endothelial cells (ECs) transitioning into the hematopoietic fate remains elusive. With optimized low-input itChIP-seq and Hi-C assays, we performed multi-omics dissection of the HSC ontogeny trajectory across early arterial ECs (eAECs), hemogenic endothelial cells (HECs), pre-HSCs and long-term HSCs (LT-HSCs) in mouse embryos. Interestingly, HSC regulatory regions are already pre-configurated with active histone modifications as early as eAECs, preceding chromatin looping dynamics within topologically associating domains. Chromatin looping structures between enhancers and promoters only become gradually strengthened over time. Notably, RUNX1, a master TF for hematopoiesis, enriched at half of these loops is observed early from eAECs through pre-HSCs but its enrichment further increases in HSCs. RUNX1 and co-TFs together constitute a central, progressively intensified enhancer-promoter interactions. Thus, our study provides a framework to decipher how temporal epigenomic configurations fulfill cell lineage specification during development.},
}
@article {pmid35026526,
year = {2022},
author = {Miura, H and Hiratani, I},
title = {Cell cycle dynamics and developmental dynamics of the 3D genome: toward linking the two timescales.},
journal = {Current opinion in genetics &amp; development},
volume = {73},
number = {},
pages = {101898},
doi = {10.1016/j.gde.2021.101898},
pmid = {35026526},
issn = {1879-0380},
mesh = {Animals ; Cell Cycle/genetics ; Cell Nucleus/genetics ; Chromatin/genetics ; *Chromosomes/genetics ; *Genome/genetics ; Interphase/genetics ; Mammals/genetics ; },
abstract = {In the mammalian cell nucleus, chromosomes are folded differently in interphase and mitosis. Interphase chromosomes are relatively decondensed and display at least two unique layers of higher-order organization: topologically associating domains (TADs) and cell-type-specific A/B compartments, which correlate well with early/late DNA replication timing (RT). In mitosis, these structures rapidly disappear but are gradually reconstructed during G1 phase, coincident with the establishment of the RT program. However, these structures also change dynamically during cell differentiation and reprogramming, and yet we are surprisingly ignorant about the relationship between their cell cycle dynamics and developmental dynamics. In this review, we summarize the recent findings on this topic, discuss how these two processes might be coordinated with each other and its potential significance.},
}
@article {pmid35016721,
year = {2022},
author = {Jablonski, KP and Carron, L and Mozziconacci, J and Forné, T and Hütt, MT and Lesne, A},
title = {Contribution of 3D genome topological domains to genetic risk of cancers: a genome-wide computational study.},
journal = {Human genomics},
volume = {16},
number = {1},
pages = {2},
pmid = {35016721},
issn = {1479-7364},
mesh = {Gene Expression Regulation ; Genome ; *Genome-Wide Association Study ; Humans ; *Neoplasms/genetics ; Polymorphism, Single Nucleotide/genetics ; },
abstract = {BACKGROUND: Genome-wide association studies have identified statistical associations between various diseases, including cancers, and a large number of single-nucleotide polymorphisms (SNPs). However, they provide no direct explanation of the mechanisms underlying the association. Based on the recent discovery that changes in three-dimensional genome organization may have functional consequences on gene regulation favoring diseases, we investigated systematically the genome-wide distribution of disease-associated SNPs with respect to a specific feature of 3D genome organization: topologically associating domains (TADs) and their borders.<br><br>RESULTS: For each of 449 diseases, we tested whether the associated SNPs are present in TAD borders more often than observed by chance, where chance (i.e., the null model in statistical terms) corresponds to the same number of pointwise loci drawn at random either in the entire genome, or in the entire set of disease-associated SNPs listed in the GWAS catalog. Our analysis shows that a fraction of diseases displays such a preferential localization of their risk loci. Moreover, cancers are relatively more frequent among these diseases, and this predominance is generally enhanced when considering only intergenic SNPs. The structure of SNP-based diseasome networks confirms that localization of risk loci in TAD borders differs between cancers and non-cancer diseases. Furthermore, different TAD border enrichments are observed in embryonic stem cells and differentiated cells, consistent with changes in topological domains along embryogenesis and delineating their contribution to disease risk.<br><br>CONCLUSIONS: Our results suggest that, for certain diseases, part of the genetic risk lies in a local genetic variation affecting the genome partitioning in topologically insulated domains. Investigating this possible contribution to genetic risk is particularly relevant in cancers. This study thus opens a way of interpreting genome-wide association studies, by distinguishing two types of disease-associated SNPs: one with an effect on an individual gene, the other acting in interplay with 3D genome organization.},
}
@article {pmid35013308,
year = {2022},
author = {Li, D and Ning, C and Zhang, J and Wang, Y and Tang, Q and Kui, H and Wang, T and He, M and Jin, L and Li, J and Lin, Y and Zeng, B and Yin, H and Zhao, X and Zhang, Y and Xu, H and Zhu, Q and Li, M},
title = {Dynamic transcriptome and chromatin architecture in granulosa cells during chicken folliculogenesis.},
journal = {Nature communications},
volume = {13},
number = {1},
pages = {131},
pmid = {35013308},
issn = {2041-1723},
mesh = {Animals ; Avian Proteins/classification/*genetics/metabolism ; Chickens/*genetics/growth &amp; development/metabolism ; Chromatin/chemistry/*ultrastructure ; Enhancer Elements, Genetic ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Developmental ; Gene Ontology ; Granulosa Cells/cytology/*metabolism ; Molecular Sequence Annotation ; Oocytes/cytology/metabolism ; Oogenesis/*genetics ; Promoter Regions, Genetic ; *Transcriptome ; },
abstract = {Folliculogenesis is a complex biological process involving a central oocyte and its surrounding somatic cells. Three-dimensional chromatin architecture is an important transcription regulator; however, little is known about its dynamics and role in transcriptional regulation of granulosa cells during chicken folliculogenesis. We investigate the transcriptomic dynamics of chicken granulosa cells over ten follicular stages and assess the chromatin architecture dynamics and how it influences gene expression in granulosa cells at three key stages: the prehierarchical small white follicles, the first largest preovulatory follicles, and the postovulatory follicles. Our results demonstrate the consistency between the global reprogramming of chromatin architecture and the transcriptomic divergence during folliculogenesis, providing ample evidence for compartmentalization rearrangement, variable organization of topologically associating domains, and rewiring of the long-range interaction between promoter and enhancers. These results provide key insights into avian reproductive biology and provide a foundational dataset for the future in-depth functional characterization of granulosa cells.},
}
@article {pmid34981210,
year = {2022},
author = {Tian, GG and Zhao, X and Hou, C and Xie, W and Li, X and Wang, Y and Wang, L and Li, H and Zhao, X and Li, J and Wu, J},
title = {Integrative analysis of the 3D genome structure reveals that CTCF maintains the properties of mouse female germline stem cells.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {79},
number = {1},
pages = {22},
pmid = {34981210},
issn = {1420-9071},
mesh = {Adult Stem Cells/metabolism ; Animals ; Base Sequence ; CCCTC-Binding Factor/*metabolism ; Cell Shape ; Chromatin/metabolism ; Chromosomes, Mammalian/metabolism ; Female ; *Genome ; *Imaging, Three-Dimensional ; Induced Pluripotent Stem Cells/metabolism ; Male ; Mice, Inbred C57BL ; Oogonial Stem Cells/cytology/*metabolism ; },
abstract = {The three-dimensional configuration of the genome ensures cell type-specific gene expression profiles by placing genes and regulatory elements in close spatial proximity. Here, we used in situ high-throughput chromosome conformation (in situ Hi-C), RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) to characterize the high-order chromatin structure signature of female germline stem cells (FGSCs) and identify its regulating key factor based on the data-driven of multiple omics data. By comparison with pluripotent stem cells (PSCs), adult stem cells (ASCs), and somatic cells at three major levels of chromatin architecture, A/B compartments, topologically associating domains, and chromatin loops, the chromatin architecture of FGSCs was most similar to that of other ASCs and largely different from that of PSCs and somatic cells. After integrative analysis of the three-dimensional chromatin structure, active compartment-associating loops (aCALs) were identified as a signature of high-order chromatin organization in FGSCs, which revealed that CCCTC-binding factor was a major factor to maintain the properties of FGSCs through regulation of aCALs. We found FGSCs belong to ASCs at chromatin structure level and characterized aCALs as the high-order chromatin structure signature of FGSCs. Furthermore, CTCF was identified to play a key role in regulating aCALS to maintain the biological functions of FGSCs. These data provide a valuable resource for future studies of the features of chromatin organization in mammalian stem cells and further understanding of the fundamental characteristics of FGSCs.},
}
@article {pmid34979097,
year = {2022},
author = {Zheng, Y and Zhang, L and Jin, L and Zhang, P and Li, F and Guo, M and Gao, Q and Zeng, Y and Li, M and Zeng, W},
title = {Unraveling three-dimensional chromatin structural dynamics during spermatogonial differentiation.},
journal = {The Journal of biological chemistry},
volume = {298},
number = {2},
pages = {101559},
pmid = {34979097},
issn = {1083-351X},
mesh = {*Adult Germline Stem Cells/cytology/metabolism ; Animals ; Cell Differentiation/physiology ; *Chromatin/metabolism ; Male ; *Spermatogenesis/physiology ; *Spermatogonia/cytology ; Swine ; },
abstract = {Spermatogonial stem cells (SSCs) are able to undergo both self-renewal and differentiation. Unlike self-renewal, which replenishes the SSC and progenitor pool, differentiation is an irreversible process committing cells to meiosis. Although the preparations for meiotic events in differentiating spermatogonia (Di-SG) are likely to be accompanied by alterations in chromatin structure, the three-dimensional chromatin architectural differences between SSCs and Di-SG, and the higher-order chromatin dynamics during spermatogonial differentiation, have not been systematically investigated. Here, we performed in situ high-throughput chromosome conformation capture, RNA-seq, and chromatin immunoprecipitation-sequencing analyses on porcine undifferentiated spermatogonia (which consist of SSCs and progenitors) and Di-SG. We identified that Di-SG exhibited less compact chromatin structural organization, weakened compartmentalization, and diminished topologically associating domains in comparison with undifferentiated spermatogonia, suggesting that diminished higher-order chromatin architecture in meiotic cells, as shown by recent reports, might be preprogrammed in Di-SG. Our data also revealed that A/B compartments, representing open or closed chromatin regions respectively, and topologically associating domains were related to dynamic gene expression during spermatogonial differentiation. Furthermore, we unraveled the contribution of promoter-enhancer interactions to premeiotic transcriptional regulation, which has not been accomplished in previous studies due to limited cell input and resolution. Together, our study uncovered the three-dimensional chromatin structure of SSCs/progenitors and Di-SG, as well as the interplay between higher-order chromatin architecture and dynamic gene expression during spermatogonial differentiation. These findings provide novel insights into the mechanisms for SSC self-renewal and differentiation and have implications for diagnosis and treatment of male sub-/infertility.},
}
@article {pmid34963660,
year = {2022},
author = {Salari, H and Di Stefano, M and Jost, D},
title = {Spatial organization of chromosomes leads to heterogeneous chromatin motion and drives the liquid- or gel-like dynamical behavior of chromatin.},
journal = {Genome research},
volume = {32},
number = {1},
pages = {28-43},
pmid = {34963660},
issn = {1549-5469},
mesh = {Cell Nucleus ; *Chromatin/genetics ; Chromatin Assembly and Disassembly ; *Chromosomes/genetics ; },
abstract = {Chromosome organization and dynamics are involved in regulating many fundamental processes such as gene transcription and DNA repair. Experiments unveiled that chromatin motion is highly heterogeneous inside cell nuclei, ranging from a liquid-like, mobile state to a gel-like, rigid regime. Using polymer modeling, we investigate how these different physical states and dynamical heterogeneities may emerge from the same structural mechanisms. We found that the formation of topologically associating domains (TADs) is a key driver of chromatin motion heterogeneity. In particular, we showed that the local degree of compaction of the TAD regulates the transition from a weakly compact, fluid state of chromatin to a more compact, gel state exhibiting anomalous diffusion and coherent motion. Our work provides a comprehensive study of chromosome dynamics and a unified view of chromatin motion enabling interpretation of the wide variety of dynamical behaviors observed experimentally across different biological conditions, suggesting that the "liquid" or "solid" state of chromatin are in fact two sides of the same coin.},
}
@article {pmid34957106,
year = {2021},
author = {Kumar, S and Kaur, S and Seem, K and Kumar, S and Mohapatra, T},
title = {Understanding 3D Genome Organization and Its Effect on Transcriptional Gene Regulation Under Environmental Stress in Plant: A Chromatin Perspective.},
journal = {Frontiers in cell and developmental biology},
volume = {9},
number = {},
pages = {774719},
pmid = {34957106},
issn = {2296-634X},
abstract = {The genome of a eukaryotic organism is comprised of a supra-molecular complex of chromatin fibers and intricately folded three-dimensional (3D) structures. Chromosomal interactions and topological changes in response to the developmental and/or environmental stimuli affect gene expression. Chromatin architecture plays important roles in DNA replication, gene expression, and genome integrity. Higher-order chromatin organizations like chromosome territories (CTs), A/B compartments, topologically associating domains (TADs), and chromatin loops vary among cells, tissues, and species depending on the developmental stage and/or environmental conditions (4D genomics). Every chromosome occupies a separate territory in the interphase nucleus and forms the top layer of hierarchical structure (CTs) in most of the eukaryotes. While the A and B compartments are associated with active (euchromatic) and inactive (heterochromatic) chromatin, respectively, having well-defined genomic/epigenomic features, TADs are the structural units of chromatin. Chromatin architecture like TADs as well as the local interactions between promoter and regulatory elements correlates with the chromatin activity, which alters during environmental stresses due to relocalization of the architectural proteins. Moreover, chromatin looping brings the gene and regulatory elements in close proximity for interactions. The intricate relationship between nucleotide sequence and chromatin architecture requires a more comprehensive understanding to unravel the genome organization and genetic plasticity. During the last decade, advances in chromatin conformation capture techniques for unravelling 3D genome organizations have improved our understanding of genome biology. However, the recent advances, such as Hi-C and ChIA-PET, have substantially increased the resolution, throughput as well our interest in analysing genome organizations. The present review provides an overview of the historical and contemporary perspectives of chromosome conformation capture technologies, their applications in functional genomics, and the constraints in predicting 3D genome organization. We also discuss the future perspectives of understanding high-order chromatin organizations in deciphering transcriptional regulation of gene expression under environmental stress (4D genomics). These might help design the climate-smart crop to meet the ever-growing demands of food, feed, and fodder.},
}
@article {pmid34942797,
year = {2021},
author = {Conte, M and Fiorillo, L and Annunziatella, C and Esposito, A and Musella, F and Abraham, A and Bianco, S and Chiariello, AM},
title = {Dynamic and equilibrium properties of finite-size polymer models of chromosome folding.},
journal = {Physical review. E},
volume = {104},
number = {5-1},
pages = {054402},
doi = {10.1103/PhysRevE.104.054402},
pmid = {34942797},
issn = {2470-0053},
mesh = {Cell Nucleus ; Chromatin ; *Chromosomes ; *Polymers ; },
abstract = {Novel technologies are revealing that chromosomes have a complex three-dimensional organization within the cell nucleus that serves functional purposes. Models from polymer physics have been developed to quantitively understand the molecular principles controlling their structure and folding mechanisms. Here, by using massive molecular-dynamics simulations we show that classical scaling laws combined with finite-size effects of a simple polymer model can effectively explain the scaling behavior that chromatin exhibits at the topologically associating domains level, as revealed by experimental observations. Model results are then validated against recently published high-resolution in situ Hi-C data.},
}
@article {pmid34933938,
year = {2022},
author = {Huang, N and Seow, WQ and Appert, A and Dong, Y and Stempor, P and Ahringer, J},
title = {Accessible Region Conformation Capture (ARC-C) gives high-resolution insights into genome architecture and regulation.},
journal = {Genome research},
volume = {32},
number = {2},
pages = {357-366},
pmid = {34933938},
issn = {1549-5469},
support = {092096/WT_/Wellcome Trust/United Kingdom ; MR/S021620/1/MRC_/Medical Research Council/United Kingdom ; C6946/A14492/CRUK_/Cancer Research UK/United Kingdom ; 101863/WT_/Wellcome Trust/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; },
mesh = {Animals ; *Caenorhabditis elegans/genetics/metabolism ; *Chromatin/genetics/metabolism ; Chromosomes/genetics ; Genome ; },
abstract = {Nuclear organization and chromatin interactions are important for genome function, yet determining chromatin connections at high resolution remains a major challenge. To address this, we developed Accessible Region Conformation Capture (ARC-C), which profiles interactions between regulatory elements genome-wide without a capture step. Applied to Caenorhabditis elegans, ARC-C identifies approximately 15,000 significant interactions between regulatory elements at 500-bp resolution. Of 105 TFs or chromatin regulators tested, we find that the binding sites of 60 are enriched for interacting with each other, making them candidates for mediating interactions. These include cohesin and condensin II. Applying ARC-C to a mutant of transcription factor BLMP-1 detected changes in interactions between its targets. ARC-C simultaneously profiles domain-level architecture, and we observe that C. elegans chromatin domains defined by either active or repressive modifications form topologically associating domains (TADs) that interact with A/B (active/inactive) compartment-like structure. Furthermore, we discover that inactive compartment interactions are dependent on H3K9 methylation. ARC-C is a powerful new tool to interrogate genome architecture and regulatory interactions at high resolution.},
}
@article {pmid34912810,
year = {2021},
author = {Tian, W and Wang, Z and Wang, D and Zhi, Y and Dong, J and Jiang, R and Han, R and Li, Z and Kang, X and Li, H and Liu, X},
title = {Chromatin Interaction Responds to Breast Muscle Development and Intramuscular Fat Deposition Between Chinese Indigenous Chicken and Fast-Growing Broiler.},
journal = {Frontiers in cell and developmental biology},
volume = {9},
number = {},
pages = {782268},
pmid = {34912810},
issn = {2296-634X},
abstract = {Skeletal muscle development and intramuscular fat (IMF) content, which positively contribute to meat production and quality, are regulated by precisely orchestrated processes. However, changes in three-dimensional chromatin structure and interaction, a newly emerged mediator of gene expression, during the skeletal muscle development and IMF deposition have remained unclear. In the present study, we analyzed the differences in muscle development and IMF content between one-day-old commercial Arbor Acres broiler (AA) and Chinese indigenous Lushi blue-shelled-egg chicken (LS) and performed Hi-C analysis on their breast muscles. Our results indicated that significantly higher IMF content, however remarkably lower muscle fiber diameter was detected in breast muscle of LS chicken compared to that of AA broiler. The chromatin intra-interaction was prior to inter-interaction in both AA and LS chicken, and chromatin inter-interaction was heavily focused on the small and gene-rich chromosomes. For genomic compartmentalization, no significant difference in the number of B type compartments was found, but AA had more A type compartments versus LS. The A/B compartment switching of AA versus LS showed more A to B switching than B to A switching. There were no significant differences in the average sizes and distributions of topologically associating domains (TAD). Additionally, approximately 50% of TAD boundaries were overlapping. The reforming and disappearing events of TAD boundaries were identified between AA and LS chicken breast muscles. Among these, the HMGCR gene was located in the TAD-boundary regions in AA broilers, but in TAD-interior regions in LS chickens, and the IGF2BP3 gene was located in the AA-unique TAD boundaries. Both HMGCR and IGF2BP3 genes exhibited increased mRNA expression in one-day-old AA broiler breast muscles. It was demonstrated that the IGF2BP3 and HMGCR genes regulated by TAD boundary sliding were potential biomarkers for chicken breast muscle development and IMF deposition. Our data not only provide a valuable understanding of higher-order chromatin dynamics during muscle development and lipid accumulation but also reveal new insights into the regulatory mechanisms of muscle development and IMF deposition in chicken.},
}
@article {pmid34889941,
year = {2022},
author = {San Martin, R and Das, P and Dos Reis Marques, R and Xu, Y and Roberts, JM and Sanders, JT and Golloshi, R and McCord, RP},
title = {Chromosome compartmentalization alterations in prostate cancer cell lines model disease progression.},
journal = {The Journal of cell biology},
volume = {221},
number = {2},
pages = {},
pmid = {34889941},
issn = {1540-8140},
support = {R35 GM133557/GM/NIGMS NIH HHS/United States ; R35GM133557/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Line, Tumor ; Chromatin/metabolism ; Chromosomes, Human/*metabolism ; Cohort Studies ; *Disease Progression ; Genes, Neoplasm ; Genome, Human ; Humans ; Male ; *Models, Biological ; Neoplasm Metastasis ; Prostatic Neoplasms/genetics/*pathology ; Serine Endopeptidases/metabolism ; Transcriptional Activation/genetics ; },
abstract = {Prostate cancer aggressiveness and metastatic potential are influenced by gene expression and genomic aberrations, features that can be influenced by the 3D structure of chromosomes inside the nucleus. Using chromosome conformation capture (Hi-C), we conducted a systematic genome architecture comparison on a cohort of cell lines that model prostate cancer progression, from normal epithelium to bone metastasis. We describe spatial compartment identity (A-open versus B-closed) changes with progression in these cell lines and their relation to gene expression changes in both cell lines and patient samples. In particular, 48 gene clusters switch from the B to the A compartment, including androgen receptor, WNT5A, and CDK14. These switches are accompanied by changes in the structure, size, and boundaries of topologically associating domains (TADs). Further, compartment changes in chromosome 21 are exacerbated with progression and may explain, in part, the genesis of the TMPRSS2-ERG translocation. These results suggest that discrete 3D genome structure changes play a deleterious role in prostate cancer progression. .},
}
@article {pmid34868269,
year = {2021},
author = {Cardozo Gizzi, AM},
title = {A Shift in Paradigms: Spatial Genomics Approaches to Reveal Single-Cell Principles of Genome Organization.},
journal = {Frontiers in genetics},
volume = {12},
number = {},
pages = {780822},
pmid = {34868269},
issn = {1664-8021},
abstract = {The genome tridimensional (3D) organization and its role towards the regulation of key cell processes such as transcription is currently a main question in biology. Interphase chromosomes are spatially segregated into "territories," epigenetically-defined large domains of chromatin that interact to form "compartments" with common transcriptional status, and insulator-flanked domains called "topologically associating domains" (TADs). Moreover, chromatin organizes around nuclear structures such as lamina, speckles, or the nucleolus to acquire a higher-order genome organization. Due to recent technological advances, the different hierarchies are being solved. Particularly, advances in microscopy technologies are shedding light on the genome structure at multiple levels. Intriguingly, more and more reports point to high variability and stochasticity at the single-cell level. However, the functional consequences of such variability in genome conformation are still unsolved. Here, I will discuss the implication of the cell-to-cell heterogeneity at the different scales in the context of newly developed imaging approaches, particularly multiplexed Fluorescence in situ hybridization methods that enabled "chromatin tracing." Extensions of these methods are now combining spatial information of dozens to thousands of genomic loci with the localization of nuclear features such as the nucleolus, nuclear speckles, or even histone modifications, creating the fast-moving field of "spatial genomics." As our view of genome organization shifts the focus from ensemble to single-cell, new insights to fundamental questions begin to emerge.},
}
@article {pmid34821995,
year = {2022},
author = {Cinque, L and Micale, L and Manara, E and Esposito, A and Palumbo, O and Chiariello, AM and Bianco, S and Guerri, G and Bertelli, M and Giuffrida, MG and Bernardini, L and Notarangelo, A and Nicodemi, M and Castori, M},
title = {A novel complex genomic rearrangement affecting the KCNJ2 regulatory region causes a variant of Cooks syndrome.},
journal = {Human genetics},
volume = {141},
number = {2},
pages = {217-227},
pmid = {34821995},
issn = {1432-1203},
mesh = {Adolescent ; Adult ; Chromosome Breakpoints ; Chromosomes, Human, Pair 1/genetics ; Chromosomes, Human, Pair 17/genetics ; Facies ; Female ; Fingers/*abnormalities ; Foot Deformities, Congenital/*genetics ; *Gene Rearrangement ; Hand Deformities, Congenital/*genetics ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Potassium Channels, Inwardly Rectifying/chemistry/*genetics ; *Regulatory Sequences, Nucleic Acid ; Sequence Deletion ; Translocation, Genetic ; Young Adult ; },
abstract = {Cooks syndrome (CS) is an ultrarare limb malformation due to in tandem microduplications involving KCNJ2 and extending to the 5' regulatory element of SOX9. To date, six CS families were resolved at the molecular level. Subsequent studies explored the evolutionary and pathological complexities of the SOX9-KCNJ2/Sox9-Kcnj2 locus, and suggested a key role for the formation of novel topologically associating domain (TAD) by inter-TAD duplications in causing CS. Here, we report a unique case of CS associated with a de novo 1;17 translocation affecting the KCNJ2 locus. On chromosome 17, the breakpoint mapped between KCNJ16 and KCNJ2, and combined with a ~ 5 kb deletion in the 5' of KCNJ2. Based on available capture Hi-C data, the breakpoint on chromosome 17 separated KCNJ2 from a putative enhancer. Gene expression analysis demonstrated downregulation of KCNJ2 in both patient's blood cells and cultured skin fibroblasts. Our findings suggest that a complex rearrangement falling in the 5' of KCNJ2 may mimic the developmental consequences of in tandem duplications affecting the SOX9-KCNJ2/Sox9-Kcnj2 locus. This finding adds weight to the notion of an intricate role of gene regulatory regions and, presumably, the related three-dimensional chromatin structure in normal and abnormal human morphology.},
}
@article {pmid34805161,
year = {2021},
author = {Maslova, A and Krasikova, A},
title = {FISH Going Meso-Scale: A Microscopic Search for Chromatin Domains.},
journal = {Frontiers in cell and developmental biology},
volume = {9},
number = {},
pages = {753097},
pmid = {34805161},
issn = {2296-634X},
abstract = {The intimate relationships between genome structure and function direct efforts toward deciphering three-dimensional chromatin organization within the interphase nuclei at different genomic length scales. For decades, major insights into chromatin structure at the level of large-scale euchromatin and heterochromatin compartments, chromosome territories, and subchromosomal regions resulted from the evolution of light microscopy and fluorescence in situ hybridization. Studies of nanoscale nucleosomal chromatin organization benefited from a variety of electron microscopy techniques. Recent breakthroughs in the investigation of mesoscale chromatin structures have emerged from chromatin conformation capture methods (C-methods). Chromatin has been found to form hierarchical domains with high frequency of local interactions from loop domains to topologically associating domains and compartments. During the last decade, advances in super-resolution light microscopy made these levels of chromatin folding amenable for microscopic examination. Here we are reviewing recent developments in FISH-based approaches for detection, quantitative measurements, and validation of contact chromatin domains deduced from C-based data. We specifically focus on the design and application of Oligopaint probes, which marked the latest progress in the imaging of chromatin domains. Vivid examples of chromatin domain FISH-visualization by means of conventional, super-resolution light and electron microscopy in different model organisms are provided.},
}
@article {pmid34785659,
year = {2021},
author = {Wu, DY and Li, X and Sun, QR and Dou, CL and Xu, T and He, H and Luo, H and Fu, H and Bu, GW and Luo, B and Zhang, X and Ma, BG and Peng, C and Miao, YL},
title = {Defective chromatin architectures in embryonic stem cells derived from somatic cell nuclear transfer impair their differentiation potentials.},
journal = {Cell death &amp; disease},
volume = {12},
number = {12},
pages = {1085},
pmid = {34785659},
issn = {2041-4889},
mesh = {Animals ; Cell Differentiation ; Chromatin/*metabolism ; Embryonic Stem Cells/*metabolism ; Female ; Humans ; Mice ; Nuclear Transfer Techniques/*standards ; },
abstract = {Nuclear transfer embryonic stem cells (ntESCs) hold enormous promise for individual-specific regenerative medicine. However, the chromatin states of ntESCs remain poorly characterized. In this study, we employed ATAC-seq and Hi-C techniques to explore the chromatin accessibility and three-dimensional (3D) genome organization of ntESCs. The results show that the chromatin accessibility and genome structures of somatic cells are re-arranged to ESC-like states overall in ntESCs, including compartments, topologically associating domains (TADs) and chromatin loops. However, compared to fertilized ESCs (fESCs), ntESCs show some abnormal openness and structures that have not been reprogrammed completely, which impair the differentiation potential of ntESCs. The histone modification H3K9me3 may be involved in abnormal structures in ntESCs, including incorrect compartment switches and incomplete TAD rebuilding. Moreover, ntESCs and iPSCs show high similarity in 3D genome structures, while a few differences are detected due to different somatic cell origins and reprogramming mechanisms. Through systematic analyses, our study provides a global view of chromatin accessibility and 3D genome organization in ntESCs, which can further facilitate the understanding of the similarities and differences between ntESCs and fESCs.},
}
@article {pmid34749781,
year = {2021},
author = {Cheng, Y and Liu, M and Hu, M and Wang, S},
title = {TAD-like single-cell domain structures exist on both active and inactive X chromosomes and persist under epigenetic perturbations.},
journal = {Genome biology},
volume = {22},
number = {1},
pages = {309},
pmid = {34749781},
issn = {1474-760X},
support = {DP2 GM137414/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromatin/chemistry ; Chromosomes, Human, X/*chemistry ; *Epigenesis, Genetic ; Female ; Humans ; Transcription, Genetic ; },
abstract = {BACKGROUND: Topologically associating domains (TADs) are important building blocks of three-dimensional genome architectures. The formation of TADs has been shown to depend on cohesin in a loop-extrusion mechanism. Recently, advances in an image-based spatial genomics technique known as chromatin tracing lead to the discovery of cohesin-independent TAD-like structures, also known as single-cell domains, which are highly variant self-interacting chromatin domains with boundaries that occasionally overlap with TAD boundaries but tend to differ among single cells and among single chromosome copies. Recent computational modeling studies suggest that epigenetic interactions may underlie the formation of the single-cell domains.<br><br>RESULTS: Here we use chromatin tracing to visualize in female human cells the fine-scale chromatin folding of inactive and active X chromosomes, which are known to have distinct global epigenetic landscapes and distinct population-averaged TAD profiles, with inactive X chromosomes largely devoid of TADs and cohesin. We show that both inactive and active X chromosomes possess highly variant single-cell domains across the same genomic region despite the fact that only active X chromosomes show clear TAD structures at the population level. These X chromosome single-cell domains exist in distinct cell lines. Perturbations of major epigenetic components and transcription mostly do not affect the frequency or strength of the single-cell domains. Increased chromatin compaction of inactive X chromosomes occurs at a length scale above that of the single-cell domains.<br><br>CONCLUSIONS: In sum, this study suggests that single-cell domains are genome architecture building blocks independent of the tested major epigenetic components.},
}
@article {pmid34747029,
year = {2022},
author = {Yildirir, G and Sperschneider, J and Malar C, M and Chen, ECH and Iwasaki, W and Cornell, C and Corradi, N},
title = {Long reads and Hi-C sequencing illuminate the two-compartment genome of the model arbuscular mycorrhizal symbiont Rhizophagus irregularis.},
journal = {The New phytologist},
volume = {233},
number = {3},
pages = {1097-1107},
doi = {10.1111/nph.17842},
pmid = {34747029},
issn = {1469-8137},
mesh = {Fungi ; Genome, Fungal ; *Glomeromycota/genetics/metabolism ; *Mycorrhizae/physiology ; Plants/genetics ; },
abstract = {Chromosome folding links genome structure with gene function by generating distinct nuclear compartments and topologically associating domains. In mammals, these undergo preferential interactions and regulate gene expression. However, their role in fungal genome biology is unclear. Here, we combine Nanopore (ONT) sequencing with chromatin conformation capture sequencing (Hi-C) to reveal chromosome and epigenetic diversity in a group of obligate plant symbionts: the arbuscular mycorrhizal fungi (AMF). We find that five phylogenetically distinct strains of the model AMF Rhizophagus irregularis carry 33 chromosomes with substantial within-species variability in size, as well as in gene and repeat content. Strain-specific Hi-C contact maps reveal a 'checkerboard' pattern that underline two dominant euchromatin (A) and heterochromatin (B) compartments. Each compartment differs in the level of gene transcription, regulation of candidate effectors and methylation frequencies. The A-compartment is more gene-dense and contains most core genes, while the B-compartment is more repeat-rich and has higher rates of chromosomal rearrangement. While the B-compartment is transcriptionally repressed, it has significantly more secreted proteins and in planta upregulated candidate effectors, suggesting a possible host-induced change in chromosome conformation. Overall, this study provides a fine-scale view into the genome biology and evolution of model plant symbionts, and opens avenues to study the epigenetic mechanisms that modify chromosome folding during host-microbe interactions.},
}
@article {pmid34741515,
year = {2022},
author = {Stilianoudakis, SC and Marshall, MA and Dozmorov, MG},
title = {preciseTAD: a transfer learning framework for 3D domain boundary prediction at base-pair resolution.},
journal = {Bioinformatics (Oxford, England)},
volume = {38},
number = {3},
pages = {621-630},
pmid = {34741515},
issn = {1367-4811},
support = {P50 AA022537/AA/NIAAA NIH HHS/United States ; },
mesh = {*Chromatin ; *Chromosomes ; Genome ; Genomics ; Machine Learning ; },
abstract = {MOTIVATION: Chromosome conformation capture technologies (Hi-C) revealed extensive DNA folding into discrete 3D domains, such as Topologically Associating Domains and chromatin loops. The correct binding of CTCF and cohesin at domain boundaries is integral in maintaining the proper structure and function of these 3D domains. 3D domains have been mapped at the resolutions of 1 kilobase and above. However, it has not been possible to define their boundaries at the resolution of boundary-forming proteins.<br><br>RESULTS: To predict domain boundaries at base-pair resolution, we developed preciseTAD, an optimized transfer learning framework trained on high-resolution genome annotation data. In contrast to current TAD/loop callers, preciseTAD-predicted boundaries are strongly supported by experimental evidence. Importantly, this approach can accurately delineate boundaries in cells without Hi-C data. preciseTAD provides a powerful framework to improve our understanding of how genomic regulators are shaping the 3D structure of the genome at base-pair resolution.<br><br>preciseTAD is an R/Bioconductor package available at https://bioconductor.org/packages/preciseTAD/.<br><br>SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},
}
@article {pmid34721522,
year = {2021},
author = {Liehr, T},
title = {Molecular Cytogenetics in the Era of Chromosomics and Cytogenomic Approaches.},
journal = {Frontiers in genetics},
volume = {12},
number = {},
pages = {720507},
pmid = {34721522},
issn = {1664-8021},
abstract = {Here the role of molecular cytogenetics in the context of yet available all other cytogenomic approaches is discussed. A short introduction how cytogenetics and molecular cytogenetics were established is followed by technical aspects of fluorescence in situ hybridization (FISH). The latter contains the methodology itself, the types of probe- and target-DNA, as well as probe sets. The main part deals with examples of modern FISH-applications, highlighting unique possibilities of the approach, like the possibility to study individual cells and even individual chromosomes. Different variants of FISH can be used to retrieve information on genomes from (almost) base pair to whole genomic level, as besides only second and third generation sequencing approaches can do. Here especially highlighted variations of FISH are molecular combing, chromosome orientation-FISH (CO-FISH), telomere-FISH, parental origin determination FISH (POD-FISH), FISH to resolve the nuclear architecture, multicolor-FISH (mFISH) approaches, among other applied in chromoanagenesis studies, Comet-FISH, and CRISPR-mediated FISH-applications. Overall, molecular cytogenetics is far from being outdated and actively involved in up-to-date diagnostics and research.},
}
@article {pmid34689653,
year = {2022},
author = {Awotoye, W and Comnick, C and Pendleton, C and Zeng, E and Alade, A and Mossey, PA and Gowans, LJJ and Eshete, MA and Adeyemo, WL and Naicker, T and Adeleke, C and Busch, T and Li, M and Petrin, A and Olotu, J and Hassan, M and Pape, J and Miller, SE and Donkor, P and Anand, D and Lachke, SA and Marazita, ML and Adeyemo, AA and Murray, JC and Albokhari, D and Sobreira, N and Butali, A},
title = {Genome-wide Gene-by-Sex Interaction Studies Identify Novel Nonsyndromic Orofacial Clefts Risk Locus.},
journal = {Journal of dental research},
volume = {101},
number = {4},
pages = {465-472},
pmid = {34689653},
issn = {1544-0591},
support = {R90 DE024296/DE/NIDCR NIH HHS/United States ; K99 DE022378/DE/NIDCR NIH HHS/United States ; R01 DE028300/DE/NIDCR NIH HHS/United States ; R03 DE024776/DE/NIDCR NIH HHS/United States ; R00 DE022378/DE/NIDCR NIH HHS/United States ; K43 DE029427/DE/NIDCR NIH HHS/United States ; },
mesh = {*Cleft Lip/genetics ; *Cleft Palate/genetics ; Female ; Genetic Predisposition to Disease/genetics ; Genome-Wide Association Study ; Humans ; Male ; Polymorphism, Single Nucleotide/genetics ; },
abstract = {Risk loci identified through genome-wide association studies have explained about 25% of the phenotypic variations in nonsyndromic orofacial clefts (nsOFCs) on the liability scale. Despite the notable sex differences in the incidences of the different cleft types, investigation of loci for sex-specific effects has been understudied. To explore the sex-specific effects in genetic etiology of nsOFCs, we conducted a genome-wide gene × sex (GxSex) interaction study in a sub-Saharan African orofacial cleft cohort. The sample included 1,019 nonsyndromic orofacial cleft cases (814 cleft lip with or without cleft palate and 205 cleft palate only) and 2,159 controls recruited from 3 sites (Ethiopia, Ghana, and Nigeria). An additive logistic model was used to examine the joint effects of the genotype and GxSex interaction. Furthermore, we examined loci with suggestive significance (P < 1E-5) in the additive model for the effect of the GxSex interaction only. We identified a novel risk locus on chromosome 8p22 with genome-wide significant joint and GxSex interaction effects (rs2720555, p2df = 1.16E-08, pGxSex = 1.49E-09, odds ratio [OR] = 0.44, 95% CI = 0.34 to 0.57). For males, the risk of cleft lip with or without cleft palate at this locus decreases with additional copies of the minor allele (p < 0.0001, OR = 0.60, 95% CI = 0.48 to 0.74), but the effect is reversed for females (p = 0.0004, OR = 1.36, 95% CI = 1.15 to 1.60). We replicated the female-specific effect of this locus in an independent cohort (p = 0.037, OR = 1.30, 95% CI = 1.02 to 1.65), but no significant effect was found for the males (p = 0.29, OR = 0.86, 95% CI = 0.65 to 1.14). This locus is in topologically associating domain with craniofacially expressed and enriched genes during embryonic development. Rare coding mutations of some of these genes were identified in nsOFC cohorts through whole exome sequencing analysis. Our study is additional proof that genome-wide GxSex interaction analysis provides an opportunity for novel findings of loci and genes that contribute to the risk of nsOFCs.},
}
@article {pmid34675966,
year = {2021},
author = {Marti-Marimon, M and Vialaneix, N and Lahbib-Mansais, Y and Zytnicki, M and Camut, S and Robelin, D and Yerle-Bouissou, M and Foissac, S},
title = {Major Reorganization of Chromosome Conformation During Muscle Development in Pig.},
journal = {Frontiers in genetics},
volume = {12},
number = {},
pages = {748239},
pmid = {34675966},
issn = {1664-8021},
abstract = {The spatial organization of the genome in the nucleus plays a crucial role in eukaryotic cell functions, yet little is known about chromatin structure variations during late fetal development in mammals. We performed in situ high-throughput chromosome conformation capture (Hi-C) sequencing of DNA from muscle samples of pig fetuses at two late stages of gestation. Comparative analysis of the resulting Hi-C interaction matrices between both groups showed widespread differences of different types. First, we discovered a complex landscape of stable and group-specific Topologically Associating Domains (TADs). Investigating the nuclear partition of the chromatin into transcriptionally active and inactive compartments, we observed a genome-wide fragmentation of these compartments between 90 and 110 days of gestation. Also, we identified and characterized the distribution of differential cis- and trans-pairwise interactions. In particular, trans-interactions at chromosome extremities revealed a mechanism of telomere clustering further confirmed by 3D Fluorescence in situ Hybridization (FISH). Altogether, we report major variations of the three-dimensional genome conformation during muscle development in pig, involving several levels of chromatin remodeling and structural regulation.},
}
@article {pmid34621295,
year = {2021},
author = {Servetti, M and Pisciotta, L and Tassano, E and Cerminara, M and Nobili, L and Boeri, S and Rosti, G and Lerone, M and Divizia, MT and Ronchetto, P and Puliti, A},
title = {Neurodevelopmental Disorders in Patients With Complex Phenotypes and Potential Complex Genetic Basis Involving Non-Coding Genes, and Double CNVs.},
journal = {Frontiers in genetics},
volume = {12},
number = {},
pages = {732002},
pmid = {34621295},
issn = {1664-8021},
abstract = {Neurodevelopmental disorders (NDDs) are a heterogeneous class of brain diseases, with a complex genetic basis estimated to account for up to 50% of cases. Nevertheless, genetic diagnostic yield is about 20%. Array-comparative genomic hybridization (array-CGH) is an established first-level diagnostic test able to detect pathogenic copy number variants (CNVs), however, most identified variants remain of uncertain significance (VUS). Failure of interpretation of VUSs may depend on various factors, including complexity of clinical phenotypes and inconsistency of genotype-phenotype correlations. Indeed, although most NDD-associated CNVs are de novo, transmission from unaffected parents to affected children of CNVs with high risk for NDDs has been observed. Moreover, variability of genetic components overlapped by CNVs, such as long non-coding genes, genomic regions with long-range effects, and additive effects of multiple CNVs can make CNV interpretation challenging. We report on 12 patients with complex phenotypes possibly explained by complex genetic mechanisms, including involvement of antisense genes and boundaries of topologically associating domains. Eight among the 12 patients carried two CNVs, either de novo or inherited, respectively, by each of their healthy parents, that could additively contribute to the patients' phenotype. CNVs overlapped either known NDD-associated or novel candidate genes (PTPRD, BUD13, GLRA3, MIR4465, ABHD4, and WSCD2). Bioinformatic enrichment analyses showed that genes overlapped by the co-occurring CNVs have synergistic roles in biological processes fundamental in neurodevelopment. Double CNVs could concur in producing deleterious effects, according to a two-hit model, thus explaining the patients' phenotypes and the incomplete penetrance, and variable expressivity, associated with the single variants. Overall, our findings could contribute to the knowledge on clinical and genetic diagnosis of complex forms of NDD.},
}
@article {pmid34605807,
year = {2021},
author = {Esquivel-López, A and Arzate-Mejía, R and Pérez-Molina, R and Furlan-Magaril, M},
title = {In-Nucleus Hi-C in Drosophila Cells.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {175},
pages = {},
doi = {10.3791/62106},
pmid = {34605807},
issn = {1940-087X},
mesh = {Animals ; Cell Nucleus ; *Chromatin ; *Drosophila/genetics ; Drosophila melanogaster/genetics ; Genomics ; },
abstract = {The genome is organized into topologically associating domains (TADs) delimited by boundaries that isolate interactions between domains. In Drosophila, the mechanisms underlying TAD formation and boundaries are still under investigation. The application of the in-nucleus Hi-C method described here helped to dissect the function of architectural protein (AP)-binding sites at TAD boundaries isolating the Notch gene. Genetic modification of domain boundaries that cause loss of APs results in TAD fusion, transcriptional defects, and long-range topological alterations. These results provided evidence demonstrating the contribution of genetic elements to domain boundary formation and gene expression control in Drosophila. Here, the in-nucleus Hi-C method has been described in detail, which provides important checkpoints to assess the quality of the experiment along with the protocol. Also shown are the required numbers of sequencing reads and valid Hi-C pairs to analyze genomic interactions at different genomic scales. CRISPR/Cas9-mediated genetic editing of regulatory elements and high-resolution profiling of genomic interactions using this in-nucleus Hi-C protocol could be a powerful combination for the investigation of the structural function of genetic elements.},
}
@article {pmid34603780,
year = {2021},
author = {Luo, H and Li, X and Tian, GG and Li, D and Hou, C and Ding, X and Hou, L and Lyu, Q and Yang, Y and Cooney, AJ and Xie, W and Xiong, J and Wang, H and Zhao, X and Wu, J},
title = {Offspring production of ovarian organoids derived from spermatogonial stem cells by defined factors with chromatin reorganization.},
journal = {Journal of advanced research},
volume = {33},
number = {},
pages = {81-98},
pmid = {34603780},
issn = {2090-1224},
mesh = {*Adult Germline Stem Cells ; Animals ; Cell Culture Techniques, Three Dimensional ; Chromatin/genetics ; Female ; Male ; Mice ; Organoids ; *Spermatogonia ; },
abstract = {INTRODUCTION: Fate determination of germline stem cells remains poorly understood at the chromatin structure level.<br><br>OBJECTIVES: Our research hopes to develop successful offspring production of ovarian organoids derived from spermatogonial stem cells (SSCs) by defined factors.<br><br>METHODS: The offspring production from oocytes transdifferentiated from mouse SSCs with tracking of transplanted SSCs in vivo, single cell whole exome sequencing, and in 3D cell culture reconstitution of the process of oogenesis derived from SSCs. The defined factors were screened with ovarian organoids. We uncovered extensive chromatin reorganization during SSC conversion into induced germline stem cells (iGSCs) using high throughput chromosome conformation.<br><br>RESULTS: We demonstrate successful production of offspring from oocytes transdifferentiated from mouse spermatogonial stem cells (SSCs). Furthermore, we demonstrate direct induction of germline stem cells (iGSCs) differentiated into functional oocytes by transduction of H19, Stella, and Zfp57 and inactivation of Plzf in SSCs after screening with ovarian organoids. We uncovered extensive chromatin reorganization during SSC conversion into iGSCs, which was highly similar to female germline stem cells. We observed that although topologically associating domains were stable during SSC conversion, chromatin interactions changed in a striking manner, altering 35% of inactive and active chromosomal compartments throughout the genome.<br><br>CONCLUSION: We demonstrate successful offspring production of ovarian organoids derived from SSCs by defined factors with chromatin reorganization. These findings have important implications in various areas including mammalian gametogenesis, genetic and epigenetic reprogramming, biotechnology, and medicine.},
}
@article {pmid34584207,
year = {2021},
author = {Grabowicz, IE and Wilczyński, B and Kamińska, B and Roura, AJ and Wojtaś, B and Dąbrowski, MJ},
title = {Author Correction: The role of epigenetic modifications, long-range contacts, enhancers and topologically associating domains in the regulation of glioma grade-specific genes.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {19628},
doi = {10.1038/s41598-021-99319-4},
pmid = {34584207},
issn = {2045-2322},
}
@article {pmid34534448,
year = {2021},
author = {He, L and Ding, Y and Zhao, Y and So, KK and Peng, XL and Li, Y and Yuan, J and He, Z and Chen, X and Sun, H and Wang, H},
title = {CRISPR/Cas9/AAV9-mediated in vivo editing identifies MYC regulation of 3D genome in skeletal muscle stem cell.},
journal = {Stem cell reports},
volume = {16},
number = {10},
pages = {2442-2458},
pmid = {34534448},
issn = {2213-6711},
mesh = {Animals ; CRISPR-Cas Systems ; Chromatin/*metabolism ; Gene Editing/methods ; Gene Expression Regulation ; *Genes, myc ; *Genome ; Mice ; MyoD Protein/genetics/*metabolism ; Nucleic Acid Conformation ; Proto-Oncogene Proteins c-bcl-6/genetics/*metabolism ; RNA, Guide, Kinetoplastida/genetics/*metabolism ; Satellite Cells, Skeletal Muscle/*physiology ; Transcription Factors/genetics/metabolism ; },
abstract = {Skeletal muscle satellite cells (SCs) are stem cells responsible for muscle development and regeneration. Although CRISPR/Cas9 has been widely used, its application in endogenous SCs remains elusive. Here, we generate mice expressing Cas9 in SCs and achieve robust editing in juvenile SCs at the postnatal stage through AAV9-mediated short guide RNA (sgRNA) delivery. Additionally, we reveal that quiescent SCs are resistant to CRISPR/Cas9-mediated editing. As a proof of concept, we demonstrate efficient editing of master transcription factor (TF) Myod1 locus using the CRISPR/Cas9/AAV9-sgRNA system in juvenile SCs. Application on two key TFs, MYC and BCL6, unveils distinct functions in SC activation and muscle regeneration. Particularly, we reveal that MYC orchestrates SC activation through regulating 3D genome architecture. Its depletion results in strengthening of the topologically associating domain boundaries thus may affect gene expression. Altogether, our study establishes a platform for editing endogenous SCs that can be harnessed to elucidate the functionality of key regulators governing SC activities.},
}
@article {pmid34518536,
year = {2021},
author = {Franke, M and De la Calle-Mustienes, E and Neto, A and Almuedo-Castillo, M and Irastorza-Azcarate, I and Acemel, RD and Tena, JJ and Santos-Pereira, JM and Gómez-Skarmeta, JL},
title = {CTCF knockout in zebrafish induces alterations in regulatory landscapes and developmental gene expression.},
journal = {Nature communications},
volume = {12},
number = {1},
pages = {5415},
pmid = {34518536},
issn = {2041-1723},
mesh = {Animals ; Body Patterning/genetics ; CCCTC-Binding Factor/deficiency/*genetics ; CRISPR-Cas Systems ; Chromatin/genetics/metabolism ; Embryo, Nonmammalian/embryology/*metabolism ; Enhancer Elements, Genetic/genetics ; *Gene Expression Regulation, Developmental ; Gene Knockout Techniques/*methods ; Organogenesis/genetics ; Promoter Regions, Genetic/genetics ; RNA-Seq/methods ; Zebrafish/embryology/*genetics ; Zebrafish Proteins/deficiency/*genetics ; },
abstract = {Coordinated chromatin interactions between enhancers and promoters are critical for gene regulation. The architectural protein CTCF mediates chromatin looping and is enriched at the boundaries of topologically associating domains (TADs), which are sub-megabase chromatin structures. In vitro CTCF depletion leads to a loss of TADs but has only limited effects over gene expression, challenging the concept that CTCF-mediated chromatin structures are a fundamental requirement for gene regulation. However, how CTCF and a perturbed chromatin structure impacts gene expression during development remains poorly understood. Here we link the loss of CTCF and gene regulation during patterning and organogenesis in a ctcf knockout zebrafish model. CTCF absence leads to loss of chromatin structure and affects the expression of thousands of genes, including many developmental regulators. Our results demonstrate the essential role of CTCF in providing the structural context for enhancer-promoter interactions, thus regulating developmental genes.},
}
@article {pmid34494283,
year = {2021},
author = {MacPhillamy, C and Pitchford, WS and Alinejad-Rokny, H and Low, WY},
title = {Opportunity to improve livestock traits using 3D genomics.},
journal = {Animal genetics},
volume = {52},
number = {6},
pages = {785-798},
doi = {10.1111/age.13135},
pmid = {34494283},
issn = {1365-2052},
mesh = {Animals ; Breeding/*methods ; Cattle/genetics ; Chickens/genetics ; Genomics/*methods ; Goats/genetics ; Livestock/*genetics ; Sheep, Domestic/genetics ; Sus scrofa/genetics ; },
abstract = {The advent of high-throughput chromosome conformation capture and sequencing (Hi-C) has enabled researchers to probe the 3D architecture of the mammalian genome in a genome-wide manner. Simultaneously, advances in epigenomic assays, such as chromatin immunoprecipitation and sequencing (ChIP-seq) and DNase-seq, have enabled researchers to study cis-regulatory interactions and chromatin accessibility across the same genome-wide scale. The use of these data has revealed many unique insights into gene regulation and disease pathomechanisms in several model organisms. With the advent of these high-throughput sequencing technologies, there has been an ever-increasing number of datasets available for study; however, this is often limited to model organisms. Livestock species play critical roles in the economies of developing and developed nations alike. Despite this, they are greatly underrepresented in the 3D genomics space; Hi-C and related technologies have the potential to revolutionise livestock breeding by enabling a more comprehensive understanding of how production traits are controlled. The growth in human and model organism Hi-C data has seen a surge in the availability of computational tools for use in 3D genomics, with some tools using machine learning techniques to predict features and improve dataset quality. In this review, we provide an overview of the 3D genome and discuss the status of 3D genomics in livestock before delving into advancing the field by drawing inspiration from research in human and mouse. We end by offering future directions for livestock research in the field of 3D genomics.},
}
@article {pmid34436670,
year = {2021},
author = {Melo, US and Piard, J and Fischer-Zirnsak, B and Klever, MK and Schöpflin, R and Mensah, MA and Holtgrewe, M and Arbez-Gindre, F and Martin, A and Guigue, V and Gaillard, D and Landais, E and Roze, V and Kremer, V and Ramanah, R and Cabrol, C and Harms, FL and Kornak, U and Spielmann, M and Mundlos, S and Van Maldergem, L},
title = {Complete lung agenesis caused by complex genomic rearrangements with neo-TAD formation at the SHH locus.},
journal = {Human genetics},
volume = {140},
number = {10},
pages = {1459-1469},
pmid = {34436670},
issn = {1432-1203},
mesh = {Abnormalities, Multiple/*genetics ; Adult ; Cadaver ; *Evolution, Molecular ; Female ; Fetus ; Genetic Variation ; Genome, Human ; Humans ; Lung/*abnormalities/*growth &amp; development/*ultrastructure ; Lung Diseases/*genetics ; Male ; Organogenesis/*genetics ; Pregnancy ; },
abstract = {During human organogenesis, lung development is a timely and tightly regulated developmental process under the control of a large number of signaling molecules. Understanding how genetic variants can disturb normal lung development causing different lung malformations is a major goal for dissecting molecular mechanisms during embryogenesis. Here, through exome sequencing (ES), array CGH, genome sequencing (GS) and Hi-C, we aimed at elucidating the molecular basis of bilateral isolated lung agenesis in three fetuses born to a non-consanguineous family. We detected a complex genomic rearrangement containing duplicated, triplicated and deleted fragments involving the SHH locus in fetuses presenting complete agenesis of both lungs and near-complete agenesis of the trachea, diagnosed by ultrasound screening and confirmed at autopsy following termination. The rearrangement did not include SHH itself, but several regulatory elements for lung development, such as MACS1, a major SHH lung enhancer, and the neighboring genes MNX1 and NOM1. The rearrangement incorporated parts of two topologically associating domains (TADs) including their boundaries. Hi-C of cells from one of the affected fetuses showed the formation of two novel TADs each containing SHH enhancers and the MNX1 and NOM1 genes. Hi-C together with GS indicate that the new 3D conformation is likely causative for this condition by an inappropriate activation of MNX1 included in the neo-TADs by MACS1 enhancer, further highlighting the importance of the 3D chromatin conformation in human disease.},
}
@article {pmid34433485,
year = {2021},
author = {Ge, X and Frank-Bertoncelj, M and Klein, K and McGovern, A and Kuret, T and Houtman, M and Burja, B and Micheroli, R and Shi, C and Marks, M and Filer, A and Buckley, CD and Orozco, G and Distler, O and Morris, AP and Martin, P and Eyre, S and Ospelt, C},
title = {Functional genomics atlas of synovial fibroblasts defining rheumatoid arthritis heritability.},
journal = {Genome biology},
volume = {22},
number = {1},
pages = {247},
pmid = {34433485},
issn = {1474-760X},
support = {207491/Z/17/Z/WT_/Wellcome Trust/United Kingdom ; 21348/VAC_/Versus Arthritis/United Kingdom ; 21745/VAC_/Versus Arthritis/United Kingdom ; 21754/VAC_/Versus Arthritis/United Kingdom ; },
mesh = {Adult ; Arthritis, Rheumatoid/*genetics/*pathology ; Base Sequence ; Chromatin/metabolism ; Databases, Genetic ; Enhancer Elements, Genetic/genetics ; Epigenesis, Genetic/drug effects ; Female ; Fibroblasts/drug effects/metabolism/*pathology ; Gene Regulatory Networks/drug effects ; Genetic Predisposition to Disease ; *Genomics ; Humans ; Immunoglobulin J Recombination Signal Sequence-Binding Protein/genetics ; Inheritance Patterns/*genetics ; Male ; Middle Aged ; Polymorphism, Single Nucleotide/genetics ; Probability ; Receptor, Interferon alpha-beta/metabolism ; Receptors, Interferon/metabolism ; Reproducibility of Results ; Risk Factors ; Synovial Membrane/*pathology ; Tumor Necrosis Factor alpha-Induced Protein 3/metabolism ; Tumor Necrosis Factor-alpha/pharmacology ; Young Adult ; },
abstract = {BACKGROUND: Genome-wide association studies have reported more than 100 risk loci for rheumatoid arthritis (RA). These loci are shown to be enriched in immune cell-specific enhancers, but the analysis so far has excluded stromal cells, such as synovial fibroblasts (FLS), despite their crucial involvement in the pathogenesis of RA. Here we integrate DNA architecture, 3D chromatin interactions, DNA accessibility, and gene expression in FLS, B cells, and T cells with genetic fine mapping of RA loci.<br><br>RESULTS: We identify putative causal variants, enhancers, genes, and cell types for 30-60% of RA loci and demonstrate that FLS account for up to 24% of RA heritability. TNF stimulation of FLS alters the organization of topologically associating domains, chromatin state, and the expression of putative causal genes such as TNFAIP3 and IFNAR1. Several putative causal genes constitute RA-relevant functional networks in FLS with roles in cellular proliferation and activation. Finally, we demonstrate that risk variants can have joint-specific effects on target gene expression in RA FLS, which may contribute to the development of the characteristic pattern of joint involvement in RA.<br><br>CONCLUSION: Overall, our research provides the first direct evidence for a causal role of FLS in the genetic susceptibility for RA accounting for up to a quarter of RA heritability.},
}
@article {pmid34432858,
year = {2021},
author = {Groves, IJ and Drane, ELA and Michalski, M and Monahan, JM and Scarpini, CG and Smith, SP and Bussotti, G and Várnai, C and Schoenfelder, S and Fraser, P and Enright, AJ and Coleman, N},
title = {Short- and long-range cis interactions between integrated HPV genomes and cellular chromatin dysregulate host gene expression in early cervical carcinogenesis.},
journal = {PLoS pathogens},
volume = {17},
number = {8},
pages = {e1009875},
pmid = {34432858},
issn = {1553-7374},
support = {13080/CRUK_/Cancer Research UK/United Kingdom ; A13080/CRUK_/Cancer Research UK/United Kingdom ; MR/T016787/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Carcinogenesis/metabolism/*pathology ; Chromatin/genetics/*metabolism ; Epigenesis, Genetic ; Female ; *Genome, Viral ; Human papillomavirus 16/*isolation &amp; purification ; Humans ; Papillomavirus Infections/*complications ; Tumor Cells, Cultured ; Uterine Cervical Neoplasms/genetics/metabolism/*pathology/virology ; *Virus Integration ; },
abstract = {Development of cervical cancer is directly associated with integration of human papillomavirus (HPV) genomes into host chromosomes and subsequent modulation of HPV oncogene expression, which correlates with multi-layered epigenetic changes at the integrated HPV genomes. However, the process of integration itself and dysregulation of host gene expression at sites of integration in our model of HPV16 integrant clone natural selection has remained enigmatic. We now show, using a state-of-the-art 'HPV integrated site capture' (HISC) technique, that integration likely occurs through microhomology-mediated repair (MHMR) mechanisms via either a direct process, resulting in host sequence deletion (in our case, partially homozygously) or via a 'looping' mechanism by which flanking host regions become amplified. Furthermore, using our 'HPV16-specific Region Capture Hi-C' technique, we have determined that chromatin interactions between the integrated virus genome and host chromosomes, both at short- (<500 kbp) and long-range (>500 kbp), appear to drive local host gene dysregulation through the disruption of host:host interactions within (but not exceeding) host structures known as topologically associating domains (TADs). This mechanism of HPV-induced host gene expression modulation indicates that integration of virus genomes near to or within a 'cancer-causing gene' is not essential to influence their expression and that these modifications to genome interactions could have a major role in selection of HPV integrants at the early stage of cervical neoplastic progression.},
}
@article {pmid34429265,
year = {2022},
author = {Chiliński, M and Sengupta, K and Plewczynski, D},
title = {From DNA human sequence to the chromatin higher order organisation and its biological meaning: Using biomolecular interaction networks to understand the influence of structural variation on spatial genome organisation and its functional effect.},
journal = {Seminars in cell &amp; developmental biology},
volume = {121},
number = {},
pages = {171-185},
doi = {10.1016/j.semcdb.2021.08.007},
pmid = {34429265},
issn = {1096-3634},
mesh = {Chromatin/*metabolism ; Genome, Human/*genetics ; Genomics/*methods ; High-Throughput Nucleotide Sequencing/*methods ; Humans ; Protein Interaction Maps/*genetics ; },
abstract = {The three-dimensional structure of the human genome has been proven to have a significant functional impact on gene expression. The high-order spatial chromatin is organised first by looping mediated by multiple protein factors, and then it is further formed into larger structures of topologically associated domains (TADs) or chromatin contact domains (CCDs), followed by A/B compartments and finally the chromosomal territories (CTs). The genetic variation observed in human population influences the multi-scale structures, posing a question regarding the functional impact of structural variants reflected by the variability of the genes expression patterns. The current methods of evaluating the functional effect include eQTLs analysis which uses statistical testing of influence of variants on spatially close genes. Rarely, non-coding DNA sequence changes are evaluated by their impact on the biomolecular interaction network (BIN) reflecting the cellular interactome that can be analysed by the classical graph-theoretic algorithms. Therefore, in the second part of the review, we introduce the concept of BIN, i.e. a meta-network model of the complete molecular interactome developed by integrating various biological networks. The BIN meta-network model includes DNA-protein binding by the plethora of protein factors as well as chromatin interactions, therefore allowing connection of genomics with the downstream biomolecular processes present in a cell. As an illustration, we scrutinise the chromatin interactions mediated by the CTCF protein detected in a ChIA-PET experiment in the human lymphoblastoid cell line GM12878. In the corresponding BIN meta-network the DNA spatial proximity is represented as a graph model, combined with the Proteins-Interaction Network (PIN) of human proteome using the Gene Association Network (GAN). Furthermore, we enriched the BIN with the signalling and metabolic pathways and Gene Ontology (GO) terms to assert its functional context. Finally, we mapped the Single Nucleotide Polymorphisms (SNPs) from the GWAS studies and identified the chromatin mutational hot-spots associated with a significant enrichment of SNPs related to autoimmune diseases. Afterwards, we mapped Structural Variants (SVs) from healthy individuals of 1000 Genomes Project and identified an interesting example of the missing protein complex associated with protein Q6GYQ0 due to a deletion on chromosome 14. Such an analysis using the meta-network BIN model is therefore helpful in evaluating the influence of genetic variation on spatial organisation of the genome and its functional effect in a cell.},
}
@article {pmid34426703,
year = {2022},
author = {Arrastia, MV and Jachowicz, JW and Ollikainen, N and Curtis, MS and Lai, C and Quinodoz, SA and Selck, DA and Ismagilov, RF and Guttman, M},
title = {Single-cell measurement of higher-order 3D genome organization with scSPRITE.},
journal = {Nature biotechnology},
volume = {40},
number = {1},
pages = {64-73},
pmid = {34426703},
issn = {1546-1696},
support = {U01 HL130007/HL/NHLBI NIH HHS/United States ; U01 DA040612/DA/NIDA NIH HHS/United States ; U01 HG007910/HG/NHGRI NIH HHS/United States ; },
mesh = {Animals ; *Cell Nucleus/genetics ; Chromatin ; DNA/genetics ; *Genome/genetics ; Mice ; Mouse Embryonic Stem Cells ; },
abstract = {Although three-dimensional (3D) genome organization is central to many aspects of nuclear function, it has been difficult to measure at the single-cell level. To address this, we developed 'single-cell split-pool recognition of interactions by tag extension' (scSPRITE). scSPRITE uses split-and-pool barcoding to tag DNA fragments in the same nucleus and their 3D spatial arrangement. Because scSPRITE measures multiway DNA contacts, it generates higher-resolution maps within an individual cell than can be achieved by proximity ligation. We applied scSPRITE to thousands of mouse embryonic stem cells and detected known genome structures, including chromosome territories, active and inactive compartments, and topologically associating domains (TADs) as well as long-range inter-chromosomal structures organized around various nuclear bodies. We observe that these structures exhibit different levels of heterogeneity across the population, with TADs representing dynamic units of genome organization across cells. We expect that scSPRITE will be a critical tool for studying genome structure within heterogeneous populations.},
}
@article {pmid34415531,
year = {2022},
author = {Nicoletti, C},
title = {Methods for the Differential Analysis of Hi-C Data.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {2301},
number = {},
pages = {61-95},
pmid = {34415531},
issn = {1940-6029},
mesh = {Cell Nucleus/genetics ; Chromatin/genetics ; Chromatin Assembly and Disassembly ; Chromosomes/genetics ; *Genome ; Software ; },
abstract = {The 3D organization of chromatin within the nucleus enables dynamic regulation and cell type-specific transcription of the genome. This is true at multiple levels of resolution: on a large scale, with chromosomes occupying distinct volumes (chromosome territories); at the level of individual chromatin fibers, which are organized into compartmentalized domains (e.g., Topologically Associating Domains-TADs), and at the level of short-range chromatin interactions between functional elements of the genome (e.g., enhancer-promoter loops).The widespread availability of Chromosome Conformation Capture (3C)-based high-throughput techniques has been instrumental in advancing our knowledge of chromatin nuclear organization. In particular, Hi-C has the potential to achieve the most comprehensive characterization of chromatin 3D interactions, as it is theoretically able to detect any pair of restriction fragments connected as a result of ligation by proximity.This chapter will illustrate how to compare the chromatin interactome in different experimental conditions, starting from pre-computed Hi-C contact matrices, how to visualize the results, and how to correlate the observed variations in chromatin interaction strength with changes in gene expression.},
}
@article {pmid34415530,
year = {2022},
author = {Zufferey, M and Tavernari, D and Ciriello, G},
title = {Methods for the Analysis of Topologically Associating Domains (TADs).},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {2301},
number = {},
pages = {39-59},
pmid = {34415530},
issn = {1940-6029},
mesh = {Cell Nucleus ; Chromatin/genetics ; Chromosomes/genetics ; Genome ; *Genomics ; },
abstract = {Chromatin folding in the 3D space of the nucleus can be explored through high-throughput chromosome conformation capture (Hi-C) approaches. These experiments quantify the number of interactions between any pair of genomic loci in the genome and, thus, allow building genome-scale maps of intra- and inter-chromosomal contacts (contact maps). Statistical and algorithmic analyses of Hi-C data consist in extracting information from these contact maps. One of the most striking patterns observed in intra-chromosomal Hi-C contact maps emerged from genomic regions that exhibit dense intra-region but sparse inter-region contacts. These have been termed topologically associating domains (TADs). The identification of TADs from Hi-C contact maps is of great interest as they have been shown to act as unit of chromosome organization and, potentially, functional activity. Several approaches have been developed to identify TADs (TAD callers). However, results from these methods are often dependent on data resolution and poorly concordant. In this chapter, we present four TAD callers and we provide detailed protocols for their use. In addition, we show how to compare TADs identified by different callers and how to assess the enrichment for TAD-associated biological features. TAD calling has become a key step in the study of chromatin 3D organization in different cellular contexts. Here we provide guidelines to improve the robustness and quality of these analyses.},
}
@article {pmid34399301,
year = {2021},
author = {Liang, J and Perez-Rathke, A},
title = {Minimalistic 3D chromatin models: Sparse interactions in single cells drive the chromatin fold and form many-body units.},
journal = {Current opinion in structural biology},
volume = {71},
number = {},
pages = {200-214},
pmid = {34399301},
issn = {1879-033X},
support = {R35 GM127084/GM/NIGMS NIH HHS/United States ; },
mesh = {*Chromatin ; Chromatin Assembly and Disassembly ; *Chromosomes ; Genome ; Molecular Conformation ; },
abstract = {Computational three-dimensional chromatin modeling has helped uncover principles of genome organization. Here, we discuss methods for modeling three-dimensional chromatin structures, with focus on a minimalistic polymer model which inverts population Hi-C into single-cell conformations. Utilizing only basic physical properties, this model reveals that a few specific Hi-C interactions can fold chromatin into conformations consistent with single-cell imaging, Dip-C, and FISH measurements. Aggregated single-cell chromatin conformations also reproduce Hi-C frequencies. This approach allows quantification of structural heterogeneity and discovery of many-body interaction units and has revealed additional insights, including (1) topologically associating domains as a byproduct of folding driven by specific interactions, (2) cell subpopulations with different structural scaffolds are developmental stage dependent, and (3) the functional landscape of many-body units within enhancer-rich regions. We also discuss these findings in relation to the genome structure-function relationship.},
}
@article {pmid34382189,
year = {2021},
author = {Boltsis, I and Nowosad, K and Brouwer, RWW and Tylzanowski, P and van IJcken, WFJ and Huylebroeck, D and Grosveld, F and Kolovos, P},
title = {Low Input Targeted Chromatin Capture (Low-T2C).},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {2351},
number = {},
pages = {165-179},
pmid = {34382189},
issn = {1940-6029},
mesh = {Chromatin/chemistry/*genetics/metabolism ; *Chromatin Assembly and Disassembly ; Chromosome Mapping ; Computational Biology/*methods ; Gene Expression Regulation ; Gene Library ; Genomics/methods ; Reproducibility of Results ; },
abstract = {Targeted chromatin capture (T2C) is a 3C-based method and is used to study the 3D chromatin organization, interactomes and structural changes associated with gene regulation, progression through the cell cycle, and cell survival and development. Low input targeted chromatin capture (low-T2C) is an optimized version of the T2C protocol for low numbers of cells. Here, we describe the protocol for low-T2C, including all experimental steps and bioinformatics tools in detail.},
}
@article {pmid34381055,
year = {2021},
author = {Yuan, J and Jiang, Q and Gong, T and Fan, D and Zhang, J and Chen, F and Zhu, X and Wang, X and Qiao, Y and Chen, H and Liu, Z and Su, J},
title = {Loss of grand histone H3 lysine 27 trimethylation domains mediated transcriptional activation in esophageal squamous cell carcinoma.},
journal = {NPJ genomic medicine},
volume = {6},
number = {1},
pages = {65},
pmid = {34381055},
issn = {2056-7944},
abstract = {Trimethylation of histone H3 lysine 27 trimethylation (H3K27me3) may be recruited by repressive Polycomb complexes to mediate gene silencing, which is critical for maintaining embryonic stem cell pluripotency and differentiation. However, the roles of aberrant H3K27me3 patterns in tumorigenesis are not fully understood. Here, we discovered that grand silencer domains (breadth > 50 kb) for H3K27me3 were significantly associated with epithelial cell differentiation and exhibited high gene essentiality and conservation in human esophageal epithelial cells. These grand H3K27me3 domains exhibited high modification signals involved in gene silencing, and preferentially occupied the entirety of topologically associating domains and interact with each other. We found that widespread loss of the grand H3K27me3 domains in of esophageal squamous cell carcinomas (ESCCs) were enriched in genes involved in epithelium and endothelium differentiation, which were significantly associated with overexpression with increase of active modifications of H3K4me3, H3K4me1, and H3K27ac marks, as well as DNA hypermethylation in the gene bodies. A total of 208 activated genes with loss of grand H3K27me3 domains in ESCC were identified, where the higher expression and mutation of T-box transcription factor 20 (TBX20) were associated with worse patients' outcomes. Our results showed that knockdown of TBX20 may have led to a striking defect in esophageal cancer cell growth and carcinogenesis-related pathway, including cell cycle and homologous recombination. Together, our results reveal that loss of grand H3K27me3 domains represent a catalog of remarkable activating regulators involved in carcinogenesis.},
}
@article {pmid34368157,
year = {2021},
author = {Adeel, MM and Jiang, H and Arega, Y and Cao, K and Lin, D and Cao, C and Cao, G and Wu, P and Li, G},
title = {Structural Variations of the 3D Genome Architecture in Cervical Cancer Development.},
journal = {Frontiers in cell and developmental biology},
volume = {9},
number = {},
pages = {706375},
pmid = {34368157},
issn = {2296-634X},
abstract = {Human papillomavirus (HPV) integration is the major contributor to cervical cancer (CC) development by inducing structural variations (SVs) in the human genome. SVs are directly associated with the three-dimensional (3D) genome structure leading to cancer development. The detection of SVs is not a trivial task, and several genome-wide techniques have greatly helped in the identification of SVs in the cancerous genome. However, in cervical cancer, precise prediction of SVs mainly translocations and their effects on 3D-genome and gene expression still need to be explored. Here, we have used high-throughput chromosome conformation capture (Hi-C) data of cervical cancer to detect the SVs, especially the translocations, and validated it through whole-genome sequencing (WGS) data. We found that the cervical cancer 3D-genome architecture rearranges itself as compared to that in the normal tissue, and 24% of the total genome switches their A/B compartments. Moreover, translocation detection from Hi-C data showed the presence of high-resolution t(4;7) (q13.1; q31.32) and t(1;16) (q21.2; q22.1) translocations, which disrupted the expression of the genes located at and nearby positions. Enrichment analysis suggested that the disrupted genes were mainly involved in controlling cervical cancer-related pathways. In summary, we detect the novel SVs through Hi-C data and unfold the association among genome-reorganization, translocations, and gene expression regulation. The results help understand the underlying pathogenicity mechanism of SVs in cervical cancer development and identify the targeted therapeutics against cervical cancer.},
}
@article {pmid34351763,
year = {2021},
author = {Wei, J and Tian, H and Zhou, R and Shao, Y and Song, F and Gao, YQ},
title = {Topological Constraints with Optimal Length Promote the Formation of Chromosomal Territories at Weakened Degree of Phase Separation.},
journal = {The journal of physical chemistry. B},
volume = {125},
number = {32},
pages = {9092-9101},
doi = {10.1021/acs.jpcb.1c03523},
pmid = {34351763},
issn = {1520-5207},
mesh = {*Cell Nucleus ; Chromatin ; *Chromosomes/genetics ; CpG Islands ; Humans ; Interphase ; },
abstract = {It is generally agreed that the nuclei of eukaryotic cells at interphase are partitioned into disjointed territories, with distinct regions occupied by certain chromosomes. However, the underlying mechanism for such territorialization is still under debate. Here we model chromosomes as coarse-grained block copolymers and to investigate the effect of loop domains (LDs) on the formation of compartments and territories based on dissipative particle dynamics. A critical length of LDs, which depends sensitively on the length of polymeric blocks, is obtained to minimize the degree of phase separation. This also applies to the two-polymer system: The critical length not only maximizes the degree of territorialization but also minimizes the degree of phase separation. Interestingly, by comparing with experimental data, we find the critical length for LDs and the corresponding length of blocks to be respectively very close to the mean length of topologically associating domains (TADs) and chromosomal segments with different densities of CpG islands for human chromosomes. The results indicate that topological constraints with optimal length can contribute to the formation of territories by weakening the degree of phase separation, which likely promotes the chromosomal flexibility in response to genetic regulations.},
}
@article {pmid34341417,
year = {2021},
author = {Grabowicz, IE and Wilczyński, B and Kamińska, B and Roura, AJ and Wojtaś, B and Dąbrowski, MJ},
title = {The role of epigenetic modifications, long-range contacts, enhancers and topologically associating domains in the regulation of glioma grade-specific genes.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {15668},
pmid = {34341417},
issn = {2045-2322},
mesh = {*Chromatin ; Chromosomes ; Enhancer Elements, Genetic ; *Epigenesis, Genetic ; Evolution, Molecular ; *Glioma ; Humans ; },
abstract = {Genome-wide studies have uncovered specific genetic alterations, transcriptomic patterns and epigenetic profiles associated with different glioma types. We have recently created a unique atlas encompassing genome-wide profiles of open chromatin, histone H3K27ac and H3Kme3 modifications, DNA methylation and transcriptomes of 33 glioma samples of different grades. Here, we intersected genome-wide atlas data with topologically associating domains (TADs) and demonstrated that the chromatin organization and epigenetic landscape of enhancers have a strong impact on genes differentially expressed in WHO low grade versus high grade gliomas. We identified TADs enriched in glioma grade-specific genes and/or epigenetic marks. We found the set of transcription factors, including REST, E2F1 and NFKB1, that are most likely to regulate gene expression in multiple TADs, containing specific glioma-related genes. Moreover, many genes associated with the cell-matrix adhesion Gene Ontology group, in particular 14 PROTOCADHERINs, were found to be regulated by long-range contacts with enhancers. Presented results demonstrate the existence of epigenetic differences associated with chromatin organization driving differential gene expression in gliomas of different malignancy.},
}
@article {pmid34340871,
year = {2022},
author = {Sexton, CE and Tillett, RL and Han, MV},
title = {The essential but enigmatic regulatory role of HERVH in pluripotency.},
journal = {Trends in genetics : TIG},
volume = {38},
number = {1},
pages = {12-21},
pmid = {34340871},
issn = {0168-9525},
support = {P20 GM121325/GM/NIGMS NIH HHS/United States ; },
mesh = {*Endogenous Retroviruses/metabolism ; Enhancer Elements, Genetic ; Humans ; *RNA, Long Noncoding/metabolism ; Stem Cells/metabolism ; },
abstract = {Human specific endogenous retrovirus H (HERVH) is highly expressed in both naive and primed stem cells and is essential for pluripotency. Despite the proven relationship between HERVH expression and pluripotency, there is no single definitive model for the function of HERVH. Instead, several hypotheses of a regulatory function have been put forward including HERVH acting as enhancers, long noncoding RNAs (lncRNAs), and most recently as markers of topologically associating domain (TAD) boundaries. Recently several enhancer-associated lncRNAs have been characterized, which bind to Mediator and are necessary for promoter-enhancer folding interactions. We propose a synergistic model of HERVH function combining relevant findings and discuss the current limitations for its role in regulation, including the lack of evidence for a pluripotency-associated target gene.},
}
@article {pmid34326481,
year = {2021},
author = {Soochit, W and Sleutels, F and Stik, G and Bartkuhn, M and Basu, S and Hernandez, SC and Merzouk, S and Vidal, E and Boers, R and Boers, J and van der Reijden, M and Geverts, B and van Cappellen, WA and van den Hout, M and Ozgur, Z and van IJcken, WFJ and Gribnau, J and Renkawitz, R and Graf, T and Houtsmuller, A and Grosveld, F and Stadhouders, R and Galjart, N},
title = {CTCF chromatin residence time controls three-dimensional genome organization, gene expression and DNA methylation in pluripotent cells.},
journal = {Nature cell biology},
volume = {23},
number = {8},
pages = {881-893},
pmid = {34326481},
issn = {1476-4679},
mesh = {Animals ; CCCTC-Binding Factor/genetics/*physiology ; Chromatin/*metabolism ; *DNA Methylation ; Female ; *Gene Expression Regulation ; *Genome ; Green Fluorescent Proteins/genetics ; Male ; Mice ; Mitosis ; Mouse Embryonic Stem Cells ; Mutation ; Pluripotent Stem Cells/metabolism/*physiology ; Time Factors ; Transcription Elongation, Genetic ; },
abstract = {The 11 zinc finger (ZF) protein CTCF regulates topologically associating domain formation and transcription through selective binding to thousands of genomic sites. Here, we replaced endogenous CTCF in mouse embryonic stem cells with green-fluorescent-protein-tagged wild-type or mutant proteins lacking individual ZFs to identify additional determinants of CTCF positioning and function. While ZF1 and ZF8-ZF11 are not essential for cell survival, ZF8 deletion strikingly increases the DNA binding off-rate of mutant CTCF, resulting in reduced CTCF chromatin residence time. Loss of ZF8 results in widespread weakening of topologically associating domains, aberrant gene expression and increased genome-wide DNA methylation. Thus, important chromatin-templated processes rely on accurate CTCF chromatin residence time, which we propose depends on local sequence and chromatin context as well as global CTCF protein concentration.},
}
@article {pmid34313981,
year = {2021},
author = {Gupta, MK and Lenz, T and Le Roch, KG},
title = {Chromosomes Conformation Capture Coupled with Next-Generation Sequencing (Hi-C) in Plasmodium falciparum.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {2369},
number = {},
pages = {15-25},
pmid = {34313981},
issn = {1940-6029},
support = {R01 AI136511/AI/NIAID NIH HHS/United States ; R21 AI142506/AI/NIAID NIH HHS/United States ; R01 AI142743/AI/NIAID NIH HHS/United States ; },
mesh = {Chromosomes/genetics ; Genome, Protozoan ; High-Throughput Nucleotide Sequencing ; Humans ; Malaria ; *Plasmodium falciparum/genetics ; },
abstract = {Over the last decades, novel methods have been developed to study the role of chromosome positioning within the nucleus may play in gene regulation. Established proximity ligation-based chromosome conformation capture (3C) techniques such as Hi-C have revealed the existence of chromosome territories, functional nuclear landmarks, and topologically associating domains (TAPs) in most eukaryotic organisms. Adaptation of these methods in apicomplexan parasites has recently uncovered new aspects of 3D genome biology in virulence factors. Here, we describe the Hi-C protocol in the human malaria parasite, Plasmodium falciparum. This method can determine the genome organization in malaria parasites and its role in gene regulation and virulence.},
}
@article {pmid34311744,
year = {2021},
author = {Li, X and Zeng, G and Li, A and Zhang, Z},
title = {DeTOKI identifies and characterizes the dynamics of chromatin TAD-like domains in a single cell.},
journal = {Genome biology},
volume = {22},
number = {1},
pages = {217},
pmid = {34311744},
issn = {1474-760X},
mesh = {*Algorithms ; Animals ; CCCTC-Binding Factor/genetics/metabolism ; Cell Cycle Proteins/genetics/metabolism ; Chromatin/*chemistry ; *Chromatin Assembly and Disassembly ; Cluster Analysis ; DNA-Binding Proteins/genetics/metabolism ; Entropy ; Gene Expression ; *Genome ; Histones/genetics/metabolism ; Humans ; Mammals ; Single-Cell Analysis/*methods ; *Software ; },
abstract = {Topologically associating domains (TAD) are a key structure of the 3D mammalian genomes. However, the prevalence and dynamics of TAD-like domains in single cells remain elusive. Here we develop a new algorithm, named deTOKI, to decode TAD-like domains with single-cell Hi-C data. By non-negative matrix factorization, deTOKI seeks regions that insulate the genome into blocks with minimal chance of clustering. deTOKI outperforms competing tools and reliably identifies TAD-like domains in single cells. Finally, we find that TAD-like domains are not only prevalent, but also subject to tight regulation in single cells.},
}
@article {pmid34311045,
year = {2021},
author = {Long, Y and Liu, Z and Wang, P and Yang, H and Wang, Y and Zhang, S and Zhang, X and Wang, M},
title = {Disruption of topologically associating domains by structural variations in tetraploid cottons.},
journal = {Genomics},
volume = {113},
number = {5},
pages = {3405-3414},
doi = {10.1016/j.ygeno.2021.07.023},
pmid = {34311045},
issn = {1089-8646},
mesh = {Animals ; Chromatin ; Chromosomes ; Gene Expression Regulation ; *Genome ; Mammals/genetics ; *Tetraploidy ; },
abstract = {Structural variations (SVs) are recognized to have an important role in transcriptional regulation, especially in the light of resolved 3D genome structure using high-throughput chromosome conformation capture (Hi-C) technology in mammals. However, the effect of SVs on 3D genome organization in plants remains rarely understood. In this study, we identified 295,496 SVs and 5251 topologically associating domains (TADs) in two diploid and two tetraploid cottons. We observed that approximately 16% of SVs occurred in TAD boundary regions that were called boundary affecting-structural variations (BA-SVs), and had a large effect on disrupting TAD organization. Nevertheless, SVs preferred occurring in TAD interior instead of TAD boundary, probably associated with the relaxed evolutionary selection pressure. We noticed the biased evolution of the At and Dt subgenomes of tetraploid cottons, in terms of SV-mediated disruption of 3D genome structure relative to diploids. In addition, we provide evidence showing that both SVs and TAD disruption could lead to expression difference of orthologous genes. This study advances our understanding of the effect of SVs on 3D genome organization and gene expression regulation in plants.},
}
@article {pmid34309794,
year = {2022},
author = {Revikumar, A and Kashyap, V and Palollathil, A and Aravind, A and Raguraman, R and Kumar, KMK and Vijayakumar, M and Prasad, TSK and Raju, R},
title = {Multiple G-quadruplex binding ligand induced transcriptomic map of cancer cell lines.},
journal = {Journal of cell communication and signaling},
volume = {16},
number = {1},
pages = {129-135},
pmid = {34309794},
issn = {1873-9601},
abstract = {The G-quadruplexes (G4s) are a class of DNA secondary structures with guanine rich DNA sequences that can fold into four stranded non-canonical structures. At the genomic level, their pivotal role is well established in DNA replication, telomerase functions, constitution of topologically associating domains, and the regulation of gene expression. Genome instability mediated by altered G4 formation and assembly has been associated with multiple disorders including cancers and neurodegenerative disorders. Multiple tools have also been developed to predict the potential G4 regions in genomes and the whole genome G4 maps are also being derived through sequencing approaches. Enrichment of G4s in the cis-regulatory elements of genes associated with tumorigenesis has accelerated the quest for identification of G4-DNA binding ligands (G4DBLs) that can selectively bind and regulate the expression of such specific genes. In this context, the analysis of G4DBL responsive transcriptome in diverse cancer cell lines is inevitable for assessment of the specificity of novel G4DBLs. Towards this, we assembled the transcripts differentially regulated by different G4DBLs and have also identified a core set of genes regulated in diverse cancer cell lines in response to 3 or more of these ligands. With the mode of action of G4DBLs towards topology shifts, folding, or disruption of G4 structure being currently visualized, we believe that this dataset will serve as a platform for assembly of G4DBL responsive transcriptome for comparative analysis of G4DBLs in multiple cancer cells based on the expression of specific cis-regulatory G4 associated genes in the future.},
}
@article {pmid34295901,
year = {2021},
author = {Tena, JJ and Santos-Pereira, JM},
title = {Topologically Associating Domains and Regulatory Landscapes in Development, Evolution and Disease.},
journal = {Frontiers in cell and developmental biology},
volume = {9},
number = {},
pages = {702787},
pmid = {34295901},
issn = {2296-634X},
abstract = {Animal genomes are folded in topologically associating domains (TADs) that have been linked to the regulation of the genes they contain by constraining regulatory interactions between cis-regulatory elements and promoters. Therefore, TADs are proposed as structural scaffolds for the establishment of regulatory landscapes (RLs). In this review, we discuss recent advances in the connection between TADs and gene regulation, their relationship with gene RLs and their dynamics during development and differentiation. Moreover, we describe how restructuring TADs may lead to pathological conditions, which explains their high evolutionary conservation, but at the same time it provides a substrate for the emergence of evolutionary innovations that lay at the origin of vertebrates and other phylogenetic clades.},
}
@article {pmid34292939,
year = {2021},
author = {Willemin, A and Lopez-Delisle, L and Bolt, CC and Gadolini, ML and Duboule, D and Rodriguez-Carballo, E},
title = {Induction of a chromatin boundary in vivo upon insertion of a TAD border.},
journal = {PLoS genetics},
volume = {17},
number = {7},
pages = {e1009691},
pmid = {34292939},
issn = {1553-7404},
support = {F32 HD093555/HD/NICHD NIH HHS/United States ; },
mesh = {Animals ; CCCTC-Binding Factor/genetics/metabolism ; Cell Cycle Proteins/genetics ; Chromatin/genetics/*physiology ; Chromatin Assembly and Disassembly ; DNA/genetics ; Enhancer Elements, Genetic/genetics ; Gene Expression/genetics ; Gene Expression Regulation/*genetics/physiology ; Gene Regulatory Networks/genetics/*physiology ; Genome/genetics/physiology ; Genomics/methods ; Mice ; Mice, Transgenic ; },
abstract = {Mammalian genomes are partitioned into sub-megabase to megabase-sized units of preferential interactions called topologically associating domains or TADs, which are likely important for the proper implementation of gene regulatory processes. These domains provide structural scaffolds for distant cis regulatory elements to interact with their target genes within the three-dimensional nuclear space and architectural proteins such as CTCF as well as the cohesin complex participate in the formation of the boundaries between them. However, the importance of the genomic context in providing a given DNA sequence the capacity to act as a boundary element remains to be fully investigated. To address this question, we randomly relocated a topological boundary functionally associated with the mouse HoxD gene cluster and show that it can indeed act similarly outside its initial genomic context. In particular, the relocated DNA segment recruited the required architectural proteins and induced a significant depletion of contacts between genomic regions located across the integration site. The host chromatin landscape was re-organized, with the splitting of the TAD wherein the boundary had integrated. These results provide evidence that topological boundaries can function independently of their site of origin, under physiological conditions during mouse development.},
}
@article {pmid34290257,
year = {2021},
author = {Fonseca, TL and Garcia, T and Fernandes, GW and Nair, TM and Bianco, AC},
title = {Neonatal thyroxine activation modifies epigenetic programming of the liver.},
journal = {Nature communications},
volume = {12},
number = {1},
pages = {4446},
pmid = {34290257},
issn = {2041-1723},
support = {R01 DK058538/DK/NIDDK NIH HHS/United States ; R01 DK065055/DK/NIDDK NIH HHS/United States ; R01 DK077148/DK/NIDDK NIH HHS/United States ; R56 DK058538/DK/NIDDK NIH HHS/United States ; },
mesh = {Animals ; Animals, Newborn ; Chromatin/metabolism ; DNA Methylation ; *Epigenesis, Genetic ; Gene Expression ; Gene Expression Regulation, Developmental ; Iodide Peroxidase/genetics/metabolism ; Liver/growth &amp; development/*metabolism ; Mice ; Mice, Knockout ; Triiodothyronine/*metabolism ; },
abstract = {The type 2 deiodinase (D2) in the neonatal liver accelerates local thyroid hormone triiodothyronine (T3) production and expression of T3-responsive genes. Here we show that this surge in T3 permanently modifies hepatic gene expression. Liver-specific Dio2 inactivation (Alb-D2KO) transiently increases H3K9me3 levels during post-natal days 1-5 (P1-P5), and results in methylation of 1,508 DNA sites (H-sites) in the adult mouse liver. These sites are associated with 1,551 areas of reduced chromatin accessibility (RCA) within core promoters and 2,426 within intergenic regions, with reduction in the expression of 1,363 genes. There is strong spatial correlation between density of H-sites and RCA sites. Chromosome conformation capture (Hi-C) data reveals a set of 81 repressed genes with a promoter RCA in contact with an intergenic RCA ~300 Kbp apart, within the same topologically associating domain (χ[2 ]= 777; p < 0.00001). These data explain how the systemic hormone T3 acts locally during development to define future expression of hepatic genes.},
}
@article {pmid34290235,
year = {2021},
author = {King, AJ and Songdej, D and Downes, DJ and Beagrie, RA and Liu, S and Buckley, M and Hua, P and Suciu, MC and Marieke Oudelaar, A and Hanssen, LLP and Jeziorska, D and Roberts, N and Carpenter, SJ and Francis, H and Telenius, J and Olijnik, AA and Sharpe, JA and Sloane-Stanley, J and Eglinton, J and Kassouf, MT and Orkin, SH and Pennacchio, LA and Davies, JOJ and Hughes, JR and Higgs, DR and Babbs, C},
title = {Reactivation of a developmentally silenced embryonic globin gene.},
journal = {Nature communications},
volume = {12},
number = {1},
pages = {4439},
pmid = {34290235},
issn = {2041-1723},
support = {R01 HG003988/HG/NHGRI NIH HHS/United States ; 209181/Z/17/Z/WT_/Wellcome Trust/United Kingdom ; MC_UU_00016/14/MRC_/Medical Research Council/United Kingdom ; MR/N00969X/1/MRC_/Medical Research Council/United Kingdom ; R01 HL032259/HL/NHLBI NIH HHS/United States ; MC_UU_12009/MRC_/Medical Research Council/United Kingdom ; 106130/Z/14/Z/WT_/Wellcome Trust/United Kingdom ; MR/T014067/1/MRC_/Medical Research Council/United Kingdom ; MC_UU_00016/1/MRC_/Medical Research Council/United Kingdom ; MC_UU_00016/4/MRC_/Medical Research Council/United Kingdom ; 108785/Z/15/Z/WT_/Wellcome Trust/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; },
mesh = {Acetylation ; Animals ; Chromatin/metabolism ; DNA-Binding Proteins/metabolism ; Enhancer Elements, Genetic ; Erythroid Cells/metabolism ; *Gene Expression Regulation, Developmental/drug effects ; *Gene Silencing/drug effects ; Histone Deacetylase Inhibitors/pharmacology ; Humans ; Mice ; Repressor Proteins/metabolism ; Transcription Factors/metabolism ; *Transcriptional Activation/drug effects ; alpha-Globins/genetics ; zeta-Globins/*genetics ; },
abstract = {The α- and β-globin loci harbor developmentally expressed genes, which are silenced throughout post-natal life. Reactivation of these genes may offer therapeutic approaches for the hemoglobinopathies, the most common single gene disorders. Here, we address mechanisms regulating the embryonically expressed α-like globin, termed ζ-globin. We show that in embryonic erythroid cells, the ζ-gene lies within a ~65 kb sub-TAD (topologically associating domain) of open, acetylated chromatin and interacts with the α-globin super-enhancer. By contrast, in adult erythroid cells, the ζ-gene is packaged within a small (~10 kb) sub-domain of hypoacetylated, facultative heterochromatin within the acetylated sub-TAD and that it no longer interacts with its enhancers. The ζ-gene can be partially re-activated by acetylation and inhibition of histone de-acetylases. In addition to suggesting therapies for severe α-thalassemia, these findings illustrate the general principles by which reactivation of developmental genes may rescue abnormalities arising from mutations in their adult paralogues.},
}
@article {pmid34274970,
year = {2021},
author = {Aavikko, M and Kaasinen, E and Andersson, N and Pentinmikko, N and Sulo, P and Donner, I and Pihlajamaa, P and Kuosmanen, A and Bramante, S and Katainen, R and Sipilä, LJ and Martin, S and Arola, J and Carpén, O and Heiskanen, I and Mecklin, JP and Taipale, J and Ristimäki, A and Lehti, K and Gucciardo, E and Katajisto, P and Schalin-Jäntti, C and Vahteristo, P and Aaltonen, LA},
title = {WNT2 activation through proximal germline deletion predisposes to small intestinal neuroendocrine tumors and intestinal adenocarcinomas.},
journal = {Human molecular genetics},
volume = {30},
number = {24},
pages = {2429-2440},
pmid = {34274970},
issn = {1460-2083},
mesh = {*Adenocarcinoma/genetics/pathology ; *Adenoma/genetics/pathology ; *Colorectal Neoplasms/genetics ; Humans ; Intestinal Mucosa/pathology ; *Neuroendocrine Tumors/genetics/pathology ; Wnt2 Protein ; },
abstract = {Many hereditary cancer syndromes are associated with an increased risk of small and large intestinal adenocarcinomas. However, conditions bearing a high risk to both adenocarcinomas and neuroendocrine tumors are yet to be described. We studied a family with 16 individuals in four generations affected by a wide spectrum of intestinal tumors, including hyperplastic polyps, adenomas, small intestinal neuroendocrine tumors, and colorectal and small intestinal adenocarcinomas. To assess the genetic susceptibility and understand the novel phenotype, we utilized multiple molecular methods, including whole genome sequencing, RNA sequencing, single cell sequencing, RNA in situ hybridization and organoid culture. We detected a heterozygous deletion at the cystic fibrosis locus (7q31.2) perfectly segregating with the intestinal tumor predisposition in the family. The deletion removes a topologically associating domain border between CFTR and WNT2, aberrantly activating WNT2 in the intestinal epithelium. These consequences suggest that the deletion predisposes to small intestinal neuroendocrine tumors and small and large intestinal adenocarcinomas, and reveals the broad tumorigenic effects of aberrant WNT activation in the human intestine.},
}
@article {pmid34253239,
year = {2021},
author = {Li, Y and Xue, B and Zhang, M and Zhang, L and Hou, Y and Qin, Y and Long, H and Su, QP and Wang, Y and Guan, X and Jin, Y and Cao, Y and Li, G and Sun, Y},
title = {Transcription-coupled structural dynamics of topologically associating domains regulate replication origin efficiency.},
journal = {Genome biology},
volume = {22},
number = {1},
pages = {206},
pmid = {34253239},
issn = {1474-760X},
mesh = {CCCTC-Binding Factor/antagonists &amp; inhibitors/genetics/metabolism ; Cell Cycle Proteins/antagonists &amp; inhibitors/genetics/metabolism ; Cell Line ; Cell Line, Tumor ; Chromatin/*chemistry ; Chromatin Assembly and Disassembly ; *DNA Replication ; DNA-Binding Proteins/antagonists &amp; inhibitors/genetics/metabolism ; G1 Phase Cell Cycle Checkpoints/*genetics ; Gene Expression ; HeLa Cells ; Humans ; In Situ Hybridization, Fluorescence ; Optical Imaging ; Osteoblasts/cytology/metabolism ; Proliferating Cell Nuclear Antigen/*genetics/metabolism ; RNA, Small Interfering/genetics/metabolism ; *Replication Origin ; Retinal Pigment Epithelium/cytology/metabolism ; *Transcription, Genetic ; },
abstract = {BACKGROUND: Metazoan cells only utilize a small subset of the potential DNA replication origins to duplicate the whole genome in each cell cycle. Origin choice is linked to cell growth, differentiation, and replication stress. Although various genetic and epigenetic signatures have been linked to the replication efficiency of origins, there is no consensus on how the selection of origins is determined.<br><br>RESULTS: We apply dual-color stochastic optical reconstruction microscopy (STORM) super-resolution imaging to map the spatial distribution of origins within individual topologically associating domains (TADs). We find that multiple replication origins initiate separately at the spatial boundary of a TAD at the beginning of the S phase. Intriguingly, while both high-efficiency and low-efficiency origins are distributed homogeneously in the TAD during the G1 phase, high-efficiency origins relocate to the TAD periphery before the S phase. Origin relocalization is dependent on both transcription and CTCF-mediated chromatin structure. Further, we observe that the replication machinery protein PCNA forms immobile clusters around TADs at the G1/S transition, explaining why origins at the TAD periphery are preferentially fired.<br><br>CONCLUSION: Our work reveals a new origin selection mechanism that the replication efficiency of origins is determined by their physical distribution in the chromatin domain, which undergoes a transcription-dependent structural re-organization process. Our model explains the complex links between replication origin efficiency and many genetic and epigenetic signatures that mark active transcription. The coordination between DNA replication, transcription, and chromatin organization inside individual TADs also provides new insights into the biological functions of sub-domain chromatin structural dynamics.},
}
@article {pmid34245617,
year = {2021},
author = {Kang, J and Kim, YW and Park, S and Kang, Y and Kim, A},
title = {Multiple CTCF sites cooperate with each other to maintain a TAD for enhancer-promoter interaction in the β-globin locus.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {35},
number = {8},
pages = {e21768},
doi = {10.1096/fj.202100105RR},
pmid = {34245617},
issn = {1530-6860},
mesh = {CCCTC-Binding Factor/genetics/*metabolism ; Cell Line ; Chromatin/genetics/*metabolism ; *Enhancer Elements, Genetic ; *Genetic Loci ; Humans ; *Promoter Regions, Genetic ; beta-Globins/*biosynthesis/genetics ; },
abstract = {Insulators are cis-regulatory elements that block enhancer activity and prevent heterochromatin spreading. The binding of CCCTC-binding factor (CTCF) protein is essential for insulators to play the roles in a chromatin context. The β-globin locus, consisting of multiple genes and enhancers, is flanked by two insulators 3'HS1 and HS5. However, it has been reported that the absence of these insulators did not affect the β-globin transcription. To explain the unexpected finding, we have deleted a CTCF motif at 3'HS1 or HS5 in the human β-globin locus and analyzed chromatin interactions around the locus. It was found that a topologically associating domain (TAD) containing the β-globin locus is maintained by neighboring CTCF sites in the CTCF motif-deleted loci. The additional deletions of neighboring CTCF motifs disrupted the β-globin TAD, resulting in decrease of the β-globin transcription. Chromatin interactions of the β-globin enhancers with gene promoter were weakened in the multiple CTCF motifs-deleted loci, even though the enhancers have still active chromatin features such as histone H3K27ac and histone H3 depletion. Genome-wide analysis using public CTCF ChIA-PET and ChIP-seq data showed that chromatin domains possessing multiple CTCF binding sites tend to contain super-enhancers like the β-globin enhancers. Taken together, our results show that multiple CTCF sites surrounding the β-globin locus cooperate with each other to maintain a TAD. The β-globin TAD appears to provide a compact spatial environment that enables enhancers to interact with promoter.},
}
@article {pmid34240140,
year = {2021},
author = {Peinado, P and Andrades, A and Martorell-Marugán, J and Haswell, JR and Slack, FJ and Carmona-Sáez, P and Medina, PP},
title = {The SWI/SNF complex regulates the expression of miR-222, a tumor suppressor microRNA in lung adenocarcinoma.},
journal = {Human molecular genetics},
volume = {30},
number = {23},
pages = {2263-2271},
doi = {10.1093/hmg/ddab187},
pmid = {34240140},
issn = {1460-2083},
support = {R35 CA232105/CA/NCI NIH HHS/United States ; },
mesh = {Adenocarcinoma of Lung/*genetics/*metabolism/pathology ; Cell Line, Tumor ; Chromosomal Proteins, Non-Histone/*metabolism ; DNA-Binding Proteins ; Enhancer Elements, Genetic ; Gene Expression Regulation, Neoplastic ; *Genes, Tumor Suppressor ; Humans ; MicroRNAs/*genetics ; Models, Biological ; Transcription Factors/*metabolism ; },
abstract = {SWitch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complexes are key epigenetic regulators that are recurrently mutated in cancer. Most studies of these complexes are focused on their role in regulating protein-coding genes. However, here, we show that SWI/SNF complexes control the expression of microRNAs. We used a SMARCA4-deficient model of lung adenocarcinoma (LUAD) to track changes in the miRNome upon SMARCA4 restoration. We found that SMARCA4-SWI/SNF complexes induced significant changes in the expression of cancer-related microRNAs. The most significantly dysregulated microRNA was miR-222, whose expression was promoted by SMARCA4-SWI/SNF complexes, but not by SMARCA2-SWI/SNF complexes via their direct binding to a miR-222 enhancer region. Importantly, miR-222 expression decreased cell viability, phenocopying the tumor suppressor role of SMARCA4-SWI/SNF complexes in LUAD. Finally, we showed that the miR-222 enhancer region resides in a topologically associating domain that does not contain any cancer-related protein-coding genes, suggesting that miR-222 may be involved in exerting the tumor suppressor role of SMARCA4. Overall, this study highlights the relevant role of the SWI/SNF complex in regulating the non-coding genome, opening new insights into the pathogenesis of LUAD.},
}
@article {pmid34234130,
year = {2021},
author = {Bag, I and Chen, S and Rosin, LF and Chen, Y and Liu, CY and Yu, GY and Lei, EP},
title = {M1BP cooperates with CP190 to activate transcription at TAD borders and promote chromatin insulator activity.},
journal = {Nature communications},
volume = {12},
number = {1},
pages = {4170},
pmid = {34234130},
issn = {2041-1723},
mesh = {Animals ; Animals, Genetically Modified ; Cell Line ; Cell Nucleus/metabolism ; Chromatin/genetics/metabolism ; Chromatin Immunoprecipitation Sequencing ; Drosophila Proteins/genetics/*metabolism ; Drosophila melanogaster/*genetics ; Gene Knockdown Techniques ; Genome, Insect ; Insulator Elements/genetics ; Male ; Microtubule-Associated Proteins/genetics/*metabolism ; Nuclear Proteins/genetics/*metabolism ; Promoter Regions, Genetic/genetics ; RNA-Seq ; Repressor Proteins/genetics/*metabolism ; Transcription Factors/genetics/*metabolism ; *Transcriptional Activation ; },
abstract = {Genome organization is driven by forces affecting transcriptional state, but the relationship between transcription and genome architecture remains unclear. Here, we identified the Drosophila transcription factor Motif 1 Binding Protein (M1BP) in physical association with the gypsy chromatin insulator core complex, including the universal insulator protein CP190. M1BP is required for enhancer-blocking and barrier activities of the gypsy insulator as well as its proper nuclear localization. Genome-wide, M1BP specifically colocalizes with CP190 at Motif 1-containing promoters, which are enriched at topologically associating domain (TAD) borders. M1BP facilitates CP190 chromatin binding at many shared sites and vice versa. Both factors promote Motif 1-dependent gene expression and transcription near TAD borders genome-wide. Finally, loss of M1BP reduces chromatin accessibility and increases both inter- and intra-TAD local genome compaction. Our results reveal physical and functional interaction between CP190 and M1BP to activate transcription at TAD borders and mediate chromatin insulator-dependent genome organization.},
}
@article {pmid34228749,
year = {2021},
author = {Srikanth, S and Jain, L and Zepeda-Mendoza, C and Cascio, L and Jones, K and Pauly, R and DuPont, B and Rogers, C and Sarasua, S and Phelan, K and Morton, C and Boccuto, L},
title = {Position effects of 22q13 rearrangements on candidate genes in Phelan-McDermid syndrome.},
journal = {PloS one},
volume = {16},
number = {7},
pages = {e0253859},
pmid = {34228749},
issn = {1932-6203},
mesh = {Adolescent ; Child ; Child, Preschool ; Chromosome Deletion ; Chromosome Disorders/*genetics ; Chromosomes, Human, Pair 22/genetics ; Cohort Studies ; Female ; *Gene Rearrangement ; Genetic Variation ; Humans ; Male ; },
abstract = {Phelan-McDermid syndrome (PMS) is a multi-system disorder characterized by significant variability in clinical presentation. The genetic etiology is also variable with differing sizes of deletions in the chromosome 22q13 region and types of genetic abnormalities (e.g., terminal or interstitial deletions, translocations, ring chromosomes, or SHANK3 variants). Position effects have been shown to affect gene expression and function and play a role in the clinical presentation of various genetic conditions. This study employed a topologically associating domain (TAD) analysis approach to investigate position effects of chromosomal rearrangements on selected candidate genes mapped to 22q13 in 81 individuals with PMS. Data collected were correlated with clinical information from these individuals and with expression and metabolic profiles of lymphoblastoid cells from selected cases. The data confirmed TAD predictions for genes encompassed in the deletions and the clinical and molecular data indicated clear differences among individuals with different 22q13 deletion sizes. The results of the study indicate a positive correlation between deletion size and phenotype severity in PMS and provide evidence of the contribution of other genes to the clinical variability in this developmental disorder by reduced gene expression and altered metabolomics.},
}
@article {pmid34201566,
year = {2021},
author = {Erenpreisa, J and Krigerts, J and Salmina, K and Gerashchenko, BI and Freivalds, T and Kurg, R and Winter, R and Krufczik, M and Zayakin, P and Hausmann, M and Giuliani, A},
title = {Heterochromatin Networks: Topology, Dynamics, and Function (a Working Hypothesis).},
journal = {Cells},
volume = {10},
number = {7},
pages = {},
pmid = {34201566},
issn = {2073-4409},
mesh = {Actomyosin/metabolism ; Animals ; Cell Line, Tumor ; Cell Nucleolus/metabolism ; Chickens ; DNA Replication Timing ; Embryonic Development/genetics ; Gene Expression Regulation ; Heterochromatin/*metabolism ; Humans ; *Models, Biological ; Organ Specificity/genetics ; Rats ; },
abstract = {Open systems can only exist by self-organization as pulsing structures exchanging matter and energy with the outer world. This review is an attempt to reveal the organizational principles of the heterochromatin supra-intra-chromosomal network in terms of nonlinear thermodynamics. The accessibility of the linear information of the genetic code is regulated by constitutive heterochromatin (CHR) creating the positional information in a system of coordinates. These features include scale-free splitting-fusing of CHR with the boundary constraints of the nucleolus and nuclear envelope. The analysis of both the literature and our own data suggests a radial-concentric network as the main structural organization principle of CHR regulating transcriptional pulsing. The dynamic CHR network is likely created together with nucleolus-associated chromatin domains, while the alveoli of this network, including springy splicing speckles, are the pulsing transcription hubs. CHR contributes to this regulation due to the silencing position variegation effect, stickiness, and flexible rigidity determined by the positioning of nucleosomes. The whole system acts in concert with the elastic nuclear actomyosin network which also emerges by self-organization during the transcriptional pulsing process. We hypothesize that the the transcriptional pulsing, in turn, adjusts its frequency/amplitudes specified by topologically associating domains to the replication timing code that determines epigenetic differentiation memory.},
}
@article {pmid34183853,
year = {2021},
author = {Pachano, T and Sánchez-Gaya, V and Ealo, T and Mariner-Faulí, M and Bleckwehl, T and Asenjo, HG and Respuela, P and Cruz-Molina, S and Muñoz-San Martín, M and Haro, E and van IJcken, WFJ and Landeira, D and Rada-Iglesias, A},
title = {Orphan CpG islands amplify poised enhancer regulatory activity and determine target gene responsiveness.},
journal = {Nature genetics},
volume = {53},
number = {7},
pages = {1036-1049},
pmid = {34183853},
issn = {1546-1718},
support = {862022/ERC_/European Research Council/International ; },
mesh = {Animals ; Chromatin/genetics/metabolism ; *CpG Islands ; *DNA Methylation ; Embryonic Stem Cells/metabolism ; *Enhancer Elements, Genetic ; *Epigenesis, Genetic ; *Gene Expression Regulation ; Gene Knock-In Techniques ; Mice ; Promoter Regions, Genetic ; },
abstract = {CpG islands (CGIs) represent a widespread feature of vertebrate genomes, being associated with ~70% of all gene promoters. CGIs control transcription initiation by conferring nearby promoters with unique chromatin properties. In addition, there are thousands of distal or orphan CGIs (oCGIs) whose functional relevance is barely known. Here we show that oCGIs are an essential component of poised enhancers that augment their long-range regulatory activity and control the responsiveness of their target genes. Using a knock-in strategy in mouse embryonic stem cells, we introduced poised enhancers with or without oCGIs within topologically associating domains harboring genes with different types of promoters. Analysis of the resulting cell lines revealed that oCGIs act as tethering elements that promote the physical and functional communication between poised enhancers and distally located genes, particularly those with large CGI clusters in their promoters. Therefore, by acting as genetic determinants of gene-enhancer compatibility, CGIs can contribute to gene expression control under both physiological and potentially pathological conditions.},
}
@article {pmid34182258,
year = {2021},
author = {Yasuhara, T and Zou, L},
title = {Impacts of chromatin dynamics and compartmentalization on DNA repair.},
journal = {DNA repair},
volume = {105},
number = {},
pages = {103162},
doi = {10.1016/j.dnarep.2021.103162},
pmid = {34182258},
issn = {1568-7856},
mesh = {Cell Nucleus/*metabolism/ultrastructure ; Chromatin/*metabolism ; Chromatin Assembly and Disassembly ; *DNA Repair ; Eukaryota/genetics/metabolism ; Humans ; },
abstract = {The proper spatial organization of DNA, RNA, and proteins is critical for a variety of cellular processes. The genome is organized into numerous functional units, such as topologically associating domains (TADs), the formation of which is regulated by both proteins and RNA. In addition, a group of chromatin-bound proteins with the ability to undergo liquid-liquid phase separation (LLPS) can affect the spatial organization and compartmentalization of chromatin, RNA, and proteins by forming condensates, conferring unique properties to specific chromosomal regions. Although the regulation of DNA repair by histone modifications and chromatin accessibility is well established, the impacts of higher-order chromatin and protein organization on the DNA damage response (DDR) have not been appreciated until recently. In this review, we will focus on the movement of chromatin during the DDR, the compartmentalization of DDR proteins via LLPS, and the roles of membraneless nuclear bodies and transcription in DNA repair. With this backdrop, we will discuss the importance of the spatial organization of chromatin and proteins for the maintenance of genome integrity.},
}
@article {pmid34168075,
year = {2021},
author = {Cai, Z and He, Y and Liu, S and Xue, Y and Quan, H and Zhang, L and Gao, YQ},
title = {Hierarchical dinucleotide distribution in genome along evolution and its effect on chromatin packing.},
journal = {Life science alliance},
volume = {4},
number = {8},
pages = {},
pmid = {34168075},
issn = {2575-1077},
mesh = {Animals ; Birds/*genetics ; Chromatin/chemistry/*genetics ; Computational Biology/methods ; *CpG Islands ; DNA Methylation ; Evolution, Molecular ; Humans ; Mammals/*genetics ; Phylogeny ; Sequence Analysis, RNA ; },
abstract = {Dinucleotide densities and their distribution patterns vary significantly among species. Previous studies revealed that CpG is susceptible to methylation, enriched at topologically associating domain boundaries and its distribution along the genome correlates with chromatin compartmentalization. However, the multi-scale organizations of CpG in the linear genome, their role in chromatin organization, and how they change along the evolution are only partially understood. By comparing the CpG distribution at different genomic length scales, we quantify the difference between the CpG distributions of different species and evaluate how the hierarchical uneven CpG distribution appears in evolution. The clustering of species based on the CpG distribution is consistent with the phylogenetic tree. Interestingly, we found the CpG distribution and chromatin structure to be correlated in many different length scales, especially for mammals and avians, consistent with the mosaic CpG distribution in the genomes of these species.},
}
@article {pmid34108480,
year = {2021},
author = {Bauer, M and Vidal, E and Zorita, E and Üresin, N and Pinter, SF and Filion, GJ and Payer, B},
title = {Chromosome compartments on the inactive X guide TAD formation independently of transcription during X-reactivation.},
journal = {Nature communications},
volume = {12},
number = {1},
pages = {3499},
pmid = {34108480},
issn = {2041-1723},
support = {R35 GM124926/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Cellular Reprogramming/genetics ; Chromatin Assembly and Disassembly ; Induced Pluripotent Stem Cells/cytology/metabolism ; Mice ; RNA, Long Noncoding/genetics/metabolism ; Sex Chromatin/genetics/metabolism ; *Transcription, Genetic ; X Chromosome/genetics/*metabolism ; X Chromosome Inactivation/*genetics ; },
abstract = {A hallmark of chromosome organization is the partition into transcriptionally active A and repressed B compartments, and into topologically associating domains (TADs). Both structures were regarded to be absent from the inactive mouse X chromosome, but to be re-established with transcriptional reactivation and chromatin opening during X-reactivation. Here, we combine a tailor-made mouse iPSC reprogramming system and high-resolution Hi-C to produce a time course combining gene reactivation, chromatin opening and chromosome topology during X-reactivation. Contrary to previous observations, we observe A/B-like compartments on the inactive X harbouring multiple subcompartments. While partial X-reactivation initiates within a compartment rich in X-inactivation escapees, it then occurs rapidly along the chromosome, concomitant with downregulation of Xist. Importantly, we find that TAD formation precedes transcription and initiates from Xist-poor compartments. Here, we show that TAD formation and transcriptional reactivation are causally independent during X-reactivation while establishing Xist as a common denominator.},
}
@article {pmid34099928,
year = {2021},
author = {Niu, L and Shen, W and Shi, Z and Tan, Y and He, N and Wan, J and Sun, J and Zhang, Y and Huang, Y and Wang, W and Fang, C and Li, J and Zheng, P and Cheung, E and Chen, Y and Li, L and Hou, C},
title = {Three-dimensional folding dynamics of the Xenopus tropicalis genome.},
journal = {Nature genetics},
volume = {53},
number = {7},
pages = {1075-1087},
pmid = {34099928},
issn = {1546-1718},
mesh = {Animals ; Apoptosis Regulatory Proteins/genetics ; Cell Cycle Proteins/genetics ; Chromatin/genetics/metabolism ; Chromatin Assembly and Disassembly ; Computational Biology/methods ; Embryonic Development/genetics ; Gene Expression Regulation, Developmental ; Gene Knockdown Techniques ; *Genome ; Genomics/methods ; *Models, Molecular ; *Nucleic Acid Conformation ; Phenotype ; Xenopus/embryology/*genetics ; Xenopus Proteins/genetics ; },
abstract = {Animal interphase chromosomes are organized into topologically associating domains (TADs). How TADs are formed is not fully understood. Here, we combined high-throughput chromosome conformation capture and gene silencing to obtain insights into TAD dynamics in Xenopus tropicalis embryos. First, TAD establishment in X. tropicalis is similar to that in mice and flies and does not depend on zygotic genome transcriptional activation. This process is followed by further refinements in active and repressive chromatin compartments and the appearance of loops and stripes. Second, within TADs, higher self-interaction frequencies at one end of the boundary are associated with higher DNA occupancy of the architectural proteins CTCF and Rad21. Third, the chromatin remodeling factor ISWI is required for de novo TAD formation. Finally, TAD structures are variable in different tissues. Our work shows that X. tropicalis is a powerful model for chromosome architecture analysis and suggests that chromatin remodeling plays an essential role in de novo TAD establishment.},
}
@article {pmid34099725,
year = {2021},
author = {Sahin, M and Wong, W and Zhan, Y and Van Deynze, K and Koche, R and Leslie, CS},
title = {HiC-DC+ enables systematic 3D interaction calls and differential analysis for Hi-C and HiChIP.},
journal = {Nature communications},
volume = {12},
number = {1},
pages = {3366},
pmid = {34099725},
issn = {2041-1723},
support = {P30 CA008748/CA/NCI NIH HHS/United States ; U01 DK128852/DK/NIDDK NIH HHS/United States ; U01 HG009395/HG/NHGRI NIH HHS/United States ; },
mesh = {Acetylation ; Algorithms ; Animals ; Cells, Cultured ; Chromatin/*genetics/metabolism ; Computational Biology/*methods ; Enhancer Elements, Genetic/*genetics ; Genomics/methods ; Histone Code/genetics ; Histones/metabolism ; Humans ; K562 Cells ; Lysine/metabolism ; Mice ; Promoter Regions, Genetic/*genetics ; },
abstract = {Recent genome-wide chromosome conformation capture assays such as Hi-C and HiChIP have vastly expanded the resolution and throughput with which we can study 3D genomic architecture and function. Here, we present HiC-DC+, a software tool for Hi-C/HiChIP interaction calling and differential analysis using an efficient implementation of the HiC-DC statistical framework. HiC-DC+ integrates with popular preprocessing and visualization tools and includes topologically associating domain (TAD) and A/B compartment callers. We found that HiC-DC+ can more accurately identify enhancer-promoter interactions in H3K27ac HiChIP, as validated by CRISPRi-FlowFISH experiments, compared to existing methods. Differential HiC-DC+ analyses of published HiChIP and Hi-C data sets in settings of cellular differentiation and cohesin perturbation systematically and quantitatively recovers biological findings, including enhancer hubs, TAD aggregation, and the relationship between promoter-enhancer loop dynamics and gene expression changes. HiC-DC+ therefore provides a principled statistical analysis tool to empower genome-wide studies of 3D chromatin architecture and function.},
}
@article {pmid34099491,
year = {2021},
author = {Gillani, R and Seong, BKA and Crowdis, J and Conway, JR and Dharia, NV and Alimohamed, S and Haas, BJ and Han, K and Park, J and Dietlein, F and He, MX and Imamovic, A and Ma, C and Bassik, MC and Boehm, JS and Vazquez, F and Gusev, A and Liu, D and Janeway, KA and McFarland, JM and Stegmaier, K and Van Allen, EM},
title = {Gene Fusions Create Partner and Collateral Dependencies Essential to Cancer Cell Survival.},
journal = {Cancer research},
volume = {81},
number = {15},
pages = {3971-3984},
pmid = {34099491},
issn = {1538-7445},
support = {T32 CA136432/CA/NCI NIH HHS/United States ; U01 CA233100/CA/NCI NIH HHS/United States ; U24 CA180922/CA/NCI NIH HHS/United States ; T32 HG002295/HG/NHGRI NIH HHS/United States ; R35 CA210030/CA/NCI NIH HHS/United States ; R01 CA227388/CA/NCI NIH HHS/United States ; R50 CA211461/CA/NCI NIH HHS/United States ; R37 CA222574/CA/NCI NIH HHS/United States ; },
mesh = {Cell Survival/*genetics ; Gene Fusion/*genetics ; Humans ; Neoplasms/*genetics ; },
abstract = {Gene fusions frequently result from rearrangements in cancer genomes. In many instances, gene fusions play an important role in oncogenesis; in other instances, they are thought to be passenger events. Although regulatory element rearrangements and copy number alterations resulting from these structural variants are known to lead to transcriptional dysregulation across cancers, the extent to which these events result in functional dependencies with an impact on cancer cell survival is variable. Here we used CRISPR-Cas9 dependency screens to evaluate the fitness impact of 3,277 fusions across 645 cell lines from the Cancer Dependency Map. We found that 35% of cell lines harbored either a fusion partner dependency or a collateral dependency on a gene within the same topologically associating domain as a fusion partner. Fusion-associated dependencies revealed numerous novel oncogenic drivers and clinically translatable alterations. Broadly, fusions can result in partner and collateral dependencies that have biological and clinical relevance across cancer types. SIGNIFICANCE: This study provides insights into how fusions contribute to fitness in different cancer contexts beyond partner-gene activation events, identifying partner and collateral dependencies that may have direct implications for clinical care.},
}
@article {pmid34099014,
year = {2021},
author = {Furlan-Magaril, M and Ando-Kuri, M and Arzate-Mejía, RG and Morf, J and Cairns, J and Román-Figueroa, A and Tenorio-Hernández, L and Poot-Hernández, AC and Andrews, S and Várnai, C and Virk, B and Wingett, SW and Fraser, P},
title = {The global and promoter-centric 3D genome organization temporally resolved during a circadian cycle.},
journal = {Genome biology},
volume = {22},
number = {1},
pages = {162},
pmid = {34099014},
issn = {1474-760X},
support = {BB/J004480/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Animals ; Base Sequence ; Biological Clocks/genetics ; Chromatin/metabolism ; Circadian Rhythm/*genetics ; Enhancer Elements, Genetic ; Gene Expression Regulation ; *Genome ; Liver/metabolism ; Male ; Mice, Inbred C57BL ; Models, Genetic ; *Promoter Regions, Genetic ; Time Factors ; Transcription, Genetic ; },
abstract = {BACKGROUND: Circadian gene expression is essential for organisms to adjust their physiology and anticipate daily changes in the environment. The molecular mechanisms controlling circadian gene transcription are still under investigation. In particular, how chromatin conformation at different genomic scales and regulatory elements impact rhythmic gene expression has been poorly characterized.<br><br>RESULTS: Here we measure changes in the spatial chromatin conformation in mouse liver using genome-wide and promoter-capture Hi-C alongside daily oscillations in gene transcription. We find topologically associating domains harboring circadian genes that switch assignments between the transcriptionally active and inactive compartment at different hours of the day, while their boundaries stably maintain their structure over time. To study chromatin contacts of promoters at high resolution over time, we apply promoter capture Hi-C. We find circadian gene promoters displayed a maximal number of chromatin contacts at the time of their peak transcriptional output. Furthermore, circadian genes, as well as contacted and transcribed regulatory elements, reach maximal expression at the same timepoints. Anchor sites of circadian gene promoter loops are enriched in DNA binding sites for liver nuclear receptors and other transcription factors, some exclusively present in either rhythmic or stable contacts. Finally, by comparing the interaction profiles between core clock and output circadian genes, we show that core clock interactomes are more dynamic compared to output circadian genes.<br><br>CONCLUSION: Our results identify chromatin conformation dynamics at different scales that parallel oscillatory gene expression and characterize the repertoire of regulatory elements that control circadian gene transcription through rhythmic or stable chromatin configurations.},
}
@article {pmid34093998,
year = {2021},
author = {Chyr, J and Zhang, Z and Chen, X and Zhou, X},
title = {PredTAD: A machine learning framework that models 3D chromatin organization alterations leading to oncogene dysregulation in breast cancer cell lines.},
journal = {Computational and structural biotechnology journal},
volume = {19},
number = {},
pages = {2870-2880},
pmid = {34093998},
issn = {2001-0370},
abstract = {Topologically associating domains, or TADs, play important roles in genome organization and gene regulation; however, they are often altered in diseases. High-throughput chromatin conformation capturing assays, such as Hi-C, can capture domains of increased interactions, and TADs and boundaries can be identified using well-established analytical tools. However, generating Hi-C data is expensive. In our study, we addressed the relationship between multi-omics data and higher-order chromatin structures using a newly developed machine-learning model called PredTAD. Our tool uses already-available and cost-effective datatypes such as transcription factor and histone modification ChIPseq data. Specifically, PredTAD utilizes both epigenetic and genetic features as well as neighboring information to classify the entire human genome as boundary or non-boundary regions. Our tool can predict boundary changes between normal and breast cancer genomes. Among the most important features for predicting boundary alterations were CTCF, subunits of cohesin (RAD21 and SMC3), and chromosome number, suggesting their roles in conserved and dynamic boundaries formation. Upon further analysis, we observed that genes near altered TAD boundaries were found to be involved in several important breast cancer signaling pathways such as Ras, Jak-STAT, and estrogen signaling pathways. We also discovered a TAD boundary alteration that contributes to RET oncogene overexpression. PredTAD can also successfully predict TAD boundary changes in other conditions and diseases. In conclusion, our newly developed machine learning tool allowed for a more complete understanding of the dynamic 3D chromatin structures involved in signaling pathway activation, altered gene expression, and disease state in breast cancer cells.},
}
@article {pmid34078267,
year = {2021},
author = {Olgun, G and Nabi, A and Tastan, O},
title = {NoRCE: non-coding RNA sets cis enrichment tool.},
journal = {BMC bioinformatics},
volume = {22},
number = {1},
pages = {294},
pmid = {34078267},
issn = {1471-2105},
mesh = {Animals ; Genome ; Mice ; *MicroRNAs ; RNA, Untranslated/genetics ; Rats ; *Zebrafish/genetics ; },
abstract = {BACKGROUND: While some non-coding RNAs (ncRNAs) are assigned critical regulatory roles, most remain functionally uncharacterized. This presents a challenge whenever an interesting set of ncRNAs needs to be analyzed in a functional context. Transcripts located close-by on the genome are often regulated together. This genomic proximity on the sequence can hint at a functional association.<br><br>RESULTS: We present a tool, NoRCE, that performs cis enrichment analysis for a given set of ncRNAs. Enrichment is carried out using the functional annotations of the coding genes located proximal to the input ncRNAs. Other biologically relevant information such as topologically associating domain (TAD) boundaries, co-expression patterns, and miRNA target prediction information can be incorporated to conduct a richer enrichment analysis. To this end, NoRCE includes several relevant datasets as part of its data repository, including cell-line specific TAD boundaries, functional gene sets, and expression data for coding &amp; ncRNAs specific to cancer. Additionally, the users can utilize custom data files in their investigation. Enrichment results can be retrieved in a tabular format or visualized in several different ways. NoRCE is currently available for the following species: human, mouse, rat, zebrafish, fruit fly, worm, and yeast.<br><br>CONCLUSIONS: NoRCE is a platform-independent, user-friendly, comprehensive R package that can be used to gain insight into the functional importance of a list of ncRNAs of any type. The tool offers flexibility to conduct the users' preferred set of analyses by designing their own pipeline of analysis. NoRCE is available in Bioconductor and https://github.com/guldenolgun/NoRCE .},
}
@article {pmid34071789,
year = {2021},
author = {Peterson, SC and Samuelson, KB and Hanlon, SL},
title = {Multi-Scale Organization of the Drosophila melanogaster Genome.},
journal = {Genes},
volume = {12},
number = {6},
pages = {},
pmid = {34071789},
issn = {2073-4425},
support = {R00 HD099276/HD/NICHD NIH HHS/United States ; },
mesh = {Animals ; Chromosomes, Insect/genetics ; Drosophila melanogaster/*genetics ; *Genome, Insect ; },
abstract = {Interphase chromatin, despite its appearance, is a highly organized framework of loops and bends. Chromosomes are folded into topologically associating domains, or TADs, and each chromosome and its homolog occupy a distinct territory within the nucleus. In Drosophila, genome organization is exceptional because homologous chromosome pairing is in both germline and somatic tissues, which promote interhomolog interactions such as transvection that can affect gene expression in trans. In this review, we focus on what is known about genome organization in Drosophila and discuss it from TADs to territory. We start by examining intrachromosomal organization at the sub-chromosome level into TADs, followed by a comprehensive analysis of the known proteins that play a key role in TAD formation and boundary establishment. We then zoom out to examine interhomolog interactions such as pairing and transvection that are abundant in Drosophila but rare in other model systems. Finally, we discuss chromosome territories that form within the nucleus, resulting in a complete picture of the multi-scale organization of the Drosophila genome.},
}
@article {pmid34034791,
year = {2021},
author = {Lee, DI and Roy, S},
title = {GRiNCH: simultaneous smoothing and detection of topological units of genome organization from sparse chromatin contact count matrices with matrix factorization.},
journal = {Genome biology},
volume = {22},
number = {1},
pages = {164},
pmid = {34034791},
issn = {1474-760X},
support = {T15 LM007359/LM/NLM NIH HHS/United States ; R01 HG010045/HG/NHGRI NIH HHS/United States ; },
mesh = {*Algorithms ; Cell Line ; Chromatin/*genetics ; Chromosomes/genetics ; Databases, Genetic ; *Genome ; Histones/metabolism ; Humans ; Protein Processing, Post-Translational ; Regulatory Sequences, Nucleic Acid/genetics ; Time Factors ; },
abstract = {High-throughput chromosome conformation capture assays, such as Hi-C, have shown that the genome is organized into organizational units such as topologically associating domains (TADs), which can impact gene regulatory processes. The sparsity of Hi-C matrices poses a challenge for reliable detection of these units. We present GRiNCH, a constrained matrix-factorization-based approach for simultaneous smoothing and discovery of TADs from sparse contact count matrices. GRiNCH shows superior performance against seven TAD-calling methods and three smoothing methods. GRiNCH is applicable to multiple platforms including SPRITE and HiChIP and can predict novel boundary factors with potential roles in genome organization.},
}
@article {pmid34033138,
year = {2021},
author = {Kim, J and Kang, J and Kim, YW and Kim, A},
title = {The human β-globin enhancer LCR HS2 plays a role in forming a TAD by activating chromatin structure at neighboring CTCF sites.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {35},
number = {6},
pages = {e21669},
doi = {10.1096/fj.202002337R},
pmid = {34033138},
issn = {1530-6860},
mesh = {Binding Sites ; CCCTC-Binding Factor/genetics/*metabolism ; Chromatin/*chemistry/genetics/metabolism ; *Enhancer Elements, Genetic ; Humans ; Promoter Regions, Genetic ; *Transcription, Genetic ; *Transcriptional Activation ; beta-Globins/*genetics/metabolism ; },
abstract = {The human β-globin locus control region (LCR) hypersensitive site 2 (HS2) is one of enhancers for transcription of the β-like globin genes in erythroid cells. Our previous study showed that the LCR HS2 has active chromatin structure before transcriptional induction of the β-globin gene, while another enhancer LCR HS3 is activated by the induction. To compare functional difference between them, we deleted each HS (ΔHS2 and ΔHS3) from the human β-globin locus in hybrid MEL/ch11 cells. Deletion of either HS2 or HS3 dramatically diminished the β-globin transcription and disrupted locus-wide histone H3K27ac and chromatin interaction between LCR HSs and gene. Surprisingly, ΔHS2 weakened interactions between CTCF sites forming the β-globin topologically associating domain (TAD), while ΔHS3 did not. CTCF occupancy and chromatin accessibility were reduced at the CTCF sites in the ΔHS2 locus. To further characterize the HS2, we deleted the maf-recognition elements for erythroid activator NF-E2 at HS2. This deletion decreased the β-globin transcription and enhancer-promoter interaction, but did not affect interactions between CTCF sites for the TAD. In light of these results, we propose that the HS2 has a role in forming a β-globin TAD by activating neighboring CTCF sites and this role is beyond typical enhancer activity.},
}
@article {pmid34030950,
year = {2022},
author = {Ulianov, SV and Razin, SV},
title = {The two waves in single-cell 3D genomics.},
journal = {Seminars in cell &amp; developmental biology},
volume = {121},
number = {},
pages = {143-152},
doi = {10.1016/j.semcdb.2021.05.021},
pmid = {34030950},
issn = {1096-3634},
mesh = {Genomics/*methods ; Humans ; Single-Cell Analysis/*methods ; },
abstract = {For decades, biochemical methods for the analysis of genome structure and function provided cell-population-averaged data that allowed general principles and tendencies to be disclosed. Microscopy-based studies, which immanently involve single-cell analysis, did not provide sufficient spatial resolution to investigate the particularly small details of 3D genome folding. Nevertheless, these studies demonstrated that mutual positions of chromosome territories within cell nuclei and individual genomic loci within chromosomal territories can vary significantly in individual cells. The development of new technologies in biochemistry and the advent of super-resolution microscopy in the last decade have made possible the full-scale study of 3D genome organization in individual cells. Maps of the 3D genome build based on C-data and super-resolution microscopy are highly consistent and, therefore, biologically relevant. The internal structures of individual chromosomes, loci, and topologically associating domains (TADs) are resolved as well as cell-cycle dynamics. 3D modeling allows one to investigate the physical mechanisms underlying genome folding. Finally, joint profiling of genome topology and epigenetic features will allow 3D genomics to handle complex cell-to-cell heterogeneity. In this review, we summarize the present state of studies into 3D genome organization in individual cells, analyze the technical problems of single-cell studies, and outline perspectives of 3D genomics.},
}
@article {pmid34019647,
year = {2021},
author = {Requena, F and Abdallah, HH and García, A and Nitschké, P and Romana, S and Malan, V and Rausell, A},
title = {CNVxplorer: a web tool to assist clinical interpretation of CNVs in rare disease patients.},
journal = {Nucleic acids research},
volume = {49},
number = {W1},
pages = {W93-W103},
pmid = {34019647},
issn = {1362-4962},
support = {/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Animals ; *DNA Copy Number Variations ; Gene Expression ; Genome, Human ; Humans ; Internet ; Mice, Knockout ; Phenotype ; Protein Interaction Mapping ; Rare Diseases/diagnosis/*genetics ; Regulatory Sequences, Nucleic Acid ; *Software ; },
abstract = {Copy Number Variants (CNVs) are an important cause of rare diseases. Array-based Comparative Genomic Hybridization tests yield a ∼12% diagnostic rate, with ∼8% of patients presenting CNVs of unknown significance. CNVs interpretation is particularly challenging on genomic regions outside of those overlapping with previously reported structural variants or disease-associated genes. Recent studies showed that a more comprehensive evaluation of CNV features, leveraging both coding and non-coding impacts, can significantly improve diagnostic rates. However, currently available CNV interpretation tools are mostly gene-centric or provide only non-interactive annotations difficult to assess in the clinical practice. Here, we present CNVxplorer, a web server suited for the functional assessment of CNVs in a clinical diagnostic setting. CNVxplorer mines a comprehensive set of clinical, genomic, and epigenomic features associated with CNVs. It provides sequence constraint metrics, impact on regulatory elements and topologically associating domains, as well as expression patterns. Analyses offered cover (a) agreement with patient phenotypes; (b) visualizations of associations among genes, regulatory elements and transcription factors; (c) enrichment on functional and pathway annotations and (d) co-occurrence of terms across PubMed publications related to the query CNVs. A flexible evaluation workflow allows dynamic re-interrogation in clinical sessions. CNVxplorer is publicly available at http://cnvxplorer.com.},
}
@article {pmid34009337,
year = {2021},
author = {Yuan, R and Zhang, J and Wang, Y and Zhu, X and Hu, S and Zeng, J and Liang, F and Tang, Q and Chen, Y and Chen, L and Zhu, W and Li, M and Mo, D},
title = {Reorganization of chromatin architecture during prenatal development of porcine skeletal muscle.},
journal = {DNA research : an international journal for rapid publication of reports on genes and genomes},
volume = {28},
number = {2},
pages = {},
pmid = {34009337},
issn = {1756-1663},
mesh = {Animals ; Chromatin/*metabolism ; Chromatin Assembly and Disassembly ; Chromatin Immunoprecipitation Sequencing ; Embryo, Mammalian/*metabolism ; Embryonic Development ; Female ; Gene Expression Regulation, Developmental ; *Muscle Development ; Muscle, Skeletal/*growth &amp; development/metabolism ; Sequence Analysis, RNA ; Sus scrofa/*genetics/growth &amp; development/metabolism ; *Transcriptome ; },
abstract = {Myofibres (primary and secondary myofibre) are the basic structure of muscle and the determinant of muscle mass. To explore the skeletal muscle developmental processes from primary myofibres to secondary myofibres in pigs, we conducted an integrative three-dimensional structure of genome and transcriptomic characterization of longissimus dorsi muscle of pig from primary myofibre formation stage [embryonic Day 35 (E35)] to secondary myofibre formation stage (E80). In the hierarchical genomic structure, we found that 11.43% of genome switched compartment A/B status, 14.53% of topologically associating domains are changed intradomain interactions (D-scores) and 2,730 genes with differential promoter-enhancer interactions and (or) enhancer activity from E35 to E80. The alterations of genome architecture were found to correlate with expression of genes that play significant roles in neuromuscular junction, embryonic morphogenesis, skeletal muscle development or metabolism, typically, NEFL, MuSK, SLN, Mef2D and GCK. Significantly, Sox6 and MATN2 play important roles in the process of primary to secondary myofibres formation and increase the regulatory potential score and genes expression in it. In brief, we reveal the genomic reorganization from E35 to E80 and construct genome-wide high-resolution interaction maps that provide a resource for studying long-range control of gene expression from E35 to E80.},
}
@article {pmid34002095,
year = {2021},
author = {Huang, H and Zhu, Q and Jussila, A and Han, Y and Bintu, B and Kern, C and Conte, M and Zhang, Y and Bianco, S and Chiariello, AM and Yu, M and Hu, R and Tastemel, M and Juric, I and Hu, M and Nicodemi, M and Zhuang, X and Ren, B},
title = {CTCF mediates dosage- and sequence-context-dependent transcriptional insulation by forming local chromatin domains.},
journal = {Nature genetics},
volume = {53},
number = {7},
pages = {1064-1074},
pmid = {34002095},
issn = {1546-1718},
support = {U54 DK107977/DK/NIDDK NIH HHS/United States ; UM1 HG011585/HG/NHGRI NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; K99 CA252020/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Binding Sites ; CCCTC-Binding Factor/chemistry/*genetics/*metabolism ; Chromatin/*genetics/*metabolism ; Enhancer Elements, Genetic ; *Gene Expression Regulation ; Humans ; Insulator Elements ; Mice ; Mouse Embryonic Stem Cells/metabolism ; Promoter Regions, Genetic ; Protein Binding ; *Transcription, Genetic ; },
abstract = {Insulators play a critical role in spatiotemporal gene regulation in animals. The evolutionarily conserved CCCTC-binding factor (CTCF) is required for insulator function in mammals, but not all of its binding sites act as insulators. Here we explore the sequence requirements of CTCF-mediated transcriptional insulation using a sensitive insulator reporter in mouse embryonic stem cells. We find that insulation potency depends on the number of CTCF-binding sites in tandem. Furthermore, CTCF-mediated insulation is dependent on upstream flanking sequences at its binding sites. CTCF-binding sites at topologically associating domain boundaries are more likely to function as insulators than those outside topologically associating domain boundaries, independently of binding strength. We demonstrate that insulators form local chromatin domain boundaries and weaken enhancer-promoter contacts. Taken together, our results provide genetic, molecular and structural evidence connecting chromatin topology to the action of insulators in the mammalian genome.},
}
@article {pmid33973633,
year = {2021},
author = {Wang, M and Li, J and Wang, P and Liu, F and Liu, Z and Zhao, G and Xu, Z and Pei, L and Grover, CE and Wendel, JF and Wang, K and Zhang, X},
title = {Comparative Genome Analyses Highlight Transposon-Mediated Genome Expansion and the Evolutionary Architecture of 3D Genomic Folding in Cotton.},
journal = {Molecular biology and evolution},
volume = {38},
number = {9},
pages = {3621-3636},
pmid = {33973633},
issn = {1537-1719},
mesh = {*DNA Transposable Elements/genetics ; Genome, Plant ; Genomics ; *Gossypium/genetics ; Synteny ; },
abstract = {Transposable element (TE) amplification has been recognized as a driving force mediating genome size expansion and evolution, but the consequences for shaping 3D genomic architecture remains largely unknown in plants. Here, we report reference-grade genome assemblies for three species of cotton ranging 3-fold in genome size, namely Gossypium rotundifolium (K2), G. arboreum (A2), and G. raimondii (D5), using Oxford Nanopore Technologies. Comparative genome analyses document the details of lineage-specific TE amplification contributing to the large genome size differences (K2, 2.44 Gb; A2, 1.62 Gb; D5, 750.19 Mb) and indicate relatively conserved gene content and synteny relationships among genomes. We found that approximately 17% of syntenic genes exhibit chromatin status change between active ("A") and inactive ("B") compartments, and TE amplification was associated with the increase of the proportion of A compartment in gene regions (∼7,000 genes) in K2 and A2 relative to D5. Only 42% of topologically associating domain (TAD) boundaries were conserved among the three genomes. Our data implicate recent amplification of TEs following the formation of lineage-specific TAD boundaries. This study sheds light on the role of transposon-mediated genome expansion in the evolution of higher-order chromatin structure in plants.},
}
@article {pmid33959385,
year = {2021},
author = {Maksimenko, OG and Fursenko, DV and Belova, EV and Georgiev, PG},
title = {CTCF As an Example of DNA-Binding Transcription Factors Containing Clusters of C2H2-Type Zinc Fingers.},
journal = {Acta naturae},
volume = {13},
number = {1},
pages = {31-46},
pmid = {33959385},
issn = {2075-8251},
abstract = {In mammals, most of the boundaries of topologically associating domains and all well-studied insulators are rich in binding sites for the CTCF protein. According to existing experimental data, CTCF is a key factor in the organization of the architecture of mammalian chromosomes. A characteristic feature of the CTCF is that the central part of the protein contains a cluster consisting of eleven domains of C2H2-type zinc fingers, five of which specifically bind to a long DNA sequence conserved in most animals. The class of transcription factors that carry a cluster of C2H2-type zinc fingers consisting of five or more domains (C2H2 proteins) is widely represented in all groups of animals. The functions of most C2H2 proteins still remain unknown. This review presents data on the structure and possible functions of these proteins, using the example of the vertebrate CTCF protein and several well- characterized C2H2 proteins in Drosophila and mammals.},
}
@article {pmid33927397,
year = {2021},
author = {Marinov, GK and Trevino, AE and Xiang, T and Kundaje, A and Grossman, AR and Greenleaf, WJ},
title = {Transcription-dependent domain-scale three-dimensional genome organization in the dinoflagellate Breviolum minutum.},
journal = {Nature genetics},
volume = {53},
number = {5},
pages = {613-617},
pmid = {33927397},
issn = {1546-1718},
support = {U01 HG009431/HG/NHGRI NIH HHS/United States ; R01 HG008140/HG/NHGRI NIH HHS/United States ; U19 AI057266/AI/NIAID NIH HHS/United States ; P50 HG007735/HG/NHGRI NIH HHS/United States ; DP2 GM123485/GM/NIGMS NIH HHS/United States ; UM1 HG009436/HG/NHGRI NIH HHS/United States ; UM1 HG009442/HG/NHGRI NIH HHS/United States ; },
mesh = {Dinoflagellida/*genetics ; *Genome ; Models, Genetic ; *Transcription, Genetic ; },
abstract = {Dinoflagellate chromosomes represent a unique evolutionary experiment, as they exist in a permanently condensed, liquid crystalline state; are not packaged by histones; and contain genes organized into tandem gene arrays, with minimal transcriptional regulation. We analyze the three-dimensional genome of Breviolum minutum, and find large topological domains (dinoflagellate topologically associating domains, which we term 'dinoTADs') without chromatin loops, which are demarcated by convergent gene array boundaries. Transcriptional inhibition disrupts dinoTADs, implicating transcription-induced supercoiling as the primary topological force in dinoflagellates.},
}
@article {pmid33903158,
year = {2021},
author = {Bohrer, CH and Larson, DR},
title = {The Stochastic Genome and Its Role in Gene Expression.},
journal = {Cold Spring Harbor perspectives in biology},
volume = {13},
number = {10},
pages = {},
pmid = {33903158},
issn = {1943-0264},
mesh = {Animals ; *Gene Expression ; *Genome ; Mammals/*genetics ; Stochastic Processes ; },
abstract = {Mammalian genomes have distinct levels of spatial organization and structure that have been hypothesized to play important roles in transcription regulation. Although much has been learned about these architectural features with ensemble techniques, single-cell studies are showing a new universal trend: Genomes are stochastic and dynamic at every level of organization. Stochastic gene expression, on the other hand, has been studied for years. In this review, we probe whether there is a causative link between the two phenomena. We specifically discuss the functionality of chromatin state, topologically associating domains (TADs), and enhancer biology in light of their stochastic nature and their specific roles in stochastic gene expression. We highlight persistent fundamental questions in this area of research.},
}
@article {pmid33897976,
year = {2021},
author = {Du, G and Li, H and Ding, Y and Jiang, S and Hong, H and Gan, J and Wang, L and Yang, Y and Li, Y and Huang, X and Sun, Y and Tao, H and Li, Y and Xu, X and Zheng, Y and Wang, J and Bai, X and Xu, K and Li, Y and Jiang, Q and Li, C and Chen, H and Bo, X},
title = {The hierarchical folding dynamics of topologically associating domains are closely related to transcriptional abnormalities in cancers.},
journal = {Computational and structural biotechnology journal},
volume = {19},
number = {},
pages = {1684-1693},
pmid = {33897976},
issn = {2001-0370},
abstract = {Recent studies have shown that the three-dimensional (3D) structure of chromatin is associated with cancer progression. However, the roles of the 3D genome structure and its dynamics in cancer remains largely unknown. In this study, we investigated hierarchical topologically associating domain (TAD) structures in cancers and defined a "TAD hierarchical score (TH score)" for genes, which allowed us to assess the TAD nesting level of all genes in a simplified way. We demonstrated that the TAD nesting levels of genes in a tumor differ from those in normal tissue. Furthermore, the hierarchical TAD level dynamics were related to transcriptional changes in cancer, and some of the genes in which the hierarchical level was altered were significantly related to the prognosis of cancer patients. Overall, the results of this study suggest that the folding dynamics of TADs are closely related to transcriptional abnormalities in cancers, emphasizing that the function of hierarchical chromatin organization goes beyond simple chromatin packaging efficiency.},
}
@article {pmid33880880,
year = {2021},
author = {Zamariolli, M and Burssed, B and Moysés-Oliveira, M and Colovati, M and Bellucco, FTDS and Dos Santos, LC and Alvarez Perez, AB and Bragagnolo, S and Melaragno, MI},
title = {Novel MYT1 variants expose the complexity of oculo-auriculo-vertebral spectrum genetic mechanisms.},
journal = {American journal of medical genetics. Part A},
volume = {185},
number = {7},
pages = {2056-2064},
doi = {10.1002/ajmg.a.62217},
pmid = {33880880},
issn = {1552-4833},
mesh = {Branchial Region/pathology ; Brazil/epidemiology ; DNA Copy Number Variations/genetics ; DNA-Binding Proteins/*genetics ; Female ; *Genetic Predisposition to Disease ; Goldenhar Syndrome/epidemiology/*genetics/pathology ; Humans ; Male ; Phenotype ; Polymorphism, Single Nucleotide/genetics ; Transcription Factors/*genetics ; },
abstract = {Oculo-auriculo-vertebral spectrum (OAVS) is a developmental disorder characterized by anomalies mainly involving the structures derived from the first and second pharyngeal arches. The spectrum presents with heterogeneous clinical features and complex etiology with genetic factors not yet completely understood. To date, MYT1 is the most important gene unambiguously associated with the spectrum and with functional data confirmation. In this work, we aimed to identify new single nucleotide variants (SNVs) affecting MYT1 in a cohort of 73 Brazilian patients diagnosed with OAVS. In addition, we investigated copy number variations (CNVs) encompassing this gene or its cis-regulatory elements and compared the frequency of these events in patients versus a cohort of 455 Brazilian control individuals. A new SNV, predicted as likely deleterious, was identified in five unrelated patients with OAVS. All five patients presented hearing impairment and orbital asymmetry suggesting an association with the variant. CNVs near MYT1, located in its neighboring topologically associating domain (TAD), were found to be enriched in patients when compared to controls, indicating a possible involvement of this region with OAVS pathogenicity. Our findings highlight the genetic complexity of the spectrum that seems to involve more than one variant type and inheritance patterns.},
}
@article {pmid33850120,
year = {2021},
author = {Zhao, Y and Hou, Y and Xu, Y and Luan, Y and Zhou, H and Qi, X and Hu, M and Wang, D and Wang, Z and Fu, Y and Li, J and Zhang, S and Chen, J and Han, J and Li, X and Zhao, S},
title = {A compendium and comparative epigenomics analysis of cis-regulatory elements in the pig genome.},
journal = {Nature communications},
volume = {12},
number = {1},
pages = {2217},
pmid = {33850120},
issn = {2041-1723},
mesh = {Animals ; Chromatin Immunoprecipitation Sequencing ; Epigenesis, Genetic ; *Epigenomics ; Gene Expression ; Genome ; Genome, Human ; HEK293 Cells ; Humans ; Mice ; RNA-Seq ; Receptors, G-Protein-Coupled/metabolism ; *Regulatory Sequences, Nucleic Acid ; Swine/*genetics ; Transcriptome ; },
abstract = {Although major advances in genomics have initiated an exciting new era of research, a lack of information regarding cis-regulatory elements has limited the genetic improvement or manipulation of pigs as a meat source and biomedical model. Here, we systematically characterize cis-regulatory elements and their functions in 12 diverse tissues from four pig breeds by adopting similar strategies as the ENCODE and Roadmap Epigenomics projects, which include RNA-seq, ATAC-seq, and ChIP-seq. In total, we generate 199 datasets and identify more than 220,000 cis-regulatory elements in the pig genome. Surprisingly, we find higher conservation of cis-regulatory elements between human and pig genomes than those between human and mouse genomes. Furthermore, the differences of topologically associating domains between the pig and human genomes are associated with morphological evolution of the head and face. Beyond generating a major new benchmark resource for pig epigenetics, our study provides basic comparative epigenetic data relevant to using pigs as models in human biomedical research.},
}
@article {pmid33841414,
year = {2021},
author = {Majumder, K and Morales, AJ},
title = {Utilization of Host Cell Chromosome Conformation by Viral Pathogens: Knowing When to Hold and When to Fold.},
journal = {Frontiers in immunology},
volume = {12},
number = {},
pages = {633762},
pmid = {33841414},
issn = {1664-3224},
support = {F32 AI131468/AI/NIAID NIH HHS/United States ; K99 AI148511/AI/NIAID NIH HHS/United States ; },
mesh = {Animals ; Cell Transformation, Viral ; *Chromosomes, Human ; DNA, Viral/*genetics ; Epigenesis, Genetic ; Gammaherpesvirinae/*genetics/pathogenicity ; Gene Expression Regulation, Viral ; *Genome, Viral ; Herpesviridae Infections/genetics/*virology ; Host-Pathogen Interactions ; Humans ; Nucleic Acid Conformation ; Tumor Virus Infections/genetics/*virology ; *Virus Integration ; Virus Internalization ; Virus Latency ; Virus Replication ; },
abstract = {Though viruses have their own genomes, many depend on the nuclear environment of their hosts for replication and survival. A substantial body of work has therefore been devoted to understanding how viral and eukaryotic genomes interact. Recent advances in chromosome conformation capture technologies have provided unprecedented opportunities to visualize how mammalian genomes are organized and, by extension, how packaging of nuclear DNA impacts cellular processes. Recent studies have indicated that some viruses, upon entry into host cell nuclei, produce factors that alter host chromatin topology, and thus, impact the 3D organization of the host genome. Additionally, a variety of distinct viruses utilize host genome architectural factors to advance various aspects of their life cycles. Indeed, human gammaherpesviruses, known for establishing long-term reservoirs of latent infection in B lymphocytes, utilize 3D principles of genome folding to package their DNA and establish latency in host cells. This manipulation of host epigenetic machinery by latent viral genomes is etiologically linked to the onset of B cell oncogenesis. Small DNA viruses, by contrast, are tethered to distinct cellular sites that support virus expression and replication. Here, we briefly review the recent findings on how viruses and host genomes spatially communicate, and how this impacts virus-induced pathology.},
}
@article {pmid33838653,
year = {2021},
author = {Xing, H and Wu, Y and Zhang, MQ and Chen, Y},
title = {Deciphering hierarchical organization of topologically associated domains through change-point testing.},
journal = {BMC bioinformatics},
volume = {22},
number = {1},
pages = {183},
pmid = {33838653},
issn = {1471-2105},
support = {R01MH109616/NH/NIH HHS/United States ; },
mesh = {Cell Nucleus ; *Chromatin/genetics ; *Chromosomes ; Computer Simulation ; Gene Expression Regulation ; Humans ; },
abstract = {BACKGROUND: The nucleus of eukaryotic cells spatially packages chromosomes into a hierarchical and distinct segregation that plays critical roles in maintaining transcription regulation. High-throughput methods of chromosome conformation capture, such as Hi-C, have revealed topologically associating domains (TADs) that are defined by biased chromatin interactions within them.<br><br>RESULTS: We introduce a novel method, HiCKey, to decipher hierarchical TAD structures in Hi-C data and compare them across samples. We first derive a generalized likelihood-ratio (GLR) test for detecting change-points in an interaction matrix that follows a negative binomial distribution or general mixture distribution. We then employ several optimal search strategies to decipher hierarchical TADs with p values calculated by the GLR test. Large-scale validations of simulation data show that HiCKey has good precision in recalling known TADs and is robust against random collisions of chromatin interactions. By applying HiCKey to Hi-C data of seven human cell lines, we identified multiple layers of TAD organization among them, but the vast majority had no more than four layers. In particular, we found that TAD boundaries are significantly enriched in active chromosomal regions compared to repressed regions.<br><br>CONCLUSIONS: HiCKey is optimized for processing large matrices constructed from high-resolution Hi-C experiments. The method and theoretical result of the GLR test provide a general framework for significance testing of similar experimental chromatin interaction data that may not fully follow negative binomial distributions but rather more general mixture distributions.},
}
@article {pmid33816958,
year = {2020},
author = {Rozenwald, MB and Galitsyna, AA and Sapunov, GV and Khrameeva, EE and Gelfand, MS},
title = {A machine learning framework for the prediction of chromatin folding in Drosophila using epigenetic features.},
journal = {PeerJ. Computer science},
volume = {6},
number = {},
pages = {e307},
pmid = {33816958},
issn = {2376-5992},
abstract = {Technological advances have lead to the creation of large epigenetic datasets, including information about DNA binding proteins and DNA spatial structure. Hi-C experiments have revealed that chromosomes are subdivided into sets of self-interacting domains called Topologically Associating Domains (TADs). TADs are involved in the regulation of gene expression activity, but the mechanisms of their formation are not yet fully understood. Here, we focus on machine learning methods to characterize DNA folding patterns in Drosophila based on chromatin marks across three cell lines. We present linear regression models with four types of regularization, gradient boosting, and recurrent neural networks (RNN) as tools to study chromatin folding characteristics associated with TADs given epigenetic chromatin immunoprecipitation data. The bidirectional long short-term memory RNN architecture produced the best prediction scores and identified biologically relevant features. Distribution of protein Chriz (Chromator) and histone modification H3K4me3 were selected as the most informative features for the prediction of TADs characteristics. This approach may be adapted to any similar biological dataset of chromatin features across various cell lines and species. The code for the implemented pipeline, Hi-ChiP-ML, is publicly available: https://github.com/MichalRozenwald/Hi-ChIP-ML.},
}
@article {pmid33796120,
year = {2021},
author = {Miyazaki, K and Miyazaki, M},
title = {The Interplay Between Chromatin Architecture and Lineage-Specific Transcription Factors and the Regulation of Rag Gene Expression.},
journal = {Frontiers in immunology},
volume = {12},
number = {},
pages = {659761},
pmid = {33796120},
issn = {1664-3224},
mesh = {Adaptive Immunity/genetics/immunology ; Cell Lineage/genetics/*immunology ; Chromatin/genetics/*immunology/metabolism ; Chromatin Assembly and Disassembly/genetics/*immunology ; DNA-Binding Proteins/genetics/*immunology/metabolism ; Gene Expression Regulation/immunology ; Homeodomain Proteins/genetics/*immunology/metabolism ; Humans ; Nuclear Proteins/genetics/*immunology/metabolism ; Promoter Regions, Genetic/genetics ; Transcription Factors/genetics/*immunology/metabolism ; },
abstract = {Cell type-specific gene expression is driven through the interplay between lineage-specific transcription factors (TFs) and the chromatin architecture, such as topologically associating domains (TADs), and enhancer-promoter interactions. To elucidate the molecular mechanisms of the cell fate decisions and cell type-specific functions, it is important to understand the interplay between chromatin architectures and TFs. Among enhancers, super-enhancers (SEs) play key roles in establishing cell identity. Adaptive immunity depends on the RAG-mediated assembly of antigen recognition receptors. Hence, regulation of the Rag1 and Rag2 (Rag1/2) genes is a hallmark of adaptive lymphoid lineage commitment. Here, we review the current knowledge of 3D genome organization, SE formation, and Rag1/2 gene regulation during B cell and T cell differentiation.},
}
@article {pmid33795867,
year = {2021},
author = {Espinola, SM and Götz, M and Bellec, M and Messina, O and Fiche, JB and Houbron, C and Dejean, M and Reim, I and Cardozo Gizzi, AM and Lagha, M and Nollmann, M},
title = {Cis-regulatory chromatin loops arise before TADs and gene activation, and are independent of cell fate during early Drosophila development.},
journal = {Nature genetics},
volume = {53},
number = {4},
pages = {477-486},
pmid = {33795867},
issn = {1546-1718},
mesh = {Animals ; Cell Differentiation ; Cell Lineage/*genetics ; Chromatin/*chemistry/metabolism ; Drosophila Proteins/*genetics/metabolism ; Drosophila melanogaster/cytology/*genetics/growth &amp; development/metabolism ; Embryo, Nonmammalian ; Enhancer Elements, Genetic ; Gene Expression Profiling ; *Gene Expression Regulation, Developmental ; Genomics ; Nuclear Proteins/*genetics/metabolism ; Promoter Regions, Genetic ; Single-Cell Analysis ; Transcription Factors/classification/*genetics/metabolism ; Transcription, Genetic ; },
abstract = {Acquisition of cell fate is thought to rely on the specific interaction of remote cis-regulatory modules (CRMs), for example, enhancers and target promoters. However, the precise interplay between chromatin structure and gene expression is still unclear, particularly within multicellular developing organisms. In the present study, we employ Hi-M, a single-cell spatial genomics approach, to detect CRM-promoter looping interactions within topologically associating domains (TADs) during early Drosophila development. By comparing cis-regulatory loops in alternate cell types, we show that physical proximity does not necessarily instruct transcriptional states. Moreover, multi-way analyses reveal that multiple CRMs spatially coalesce to form hubs. Loops and CRM hubs are established early during development, before the emergence of TADs. Moreover, CRM hubs are formed, in part, via the action of the pioneer transcription factor Zelda and precede transcriptional activation. Our approach provides insight into the role of CRM-promoter interactions in defining transcriptional states, as well as distinct cell types.},
}
@article {pmid33767413,
year = {2021},
author = {Davidson, IF and Peters, JM},
title = {Genome folding through loop extrusion by SMC complexes.},
journal = {Nature reviews. Molecular cell biology},
volume = {22},
number = {7},
pages = {445-464},
pmid = {33767413},
issn = {1471-0080},
mesh = {Adenosine Triphosphatases/chemistry/metabolism ; Animals ; Cell Cycle Proteins/chemistry/metabolism ; Chromatin/chemistry/metabolism ; Chromosomal Proteins, Non-Histone/chemistry/*metabolism ; DNA/*chemistry/metabolism ; DNA-Binding Proteins/chemistry/metabolism ; *Genome ; Humans ; Models, Biological ; Multiprotein Complexes/chemistry/metabolism ; Nucleic Acid Conformation ; },
abstract = {Genomic DNA is folded into loops and topologically associating domains (TADs), which serve important structural and regulatory roles. It has been proposed that these genomic structures are formed by a loop extrusion process, which is mediated by structural maintenance of chromosomes (SMC) protein complexes. Recent single-molecule studies have shown that the SMC complexes condensin and cohesin are indeed able to extrude DNA into loops. In this Review, we discuss how the loop extrusion hypothesis can explain key features of genome architecture; cellular functions of loop extrusion, such as separation of replicated DNA molecules, facilitation of enhancer-promoter interactions and immunoglobulin gene recombination; and what is known about the mechanism of loop extrusion and its regulation, for example, by chromatin boundaries that depend on the DNA binding protein CTCF. We also discuss how the loop extrusion hypothesis has led to a paradigm shift in our understanding of both genome architecture and the functions of SMC complexes.},
}
@article {pmid33761883,
year = {2021},
author = {Goldfarb, CN and Waxman, DJ},
title = {Global analysis of expression, maturation and subcellular localization of mouse liver transcriptome identifies novel sex-biased and TCPOBOP-responsive long non-coding RNAs.},
journal = {BMC genomics},
volume = {22},
number = {1},
pages = {212},
pmid = {33761883},
issn = {1471-2164},
support = {R01 DK121998/DK/NIDDK NIH HHS/United States ; R01 ES024421/ES/NIEHS NIH HHS/United States ; },
mesh = {Animals ; Constitutive Androstane Receptor ; Liver ; Mice ; Pyridines ; *RNA, Long Noncoding/genetics ; Transcriptome ; },
abstract = {BACKGROUND: While nuclear transcription and RNA processing and localization are well established for protein coding genes (PCGs), these processes are poorly understood for long non-coding (lnc)RNAs. Here, we characterize global patterns of transcript expression, maturation and localization for mouse liver RNA, including more than 15,000 lncRNAs. PolyA-selected liver RNA was isolated and sequenced from four subcellular fractions (chromatin, nucleoplasm, total nucleus, and cytoplasm), and from the chromatin-bound fraction without polyA selection.<br><br>RESULTS: Transcript processing, determined from normalized intronic to exonic sequence read density ratios, progressively increased for PCG transcripts in going from the chromatin-bound fraction to the nucleoplasm and then on to the cytoplasm. Transcript maturation was similar for lncRNAs in the chromatin fraction, but was significantly lower in the nucleoplasm and cytoplasm. LncRNA transcripts were 11-fold more likely to be significantly enriched in the nucleus than cytoplasm, and 100-fold more likely to be significantly chromatin-bound than nucleoplasmic. Sequencing chromatin-bound RNA greatly increased the sensitivity for detecting lowly expressed lncRNAs and enabled us to discover and localize hundreds of novel regulated liver lncRNAs, including lncRNAs showing sex-biased expression or responsiveness to TCPOBOP a xenobiotic agonist ligand of constitutive androstane receptor (Nr1i3).<br><br>CONCLUSIONS: Integration of our findings with prior studies and lncRNA annotations identified candidate regulatory lncRNAs for a variety of hepatic functions based on gene co-localization within topologically associating domains or transcription divergent or antisense to PCGs associated with pathways linked to hepatic physiology and disease.},
}
@article {pmid33750794,
year = {2021},
author = {Zhang, L and Zhao, J and Bi, H and Yang, X and Zhang, Z and Su, Y and Li, Z and Zhang, L and Sanderson, BJ and Liu, J and Ma, T},
title = {Bioinformatic analysis of chromatin organization and biased expression of duplicated genes between two poplars with a common whole-genome duplication.},
journal = {Horticulture research},
volume = {8},
number = {1},
pages = {62},
pmid = {33750794},
issn = {2662-6810},
abstract = {The nonrandom three-dimensional organization of chromatin plays an important role in the regulation of gene expression. However, it remains unclear whether this organization is conserved and whether it is involved in regulating gene expression during speciation after whole-genome duplication (WGD) in plants. In this study, high-resolution interaction maps were generated using high-throughput chromatin conformation capture (Hi-C) techniques for two poplar species, Populus euphratica and Populus alba var. pyramidalis, which diverged ~14 Mya after a common WGD. We examined the similarities and differences in the hierarchical chromatin organization between the two species, including A/B compartment regions and topologically associating domains (TADs), as well as in their DNA methylation and gene expression patterns. We found that chromatin status was strongly associated with epigenetic modifications and gene transcriptional activity, yet the conservation of hierarchical chromatin organization across the two species was low. The divergence of gene expression between WGD-derived paralogs was associated with the strength of chromatin interactions, and colocalized paralogs exhibited strong similarities in epigenetic modifications and expression levels. Thus, the spatial localization of duplicated genes is highly correlated with biased expression during the diploidization process. This study provides new insights into the evolution of chromatin organization and transcriptional regulation during the speciation process of poplars after WGD.},
}
@article {pmid33730165,
year = {2021},
author = {Wang, L and Jia, G and Jiang, X and Cao, S and Chen, ZJ and Song, Q},
title = {Altered chromatin architecture and gene expression during polyploidization and domestication of soybean.},
journal = {The Plant cell},
volume = {33},
number = {5},
pages = {1430-1446},
pmid = {33730165},
issn = {1532-298X},
mesh = {Chromatin/*chemistry ; Chromosomes, Plant/genetics ; Diploidy ; *Domestication ; Gene Duplication ; *Gene Expression Regulation, Plant ; Genome, Plant ; Phaseolus/genetics ; *Polyploidy ; Soybeans/anatomy &amp; histology/*genetics ; },
abstract = {Polyploidy or whole-genome duplication (WGD) is widespread in plants and is a key driver of evolution and speciation, accompanied by rapid and dynamic changes in genomic structure and gene expression. The 3D structure of the genome is intricately linked to gene expression, but its role in transcription regulation following polyploidy and domestication remains unclear. Here, we generated high-resolution (∼2 kb) Hi-C maps for cultivated soybean (Glycine max), wild soybean (Glycine soja), and common bean (Phaseolus vulgaris). We found polyploidization in soybean may induce architecture changes of topologically associating domains and subsequent diploidization led to chromatin topology alteration around chromosome-rearrangement sites. Compared with single-copy and small-scale duplicated genes, WGD genes displayed more long-range chromosomal interactions and were coupled with higher levels of gene expression and chromatin accessibilities but void of DNA methylation. Interestingly, chromatin loop reorganization was involved in expression divergence of the genes during soybean domestication. Genes with chromatin loops were under stronger artificial selection than genes without loops. These findings provide insights into the roles of dynamic chromatin structures on gene expression during polyploidization, diploidization, and domestication of soybean.},
}
@article {pmid33720766,
year = {2021},
author = {Soto, C and Bryner, D and Neretti, N and Srivastava, A},
title = {Toward a Three-Dimensional Chromosome Shape Alphabet.},
journal = {Journal of computational biology : a journal of computational molecular cell biology},
volume = {28},
number = {6},
pages = {601-618},
pmid = {33720766},
issn = {1557-8666},
support = {R01 GM126558/GM/NIGMS NIH HHS/United States ; U01 CA200147/CA/NCI NIH HHS/United States ; R01 AG050582/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; Chromosome Structures ; Chromosomes/chemistry/*genetics ; Computational Biology/*methods ; Humans ; },
abstract = {The study of the three-dimensional (3D) structure of chromosomes-the largest macromolecules in biology-is one of the most challenging to date in structural biology. Here, we develop a novel representation of 3D chromosome structures, as sequences of shape letters from a finite shape alphabet, which provides a compact and efficient way to analyze ensembles of chromosome shape data, akin to the analysis of texts in a language by using letters. We construct a Chromosome Shape Alphabet from an ensemble of chromosome 3D structures inferred from Hi-C data-via SIMBA3D or other methods-by segmenting curves based on topologically associating domains (TADs) boundaries, and by clustering all TADs' 3D structures into groups of similar shapes. The median shapes of these groups, with some pruning and processing, form the Chromosome Shape Letters (CSLs) of the alphabet. We provide a proof of concept for these CSLs by reconstructing independent test curves by using only CSLs (and corresponding transformations) and comparing these reconstructions with the original curves. Finally, we demonstrate how CSLs can be used to summarize shapes in an ensemble of chromosome 3D structures by using generalized sequence logos.},
}
@article {pmid33677565,
year = {2021},
author = {Tian, L and Ku, L and Yuan, Z and Wang, C and Su, H and Wang, S and Song, X and Dou, D and Ren, Z and Lai, J and Liu, T and Du, C and Chen, Y},
title = {Large-scale reconstruction of chromatin structures of maize temperate and tropical inbred lines.},
journal = {Journal of experimental botany},
volume = {72},
number = {10},
pages = {3582-3596},
doi = {10.1093/jxb/erab087},
pmid = {33677565},
issn = {1460-2431},
mesh = {*Chromatin ; Epigenesis, Genetic ; Genome ; Genomics ; *Zea mays/genetics ; },
abstract = {Maize is a model plant species often used for genetics and genomics research because of its genetic diversity. There are prominent morphological, genetic, and epigenetic variations between tropical and temperate maize lines. However, the genome-wide chromatin conformations of these two maize types remain unexplored. We applied a Hi-C approach to compare the genome-wide chromatin interactions between temperate inbred line D132 and tropical line CML288. A reconstructed maize three-dimensional genome model revealed the spatial segregation of the global A and B compartments. The A compartments contain enriched genes and active epigenome marks, whereas the B compartments are gene-poor, transcriptionally silent chromatin regions. Whole-genome analyses indicated that the global A compartment content of CML288 was 3.12% lower than that of D132. Additionally, global and A/B sub-compartments were associated with differential gene expression and epigenetic changes between two inbred lines. About 25.3% of topologically associating domains (TADs) were determined to be associated with complex domain-level modifications that induced transcriptional changes, indicative of a large-scale reorganization of chromatin structures between the inbred maize lines. Furthermore, differences in chromatin interactions between the two lines correlated with epigenetic changes. These findings provide a solid foundation for the wider plant community to further investigate the genome-wide chromatin structures in other plant species.},
}
@article {pmid33631432,
year = {2022},
author = {Liu, X and Sun, Q and Wang, Q and Hu, C and Chen, X and Li, H and Czajkowsky, DM and Shao, Z},
title = {Epithelial Cells in 2D and 3D Cultures Exhibit Large Differences in Higher-order Genomic Interactions.},
journal = {Genomics, proteomics &amp; bioinformatics},
volume = {20},
number = {1},
pages = {101-109},
pmid = {33631432},
issn = {2210-3244},
mesh = {Animals ; Cell Line ; Chromatin ; Epithelial Cells ; Gene Expression Regulation ; *Genome ; *Genomics ; Mice ; },
abstract = {Recent studies have characterized the genomic structures of many eukaryotic cells, often focusing on their relation to gene expression. However, these studies have largely investigated cells grown in 2D cultures, although the transcriptomes of 3D-cultured cells are generally closer to their in vivo phenotypes. To examine the effects of spatial constraints on chromosome conformation, we investigated the genomic architecture of mouse hepatocytes grown in 2D and 3D cultures using in situ Hi-C. Our results reveal significant differences in higher-order genomic interactions, notably in compartment identity and strength as well as in topologically associating domain (TAD)-TAD interactions, but only minor differences are found at the TAD level. Our RNA-seq analysis reveals an up-regulated expression of genes involved in physiological hepatocyte functions in the 3D-cultured cells. These genes are associated with a subset of structural changes, suggesting that differences in genomic structure are critically important for transcriptional regulation. However, there are also many structural differences that are not directly associated with changes in gene expression, whose cause remains to be determined. Overall, our results indicate that growth in 3D significantly alters higher-order genomic interactions, which may be consequential for a subset of genes that are important for the physiological functioning of the cell.},
}
@article {pmid33597753,
year = {2021},
author = {Arnould, C and Rocher, V and Finoux, AL and Clouaire, T and Li, K and Zhou, F and Caron, P and Mangeot, PE and Ricci, EP and Mourad, R and Haber, JE and Noordermeer, D and Legube, G},
title = {Loop extrusion as a mechanism for formation of DNA damage repair foci.},
journal = {Nature},
volume = {590},
number = {7847},
pages = {660-665},
pmid = {33597753},
issn = {1476-4687},
support = {647344/ERC_/European Research Council/International ; R35 GM127029/GM/NIGMS NIH HHS/United States ; T32 GM007122/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Cycle Proteins/metabolism ; Cell Line ; Chromosomal Proteins, Non-Histone/metabolism ; DNA/*chemistry/genetics/*metabolism ; *DNA Breaks, Double-Stranded ; *DNA Repair ; Genome/genetics ; Histones/metabolism ; Humans ; *Nucleic Acid Conformation ; Nucleosomes/chemistry/genetics/metabolism ; Phosphorylation ; *Saccharomyces cerevisiae/cytology/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Tumor Suppressor p53-Binding Protein 1/metabolism ; },
abstract = {The repair of DNA double-strand breaks (DSBs) is essential for safeguarding genome integrity. When a DSB forms, the PI3K-related ATM kinase rapidly triggers the establishment of megabase-sized, chromatin domains decorated with phosphorylated histone H2AX (γH2AX), which act as seeds for the formation of DNA-damage response foci[1]. It is unclear how these foci are rapidly assembled to establish a 'repair-prone' environment within the nucleus. Topologically associating domains are a key feature of 3D genome organization that compartmentalize transcription and replication, but little is known about their contribution to DNA repair processes[2,3]. Here we show that topologically associating domains are functional units of the DNA damage response, and are instrumental for the correct establishment of γH2AX-53BP1 chromatin domains in a manner that involves one-sided cohesin-mediated loop extrusion on both sides of the DSB. We propose a model in which H2AX-containing nucleosomes are rapidly phosphorylated as they actively pass by DSB-anchored cohesin. Our work highlights the importance of chromosome conformation in the maintenance of genome integrity and demonstrates the establishment of a chromatin modification by loop extrusion.},
}
@article {pmid33591308,
year = {2021},
author = {Li, D and Sun, X and Yu, F and Perle, MA and Araten, D and Boeke, JD},
title = {Application of counter-selectable marker PIGA in engineering designer deletion cell lines and characterization of CRISPR deletion efficiency.},
journal = {Nucleic acids research},
volume = {49},
number = {5},
pages = {2642-2654},
pmid = {33591308},
issn = {1362-4962},
support = {P01 AG051449/AG/NIA NIH HHS/United States ; RM1 HG009491/HG/NHGRI NIH HHS/United States ; P50 GM107632/GM/NIGMS NIH HHS/United States ; },
mesh = {Bacterial Toxins/toxicity ; *CRISPR-Cas Systems ; *Cell Engineering ; Cell Line ; Chromosomes, Human, X ; Genetic Markers ; Heterozygote ; Humans ; Membrane Proteins/*genetics ; Mutation ; N-Acetylglucosaminyltransferases/genetics ; Pore Forming Cytotoxic Proteins/toxicity ; RNA/genetics ; *Sequence Deletion ; },
abstract = {The CRISPR/Cas9 system is a technology for genome engineering, which has been applied to indel mutations in genes as well as targeted gene deletion and replacement. Here, we describe paired gRNA deletions along the PIGA locus on the human X chromosome ranging from 17 kb to 2 Mb. We found no compelling linear correlation between deletion size and the deletion efficiency, and there is no substantial impact of topologically associating domains on deletion frequency. Using this precise deletion technique, we have engineered a series of designer deletion cell lines, including one with deletions of two X-chromosomal counterselectable (negative selection) markers, PIGA and HPRT1, and additional cell lines bearing each individual deletion. PIGA encodes a component of the glycosylphosphatidylinositol (GPI) anchor biosynthetic apparatus. The PIGA gene counterselectable marker has unique features, including existing single cell level assays for both function and loss of function of PIGA and the existence of a potent counterselectable agent, proaerolysin, which we use routinely for selection against cells expressing PIGA. These designer cell lines may serve as a general platform with multiple selection markers and may be particularly useful for large scale genome engineering projects such as Genome Project-Write (GP-write).},
}
@article {pmid33573880,
year = {2021},
author = {Zheng, W and Yang, Z and Ge, X and Feng, Y and Wang, Y and Liu, C and Luan, Y and Cai, K and Vakal, S and You, F and Guo, W and Wang, W and Feng, Z and Li, F},
title = {Freeze substitution Hi-C, a convenient and cost-effective method for capturing the natural 3D chromatin conformation from frozen samples.},
journal = {Journal of genetics and genomics = Yi chuan xue bao},
volume = {48},
number = {3},
pages = {237-247},
doi = {10.1016/j.jgg.2020.11.002},
pmid = {33573880},
issn = {1673-8527},
mesh = {Animals ; Cost-Benefit Analysis ; *Drosophila melanogaster ; Freeze Substitution ; },
abstract = {Chromatin interactions functionally affect genome architecture and gene regulation, but to date, only fresh samples must be used in High-through chromosome conformation capture (Hi-C) to keep natural chromatin conformation intact. This requirement has impeded the advancement of 3D genome research by limiting sample collection and storage options for researchers and severely limiting the number of samples that can be processed in a short time. Here, we develop a freeze substitution Hi-C (FS-Hi-C) technique that overcomes the need for fresh samples. FS-Hi-C can be used with samples stored in liquid nitrogen (LN2): the water in a vitreous form in the sample cells is replaced with ethanol via automated freeze substitution. After confirming that the FS step preserves the natural chromosome conformation during sample thawing, we tested the performance of FS-Hi-C with Drosophila melanogaster and Gossypium hirsutum. Beyond allowing the use of frozen samples and confirming that FS-Hi-C delivers robust data for generating contact heat maps and delineating A/B compartments and topologically associating domains, we found that FS-Hi-C outperforms the in situ Hi-C in terms of library quality, reproducibility, and valid interactions. Thus, FS-Hi-C will probably extend the application of 3D genome structure analysis to the vast number of experimental contexts in biological and medical research for which Hi-C methods have been unfeasible to date.},
}
@article {pmid33563719,
year = {2021},
author = {Liao, Y and Zhang, X and Chakraborty, M and Emerson, JJ},
title = {Topologically associating domains and their role in the evolution of genome structure and function in Drosophila.},
journal = {Genome research},
volume = {31},
number = {3},
pages = {397-410},
pmid = {33563719},
issn = {1549-5469},
support = {K99 GM129411/GM/NIGMS NIH HHS/United States ; R01 GM123303/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Chromatin/*chemistry/*genetics ; Drosophila/*classification/*genetics ; Drosophila melanogaster/genetics ; *Evolution, Molecular ; Female ; Genome, Insect/*genetics ; Genomics ; Male ; },
abstract = {Topologically associating domains (TADs) were recently identified as fundamental units of three-dimensional eukaryotic genomic organization, although our knowledge of the influence of TADs on genome evolution remains preliminary. To study the molecular evolution of TADs in Drosophila species, we constructed a new reference-grade genome assembly and accompanying high-resolution TAD map for D. pseudoobscura Comparison of D. pseudoobscura and D. melanogaster, which are separated by ∼49 million years of divergence, showed that ∼30%-40% of their genomes retain conserved TADs. Comparative genomic analysis of 17 Drosophila species revealed that chromosomal rearrangement breakpoints are enriched at TAD boundaries but depleted within TADs. Additionally, genes within conserved TADs show lower expression divergence than those located in nonconserved TADs. Furthermore, we found that a substantial proportion of long genes (>50 kbp) in D. melanogaster (42%) and D. pseudoobscura (26%) constitute their own TADs, implying transcript structure may be one of the deterministic factors for TAD formation. By using structural variants (SVs) identified from 14 D. melanogaster strains, its three closest sibling species from the D. simulans species complex, and two obscura clade species, we uncovered evidence of selection acting on SVs at TAD boundaries, but with the nature of selection differing between SV types. Deletions are depleted at TAD boundaries in both divergent and polymorphic SVs, suggesting purifying selection, whereas divergent tandem duplications are enriched at TAD boundaries relative to polymorphism, suggesting they are adaptive. Our findings highlight how important TADs are in shaping the acquisition and retention of structural mutations that fundamentally alter genome organization.},
}
@article {pmid33545030,
year = {2021},
author = {McArthur, E and Capra, JA},
title = {Topologically associating domain boundaries that are stable across diverse cell types are evolutionarily constrained and enriched for heritability.},
journal = {American journal of human genetics},
volume = {108},
number = {2},
pages = {269-283},
pmid = {33545030},
issn = {1537-6605},
support = {F30 HG011200/HG/NHGRI NIH HHS/United States ; R35 GM127087/GM/NIGMS NIH HHS/United States ; T32 GM007347/GM/NIGMS NIH HHS/United States ; },
mesh = {Cells, Cultured ; *Chromatin ; Embryonic Stem Cells ; *Evolution, Molecular ; Gene Expression Regulation ; *Genetic Variation ; *Genome, Human ; Genome-Wide Association Study ; Humans ; *Multifactorial Inheritance ; },
abstract = {Topologically associating domains (TADs) are fundamental units of three-dimensional (3D) nuclear organization. The regions bordering TADs-TAD boundaries-contribute to the regulation of gene expression by restricting interactions of cis-regulatory sequences to their target genes. TAD and TAD-boundary disruption have been implicated in rare-disease pathogenesis; however, we have a limited framework for integrating TADs and their variation across cell types into the interpretation of common-trait-associated variants. Here, we investigate an attribute of 3D genome architecture-the stability of TAD boundaries across cell types-and demonstrate its relevance to understanding how genetic variation in TADs contributes to complex disease. By synthesizing TAD maps across 37 diverse cell types with 41 genome-wide association studies (GWASs), we investigate the differences in disease association and evolutionary pressure on variation in TADs versus TAD boundaries. We demonstrate that genetic variation in TAD boundaries contributes more to complex-trait heritability, especially for immunologic, hematologic, and metabolic traits. We also show that TAD boundaries are more evolutionarily constrained than TADs. Next, stratifying boundaries by their stability across cell types, we find substantial variation. Compared to boundaries unique to a specific cell type, boundaries stable across cell types are further enriched for complex-trait heritability, evolutionary constraint, CTCF binding, and housekeeping genes. Thus, considering TAD boundary stability across cell types provides valuable context for understanding the genome's functional landscape and enabling variant interpretation that takes 3D structure into account.},
}
@article {pmid33542322,
year = {2021},
author = {Halsall, JA and Andrews, S and Krueger, F and Rutledge, CE and Ficz, G and Reik, W and Turner, BM},
title = {Histone modifications form a cell-type-specific chromosomal bar code that persists through the cell cycle.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {3009},
pmid = {33542322},
issn = {2045-2322},
support = {C1015/A13794/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Acetylation ; Cell Cycle ; Chromatin/genetics ; Chromosomes/*genetics ; *Epigenesis, Genetic ; HeLa Cells ; Histone Code/*genetics ; Histones/genetics ; Humans ; Lysine ; Methylation ; Mitosis/genetics ; Nucleosomes/genetics ; Protein Processing, Post-Translational/*genetics ; },
abstract = {Chromatin configuration influences gene expression in eukaryotes at multiple levels, from individual nucleosomes to chromatin domains several Mb long. Post-translational modifications (PTM) of core histones seem to be involved in chromatin structural transitions, but how remains unclear. To explore this, we used ChIP-seq and two cell types, HeLa and lymphoblastoid (LCL), to define how changes in chromatin packaging through the cell cycle influence the distributions of three transcription-associated histone modifications, H3K9ac, H3K4me3 and H3K27me3. We show that chromosome regions (bands) of 10-50 Mb, detectable by immunofluorescence microscopy of metaphase (M) chromosomes, are also present in G1 and G2. They comprise 1-5 Mb sub-bands that differ between HeLa and LCL but remain consistent through the cell cycle. The same sub-bands are defined by H3K9ac and H3K4me3, while H3K27me3 spreads more widely. We found little change between cell cycle phases, whether compared by 5 Kb rolling windows or when analysis was restricted to functional elements such as transcription start sites and topologically associating domains. Only a small number of genes showed cell-cycle related changes: at genes encoding proteins involved in mitosis, H3K9 became highly acetylated in G2M, possibly because of ongoing transcription. In conclusion, modified histone isoforms H3K9ac, H3K4me3 and H3K27me3 exhibit a characteristic genomic distribution at resolutions of 1 Mb and below that differs between HeLa and lymphoblastoid cells but remains remarkably consistent through the cell cycle. We suggest that this cell-type-specific chromosomal bar-code is part of a homeostatic mechanism by which cells retain their characteristic gene expression patterns, and hence their identity, through multiple mitoses.},
}
@article {pmid33526923,
year = {2021},
author = {Laffleur, B and Lim, J and Zhang, W and Chen, Y and Pefanis, E and Bizarro, J and Batista, CR and Wu, L and Economides, AN and Wang, J and Basu, U},
title = {Noncoding RNA processing by DIS3 regulates chromosomal architecture and somatic hypermutation in B cells.},
journal = {Nature genetics},
volume = {53},
number = {2},
pages = {230-242},
pmid = {33526923},
issn = {1546-1718},
support = {P30 CA013696/CA/NCI NIH HHS/United States ; R01 AI099195/AI/NIAID NIH HHS/United States ; R01 AI134988/AI/NIAID NIH HHS/United States ; R01 AI143897/AI/NIAID NIH HHS/United States ; },
mesh = {Animals ; B-Lymphocytes/drug effects/*physiology ; CCCTC-Binding Factor/genetics/metabolism ; Cell Cycle Proteins/genetics/metabolism ; Chromosomal Proteins, Non-Histone/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Embryonic Stem Cells/physiology ; Exosome Multienzyme Ribonuclease Complex/*genetics/metabolism ; Exosomes/genetics ; Green Fluorescent Proteins/genetics ; Mice, Knockout ; Mice, Transgenic ; Mutation ; RNA Processing, Post-Transcriptional ; RNA, Untranslated/*genetics ; Recombination, Genetic ; Somatic Hypermutation, Immunoglobulin/*physiology ; Tamoxifen/pharmacology ; },
abstract = {Noncoding RNAs are exquisitely titrated by the cellular RNA surveillance machinery for regulating diverse biological processes. The RNA exosome, the predominant 3' RNA exoribonuclease in mammalian cells, is composed of nine core and two catalytic subunits. Here, we developed a mouse model with a conditional allele to study the RNA exosome catalytic subunit DIS3. In DIS3-deficient B cells, integrity of the immunoglobulin heavy chain (Igh) locus in its topologically associating domain is affected, with accumulation of DNA-associated RNAs flanking CTCF-binding elements, decreased CTCF binding to CTCF-binding elements and disorganized cohesin localization. DIS3-deficient B cells also accumulate activation-induced cytidine deaminase-mediated asymmetric nicks, altering somatic hypermutation patterns and increasing microhomology-mediated end-joining DNA repair. Altered mutation patterns and Igh architectural defects in DIS3-deficient B cells lead to decreased class-switch recombination but increased chromosomal translocations. Our observations of DIS3-mediated architectural regulation at the Igh locus are reflected genome wide, thus providing evidence that noncoding RNA processing is an important mechanism for controlling genome organization.},
}
@article {pmid33523102,
year = {2021},
author = {Franzini, S and Di Stefano, M and Micheletti, C},
title = {essHi-C: Essential component analysis of Hi-C matrices.},
journal = {Bioinformatics (Oxford, England)},
volume = {},
number = {},
pages = {},
doi = {10.1093/bioinformatics/btab062},
pmid = {33523102},
issn = {1367-4811},
abstract = {MOTIVATION: Hi-C matrices are cornerstones for qualitative and quantitative studies of genome folding, from its territorial organization to compartments and topological domains. The high dynamic range of genomic distances probed in Hi-C assays reflects in an inherent stochastic background of the interactions matrices, which inevitably convolve the features of interest with largely non-specific ones.<br><br>RESULTS: Here we introduce and discuss essHi-C, a method to isolate the specific, or essential component of Hi-C matrices from the non-specific portion of the spectrum that is compatible with random matrices. Systematic comparisons show that essHi-C improves the clarity of the interaction patterns, enhances the robustness against sequencing depth of topologically associating domains identification, allows the unsupervised clustering of experiments in different cell lines and recovers the cell-cycle phasing of single-cells based on Hi-C data. Thus, essHi-C provides means for isolating significant biological and physical features from Hi-C matrices.<br><br>AVAILABILITY: The essHi-C software package is available at: https://github.com/stefanofranzini/essHIC .<br><br>SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},
}
@article {pmid33512425,
year = {2021},
author = {Qi, Q and Cheng, L and Tang, X and He, Y and Li, Y and Yee, T and Shrestha, D and Feng, R and Xu, P and Zhou, X and Pruett-Miller, S and Hardison, RC and Weiss, MJ and Cheng, Y},
title = {Dynamic CTCF binding directly mediates interactions among cis-regulatory elements essential for hematopoiesis.},
journal = {Blood},
volume = {137},
number = {10},
pages = {1327-1339},
pmid = {33512425},
issn = {1528-0020},
support = {R24 DK106766/DK/NIDDK NIH HHS/United States ; R35 GM133614/GM/NIGMS NIH HHS/United States ; R56 DK065806/DK/NIDDK NIH HHS/United States ; },
mesh = {Binding Sites ; CCCTC-Binding Factor/*metabolism ; Cell Line ; Cells, Cultured ; Enhancer Elements, Genetic ; Erythroid Cells/cytology/metabolism ; *Erythropoiesis ; Humans ; Promoter Regions, Genetic ; Protein Binding ; RNA-Binding Proteins/genetics/metabolism ; *Regulatory Elements, Transcriptional ; Transcriptional Activation ; },
abstract = {While constitutive CCCTC-binding factor (CTCF)-binding sites are needed to maintain relatively invariant chromatin structures, such as topologically associating domains, the precise roles of CTCF to control cell-type-specific transcriptional regulation remain poorly explored. We examined CTCF occupancy in different types of primary blood cells derived from the same donor to elucidate a new role for CTCF in gene regulation during blood cell development. We identified dynamic, cell-type-specific binding sites for CTCF that colocalize with lineage-specific transcription factors. These dynamic sites are enriched for single-nucleotide polymorphisms that are associated with blood cell traits in different linages, and they coincide with the key regulatory elements governing hematopoiesis. CRISPR-Cas9-based perturbation experiments demonstrated that these dynamic CTCF-binding sites play a critical role in red blood cell development. Furthermore, precise deletion of CTCF-binding motifs in dynamic sites abolished interactions of erythroid genes, such as RBM38, with their associated enhancers and led to abnormal erythropoiesis. These results suggest a novel, cell-type-specific function for CTCF in which it may serve to facilitate interaction of distal regulatory emblements with target promoters. Our study of the dynamic, cell-type-specific binding and function of CTCF provides new insights into transcriptional regulation during hematopoiesis.},
}
@article {pmid33508230,
year = {2021},
author = {Luo, X and Liu, Y and Dang, D and Hu, T and Hou, Y and Meng, X and Zhang, F and Li, T and Wang, C and Li, M and Wu, H and Shen, Q and Hu, Y and Zeng, X and He, X and Yan, L and Zhang, S and Li, C and Su, B},
title = {3D Genome of macaque fetal brain reveals evolutionary innovations during primate corticogenesis.},
journal = {Cell},
volume = {184},
number = {3},
pages = {723-740.e21},
doi = {10.1016/j.cell.2021.01.001},
pmid = {33508230},
issn = {1097-4172},
mesh = {Animals ; Base Sequence ; Brain/*embryology ; Chromatin/metabolism ; DNA Transposable Elements/genetics ; Enhancer Elements, Genetic/genetics ; *Evolution, Molecular ; Fetus/*embryology ; Gene Expression Regulation, Developmental ; *Genome ; Humans ; Macaca mulatta ; Mice ; Organogenesis/*genetics ; Species Specificity ; Synteny/genetics ; Transcription Factors/metabolism ; },
abstract = {Elucidating the regulatory mechanisms of human brain evolution is essential to understanding human cognition and mental disorders. We generated multi-omics profiles and constructed a high-resolution map of 3D genome architecture of rhesus macaque during corticogenesis. By comparing the 3D genomes of human, macaque, and mouse brains, we identified many human-specific chromatin structure changes, including 499 topologically associating domains (TADs) and 1,266 chromatin loops. The human-specific loops are significantly enriched in enhancer-enhancer interactions, and the regulated genes show human-specific expression changes in the subplate, a transient zone of the developing brain critical for neural circuit formation and plasticity. Notably, many human-specific sequence changes are located in the human-specific TAD boundaries and loop anchors, which may generate new transcription factor binding sites and chromatin structures in human. Collectively, the presented data highlight the value of comparative 3D genome analyses in dissecting the regulatory mechanisms of brain development and evolution.},
}
@article {pmid33497970,
year = {2021},
author = {Cavalheiro, GR and Pollex, T and Furlong, EE},
title = {To loop or not to loop: what is the role of TADs in enhancer function and gene regulation?.},
journal = {Current opinion in genetics &amp; development},
volume = {67},
number = {},
pages = {119-129},
doi = {10.1016/j.gde.2020.12.015},
pmid = {33497970},
issn = {1879-0380},
mesh = {Animals ; Chromatin/genetics/*ultrastructure ; Chromatin Assembly and Disassembly/genetics ; Enhancer Elements, Genetic/*genetics ; Gene Expression Regulation/genetics ; Genome/*genetics ; Humans ; },
abstract = {The past decade has seen a huge jump in the resolution and scale at which we can interrogate the three-dimensional properties of the genome. This revealed different types of chromatin structures including topologically associating domains, partitioning genes and their enhancers into interacting domains. While the visualisation of these topologies and their dynamics has dramatically improved, our understanding of their underlying mechanisms and functional roles in gene expression has lagged behind. A suite of recent studies have addressed this using genetic manipulations to perturb topological features and loops at different scales. Here we assess the new biological insights gained on the functional relationship between genome topology and gene expression, with a particular focus on enhancer function.},
}
@article {pmid33497014,
year = {2021},
author = {Beccari, L and Jaquier, G and Lopez-Delisle, L and Rodriguez-Carballo, E and Mascrez, B and Gitto, S and Woltering, J and Duboule, D},
title = {Dbx2 regulation in limbs suggests interTAD sharing of enhancers.},
journal = {Developmental dynamics : an official publication of the American Association of Anatomists},
volume = {250},
number = {9},
pages = {1280-1299},
pmid = {33497014},
issn = {1097-0177},
mesh = {Animals ; Extremities ; *Gene Expression Regulation, Developmental ; *Genes, Homeobox ; Homeodomain Proteins/genetics/metabolism ; Limb Buds/metabolism ; Mammals/genetics/metabolism ; Transcription Factors/genetics/metabolism ; },
abstract = {BACKGROUND: During tetrapod limb development, the HOXA13 and HOXD13 transcription factors are critical for the emergence and organization of the autopod, the most distal aspect where digits will develop. Since previous work had suggested that the Dbx2 gene is a target of these factors, we set up to analyze in detail this potential regulatory interaction.<br><br>RESULTS: We show that HOX13 proteins bind to mammalian-specific sequences at the vicinity of the Dbx2 locus that have enhancer activity in developing digits. However, the functional inactivation of the DBX2 protein did not elicit any particular phenotype related to Hox genes inactivation in digits, suggesting either redundant or compensatory mechanisms. We report that the neighboring Nell2 and Ano6 genes are also expressed in distal limb buds and are in part controlled by the same Dbx2 enhancers despite being localized into two different topologically associating domains (TADs) flanking the Dbx2 locus.<br><br>CONCLUSIONS: We conclude that Hoxa13 and Hoxd genes cooperatively activate Dbx2 expression in developing digits through binding to mammalian specific regulatory sequences in the Dbx2 neighborhood. Furthermore, these enhancers can overcome TAD boundaries in either direction to co-regulate a set of genes located in distinct chromatin domains.},
}
@article {pmid33494803,
year = {2021},
author = {Zhang, YW and Wang, MB and Li, SC},
title = {SuperTAD: robust detection of hierarchical topologically associated domains with optimized structural information.},
journal = {Genome biology},
volume = {22},
number = {1},
pages = {45},
pmid = {33494803},
issn = {1474-760X},
mesh = {Algorithms ; Animals ; Cell Line ; Chromatin ; Epigenomics ; Gene Expression Regulation ; *Histone Code ; Histones ; Humans ; Software ; },
abstract = {Topologically associating domains (TADs) are the organizational units of chromosome structures. TADs can contain TADs, thus forming a hierarchy. TAD hierarchies can be inferred from Hi-C data through coding trees. However, the current method for computing coding trees is not optimal. In this paper, we propose optimal algorithms for this computation. In comparison with seven state-of-art methods using two public datasets, from GM12878 and IMR90 cells, SuperTAD shows a significant enrichment of structural proteins around detected boundaries and histone modifications within TADs and displays a high consistency between various resolutions of identical Hi-C matrices.},
}
@article {pmid33479238,
year = {2021},
author = {Madani Tonekaboni, SA and Haibe-Kains, B and Lupien, M},
title = {Large organized chromatin lysine domains help distinguish primitive from differentiated cell populations.},
journal = {Nature communications},
volume = {12},
number = {1},
pages = {499},
pmid = {33479238},
issn = {2041-1723},
support = {136963//CIHR/Canada ; 363288//CIHR/Canada ; },
mesh = {Animals ; Binding Sites/genetics ; Cell Differentiation/*genetics ; Chromatin/*genetics ; DNA Transposable Elements/genetics ; Enhancer Elements, Genetic/genetics ; Genome, Human/genetics ; Histone Code/*genetics ; Histones/*genetics ; Humans ; Lysine/*genetics ; Promoter Regions, Genetic/genetics ; },
abstract = {The human genome is partitioned into a collection of genomic features, inclusive of genes, transposable elements, lamina interacting regions, early replicating control elements and cis-regulatory elements, such as promoters, enhancers, and anchors of chromatin interactions. Uneven distribution of these features within chromosomes gives rise to clusters, such as topologically associating domains (TADs), lamina-associated domains, clusters of cis-regulatory elements or large organized chromatin lysine (K) domains (LOCKs). Here we show that LOCKs from diverse histone modifications discriminate primitive from differentiated cell types. Active LOCKs (H3K4me1, H3K4me3 and H3K27ac) cover a higher fraction of the genome in primitive compared to differentiated cell types while repressive LOCKs (H3K9me3, H3K27me3 and H3K36me3) do not. Active LOCKs in differentiated cells lie proximal to highly expressed genes while active LOCKs in primitive cells tend to be bivalent. Genes proximal to bivalent LOCKs are minimally expressed in primitive cells. Furthermore, bivalent LOCKs populate TAD boundaries and are preferentially bound by regulators of chromatin interactions, including CTCF, RAD21 and ZNF143. Together, our results argue that LOCKs discriminate primitive from differentiated cell populations.},
}
@article {pmid33456975,
year = {2020},
author = {Melnikova, LS and Georgiev, PG and Golovnin, AK},
title = {The Functions and Mechanisms of Action of Insulators in the Genomes of Higher Eukaryotes.},
journal = {Acta naturae},
volume = {12},
number = {4},
pages = {15-33},
pmid = {33456975},
issn = {2075-8251},
abstract = {The mechanisms underlying long-range interactions between chromatin regions and the principles of chromosomal architecture formation are currently under extensive scrutiny. A special class of regulatory elements known as insulators is believed to be involved in the regulation of specific long-range interactions between enhancers and promoters. This review focuses on the insulators of Drosophila and mammals, and it also briefly characterizes the proteins responsible for their functional activity. It was initially believed that the main properties of insulators are blocking of enhancers and the formation of independent transcription domains. We present experimental data proving that the chromatin loops formed by insulators play only an auxiliary role in enhancer blocking. The review also discusses the mechanisms involved in the formation of topologically associating domains and their role in the formation of the chromosomal architecture and regulation of gene transcription.},
}
@article {pmid33436846,
year = {2021},
author = {Bediaga, NG and Coughlan, HD and Johanson, TM and Garnham, AL and Naselli, G and Schröder, J and Fearnley, LG and Bandala-Sanchez, E and Allan, RS and Smyth, GK and Harrison, LC},
title = {Multi-level remodelling of chromatin underlying activation of human T cells.},
journal = {Scientific reports},
volume = {11},
number = {1},
pages = {528},
pmid = {33436846},
issn = {2045-2322},
mesh = {CD4-Positive T-Lymphocytes ; CD8-Positive T-Lymphocytes ; Cells, Cultured ; Chromatin/*chemistry/*genetics ; Chromatin Assembly and Disassembly/*genetics/*physiology ; Gene Expression Regulation, Developmental/*genetics ; Humans ; Lymphocyte Activation/*genetics ; Male ; Nucleosomes/genetics ; T-Lymphocytes/*immunology ; Transcription Factors ; Transcription, Genetic/genetics ; },
abstract = {Remodelling of chromatin architecture is known to regulate gene expression and has been well characterized in cell lineage development but less so in response to cell perturbation. Activation of T cells, which triggers extensive changes in transcriptional programs, serves as an instructive model to elucidate how changes in chromatin architecture orchestrate gene expression in response to cell perturbation. To characterize coordinate changes at different levels of chromatin architecture, we analyzed chromatin accessibility, chromosome conformation and gene expression in activated human T cells. T cell activation was characterized by widespread changes in chromatin accessibility and interactions that were shared between activated CD4[+] and CD8[+] T cells, and with the formation of active regulatory regions associated with transcription factors relevant to T cell biology. Chromatin interactions that increased and decreased were coupled, respectively, with up- and down-regulation of corresponding target genes. Furthermore, activation was associated with disruption of long-range chromatin interactions and with partitioning of topologically associating domains (TADs) and remodelling of their TAD boundaries. Newly formed/strengthened TAD boundaries were associated with higher nucleosome occupancy and lower accessibility, linking changes in lower and higher order chromatin architecture. T cell activation exemplifies coordinate multi-level remodelling of chromatin underlying gene transcription.},
}
@article {pmid33436383,
year = {2021},
author = {Ha, E and Bang, SY and Lim, J and Yun, JH and Kim, JM and Bae, JB and Lee, HS and Kim, BJ and Kim, K and Bae, SC},
title = {Genetic variants shape rheumatoid arthritis-specific transcriptomic features in CD4[+] T cells through differential DNA methylation, explaining a substantial proportion of heritability.},
journal = {Annals of the rheumatic diseases},
volume = {80},
number = {7},
pages = {876-883},
doi = {10.1136/annrheumdis-2020-219152},
pmid = {33436383},
issn = {1468-2060},
mesh = {Adult ; Aged ; Arthritis, Rheumatoid/*genetics/*immunology ; CD4-Positive T-Lymphocytes/*immunology ; DNA Methylation/*genetics/*immunology ; Female ; Genetic Variation ; Genome-Wide Association Study ; Humans ; Male ; Middle Aged ; Transcriptome ; },
abstract = {OBJECTIVE: CD4[+] T cells have been suggested as the most disease-relevant cell type in rheumatoid arthritis (RA) in which RA-risk non-coding variants exhibit allele-specific effects on regulation of RA-driving genes. This study aimed to understand RA-specific signatures in CD4[+] T cells using multi-omics data, interpreting inter-omics relationships in shaping the RA transcriptomic landscape.<br><br>METHODS: We profiled genome-wide variants, gene expression and DNA methylation in CD4[+] T cells from 82 patients with RA and 40 healthy controls using high-throughput technologies. We investigated differentially expressed genes (DEGs) and differential methylated regions (DMRs) in RA and localised quantitative trait loci (QTLs) for expression and methylation. We then integrated these based on individual-level correlations to inspect DEG-regulating sources and investigated the potential regulatory roles of RA-risk variants by a partitioned-heritability enrichment analysis with RA genome-wide association summary statistics.<br><br>RESULTS: A large number of RA-specific DEGs were identified (n=2575), highlighting T cell differentiation and activation pathways. RA-specific DMRs, preferentially located in T cell regulatory regions, were correlated with the expression levels of 548 DEGs mostly in the same topologically associating domains. In addition, expressional variances in 771 and 83 DEGs were partially explained by expression QTLs for DEGs and methylation QTLs (meQTLs) for DEG-correlated DMRs, respectively. A large number of RA variants were moderately to strongly correlated with meQTLs. DEG-correlated DMRs, enriched with meQTLs, had strongly enriched heritability of RA.<br><br>CONCLUSION: Our findings revealed that the methylomic changes, driven by RA heritability-explaining variants, shape the differential expression of a substantial fraction of DEGs in CD4[+] T cells in patients with RA, reinforcing the importance of a multidimensional approach in disease-relevant tissues.},
}
@article {pmid33422934,
year = {2021},
author = {Peters, JM},
title = {How DNA loop extrusion mediated by cohesin enables V(D)J recombination.},
journal = {Current opinion in cell biology},
volume = {70},
number = {},
pages = {75-83},
doi = {10.1016/j.ceb.2020.11.007},
pmid = {33422934},
issn = {1879-0410},
mesh = {Animals ; *Cell Cycle Proteins/genetics ; Chromatin ; *Chromosomal Proteins, Non-Histone/genetics ; Mice ; *V(D)J Recombination ; },
abstract = {'Structural maintenance of chromosomes' (SMC) complexes are required for the folding of genomic DNA into loops. Theoretical considerations and single-molecule experiments performed with the SMC complexes cohesin and condensin indicate that DNA folding occurs via loop extrusion. Recent work indicates that this process is essential for the assembly of antigen receptor genes by V(D)J recombination in developing B and T cells of the vertebrate immune system. Here, I review how recent studies of the mouse immunoglobulin heavy chain locus Igh have provided evidence for this hypothesis and how the formation of chromatin loops by cohesin and regulation of this process by CTCF and Wapl might ensure that all variable gene segments in this locus (VH segments) participate in recombination with a re-arranged DJH segment, to ensure generation of a maximally diverse repertoire of B-cell receptors and antibodies.},
}
@article {pmid33420075,
year = {2021},
author = {Sun, Q and Perez-Rathke, A and Czajkowsky, DM and Shao, Z and Liang, J},
title = {High-resolution single-cell 3D-models of chromatin ensembles during Drosophila embryogenesis.},
journal = {Nature communications},
volume = {12},
number = {1},
pages = {205},
pmid = {33420075},
issn = {2041-1723},
support = {R35 GM127084/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Biophysics ; Chromatin/*chemistry ; *Chromatin Assembly and Disassembly ; Chromosomes, Insect/chemistry/genetics ; Computational Biology ; Drosophila/*genetics ; *Embryonic Development ; Genetic Heterogeneity ; Genome ; Models, Molecular ; Molecular Conformation ; },
abstract = {Single-cell chromatin studies provide insights into how chromatin structure relates to functions of individual cells. However, balancing high-resolution and genome wide-coverage remains challenging. We describe a computational method for the reconstruction of large 3D-ensembles of single-cell (sc) chromatin conformations from population Hi-C that we apply to study embryogenesis in Drosophila. With minimal assumptions of physical properties and without adjustable parameters, our method generates large ensembles of chromatin conformations via deep-sampling. Our method identifies specific interactions, which constitute 5-6% of Hi-C frequencies, but surprisingly are sufficient to drive chromatin folding, giving rise to the observed Hi-C patterns. Modeled sc-chromatins quantify chromatin heterogeneity, revealing significant changes during embryogenesis. Furthermore, >50% of modeled sc-chromatin maintain topologically associating domains (TADs) in early embryos, when no population TADs are perceptible. Domain boundaries become fixated during development, with strong preference at binding-sites of insulator-complexes upon the midblastula transition. Overall, high-resolution 3D-ensembles of sc-chromatin conformations enable further in-depth interpretation of population Hi-C, improving understanding of the structure-function relationship of genome organization.},
}
@article {pmid33419466,
year = {2021},
author = {Jia, J and Xie, Y and Cheng, J and Kong, C and Wang, M and Gao, L and Zhao, F and Guo, J and Wang, K and Li, G and Cui, D and Hu, T and Zhao, G and Wang, D and Ru, Z and Zhang, Y},
title = {Homology-mediated inter-chromosomal interactions in hexaploid wheat lead to specific subgenome territories following polyploidization and introgression.},
journal = {Genome biology},
volume = {22},
number = {1},
pages = {26},
pmid = {33419466},
issn = {1474-760X},
mesh = {China ; Chromatin ; *Chromosomes, Plant ; DNA Transposable Elements ; Evolution, Molecular ; Genes, Plant/genetics ; *Genome, Plant ; Plant Breeding ; *Polyploidy ; Translocation, Genetic ; Triticum/*genetics ; },
abstract = {BACKGROUND: Polyploidization and introgression are major events driving plant genome evolution and influencing crop breeding. However, the mechanisms underlying the higher-order chromatin organization of subgenomes and alien chromosomes are largely unknown.<br><br>RESULTS: We probe the three-dimensional chromatin architecture of Aikang 58 (AK58), a widely cultivated allohexaploid wheat variety in China&#xa0;carrying the 1RS/1BL translocation chromosome. The regions involved in inter-chromosomal interactions, both within and between subgenomes, have highly similar sequences. Subgenome-specific territories tend to be connected by subgenome-dominant homologous transposable elements (TEs). The alien 1RS chromosomal arm, which was introgressed from rye and differs from its wheat counterpart, has relatively few inter-chromosome interactions with wheat chromosomes. An analysis of local chromatin structures reveals topologically associating domain (TAD)-like regions covering 52% of the AK58 genome, the boundaries of which are enriched with active genes, zinc-finger factor-binding motifs, CHH methylation, and 24-nt small RNAs. The chromatin loops are mostly localized around TAD boundaries, and the number of gene loops is positively associated with gene activity.<br><br>CONCLUSIONS: The present study reveals the impact of the genetic sequence context on the higher-order chromatin structure and subgenome stability in hexaploid wheat. Specifically, we characterized the sequence homology-mediated inter-chromosome interactions and the non-canonical role of subgenome-biased TEs. Our findings may have profound implications for future investigations of the interplay between genetic sequences and higher-order structures and their consequences on polyploid genome evolution and introgression-based breeding of crop plants.},
}
@article {pmid33414725,
year = {2020},
author = {Russo, R and Marra, R and Rosato, BE and Iolascon, A and Andolfo, I},
title = {Genetics and Genomics Approaches for Diagnosis and Research Into Hereditary Anemias.},
journal = {Frontiers in physiology},
volume = {11},
number = {},
pages = {613559},
pmid = {33414725},
issn = {1664-042X},
abstract = {The hereditary anemias are a relatively heterogeneous set of disorders that can show wide clinical and genetic heterogeneity, which often hampers correct clinical diagnosis. The classical diagnostic workflow for these conditions generally used to start with analysis of the family and personal histories, followed by biochemical and morphological evaluations, and ending with genetic testing. However, the diagnostic framework has changed more recently, and genetic testing is now a suitable approach for differential diagnosis of these patients. There are several approaches to this genetic testing, the choice of which depends on phenotyping, genetic heterogeneity, and gene size. For patients who show complete phenotyping, single-gene testing remains recommended. However, genetic analysis now includes next-generation sequencing, which is generally based on custom-designed targeting panels and whole-exome sequencing. The use of next-generation sequencing also allows the identification of new causative genes, and of polygenic conditions and genetic factors that modify disease severity of hereditary anemias. In the research field, whole-genome sequencing is useful for the identification of non-coding causative mutations, which might account for the disruption of transcriptional factor occupancy sites and cis-regulatory elements. Moreover, advances in high-throughput sequencing techniques have now resulted in the identification of genome-wide profiling of the chromatin structures known as the topologically associating domains. These represent a recurrent disease mechanism that exposes genes to inappropriate regulatory elements, causing errors in gene expression. This review focuses on the challenges of diagnosis and research into hereditary anemias, with indications of both the advantages and disadvantages. Finally, we consider the future perspectives for the use of next-generation sequencing technologies in this era of precision medicine.},
}
@article {pmid33407087,
year = {2021},
author = {Deschamps, S and Crow, JA and Chaidir, N and Peterson-Burch, B and Kumar, S and Lin, H and Zastrow-Hayes, G and May, GD},
title = {Chromatin loop anchors contain core structural components of the gene expression machinery in maize.},
journal = {BMC genomics},
volume = {22},
number = {1},
pages = {23},
pmid = {33407087},
issn = {1471-2164},
mesh = {*Chromatin/genetics ; Chromatin Assembly and Disassembly ; Gene Expression ; Genome, Plant ; *Zea mays/genetics ; },
abstract = {BACKGROUND: Three-dimensional chromatin loop structures connect regulatory elements to their target genes in regions known as anchors. In complex plant genomes, such as maize, it has been proposed that loops span heterochromatic regions marked by higher repeat content, but little is known on their spatial organization and genome-wide occurrence in relation to transcriptional activity.<br><br>RESULTS: Here, ultra-deep Hi-C sequencing of maize B73 leaf tissue was combined with gene expression and open chromatin sequencing for chromatin loop discovery and correlation with hierarchical topologically-associating domains (TADs) and transcriptional activity. A majority of all anchors are shared between multiple loops from previous public maize high-resolution interactome datasets, suggesting a highly dynamic environment, with a conserved set of anchors involved in multiple interaction networks. Chromatin loop interiors are marked by higher repeat contents than the anchors flanking them. A small fraction of high-resolution interaction anchors, fully embedded in larger chromatin loops, co-locate with active genes and putative protein-binding sites. Combinatorial analyses indicate that all anchors studied here co-locate with at least 81.5% of expressed genes and 74% of open chromatin regions. Approximately 38% of all Hi-C chromatin loops are fully embedded within hierarchical TAD-like domains, while the remaining ones share anchors with domain boundaries or with distinct domains. Those various loop types exhibit specific patterns of overlap for open chromatin regions and expressed genes, but no apparent pattern of gene expression. In addition, up to 63% of all unique variants derived from a prior public maize eQTL dataset overlap with Hi-C loop anchors. Anchor annotation suggests that <&#x2009;7% of all loops detected here are potentially devoid of any genes or regulatory elements. The overall organization of chromatin loop anchors in the maize genome suggest a loop modeling system hypothesized to resemble phase separation of repeat-rich regions.<br><br>CONCLUSIONS: Sets of conserved chromatin loop anchors mapping to hierarchical domains contains core structural components of the gene expression machinery in maize. The data presented here will be a useful reference to further investigate their function in regard to the formation of transcriptional complexes and the regulation of transcriptional activity in the maize genome.},
}
@article {pmid33398174,
year = {2021},
author = {Kubo, N and Ishii, H and Xiong, X and Bianco, S and Meitinger, F and Hu, R and Hocker, JD and Conte, M and Gorkin, D and Yu, M and Li, B and Dixon, JR and Hu, M and Nicodemi, M and Zhao, H and Ren, B},
title = {Promoter-proximal CTCF binding promotes distal enhancer-dependent gene activation.},
journal = {Nature structural &amp; molecular biology},
volume = {28},
number = {2},
pages = {152-161},
pmid = {33398174},
issn = {1545-9985},
support = {U54 DK107977/DK/NIDDK NIH HHS/United States ; T32 GM008666/GM/NIGMS NIH HHS/United States ; U54 DK107965/DK/NIDDK NIH HHS/United States ; UM1 HG011585/HG/NHGRI NIH HHS/United States ; T32 GM007198/GM/NIGMS NIH HHS/United States ; P30 CA014195/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Binding Sites ; CCCTC-Binding Factor/*metabolism ; Cell Line ; Chromatin/*metabolism ; Enhancer Elements, Genetic ; Gene Expression Regulation ; Mice ; Mouse Embryonic Stem Cells/cytology/*metabolism ; Neural Stem Cells/cytology/*metabolism ; Promoter Regions, Genetic ; Protein Binding ; Transcriptional Activation ; },
abstract = {The CCCTC-binding factor (CTCF) works together with the cohesin complex to drive the formation of chromatin loops and topologically associating domains, but its role in gene regulation has not been fully defined. Here, we investigated the effects of acute CTCF loss on chromatin architecture and transcriptional programs in mouse embryonic stem cells undergoing differentiation to neural precursor cells. We identified CTCF-dependent enhancer-promoter contacts genome-wide and found that they disproportionately affect genes that are bound by CTCF at the promoter and are dependent on long-distance enhancers. Disruption of promoter-proximal CTCF binding reduced both long-range enhancer-promoter contacts and transcription, which were restored by artificial tethering of CTCF to the promoter. Promoter-proximal CTCF binding is correlated with the transcription of over 2,000 genes across a diverse set of adult tissues. Taken together, the results of our study show that CTCF binding to promoters may promote long-distance enhancer-dependent transcription at specific genes in diverse cell types.},
}
@article {pmid33397980,
year = {2021},
author = {Ulianov, SV and Zakharova, VV and Galitsyna, AA and Kos, PI and Polovnikov, KE and Flyamer, IM and Mikhaleva, EA and Khrameeva, EE and Germini, D and Logacheva, MD and Gavrilov, AA and Gorsky, AS and Nechaev, SK and Gelfand, MS and Vassetzky, YS and Chertovich, AV and Shevelyov, YY and Razin, SV},
title = {Order and stochasticity in the folding of individual Drosophila genomes.},
journal = {Nature communications},
volume = {12},
number = {1},
pages = {41},
pmid = {33397980},
issn = {2041-1723},
mesh = {Animals ; Biopolymers/metabolism ; Chromatin/genetics ; Databases, Genetic ; Drosophila melanogaster/*genetics ; Epigenesis, Genetic ; *Genome, Insect ; Haploidy ; Models, Genetic ; *Nucleic Acid Conformation ; Stochastic Processes ; X Chromosome/genetics ; },
abstract = {Mammalian and Drosophila genomes are partitioned into topologically associating domains (TADs). Although this partitioning has been reported to be functionally relevant, it is unclear whether TADs represent true physical units located at the same genomic positions in each cell nucleus or emerge as an average of numerous alternative chromatin folding patterns in a cell population. Here, we use a single-nucleus Hi-C technique to construct high-resolution Hi-C maps in individual Drosophila genomes. These maps demonstrate chromatin compartmentalization at the megabase scale and partitioning of the genome into non-hierarchical TADs at the scale of 100 kb, which closely resembles the TAD profile in the bulk in situ Hi-C data. Over 40% of TAD boundaries are conserved between individual nuclei and possess a high level of active epigenetic marks. Polymer simulations demonstrate that chromatin folding is best described by the random walk model within TADs and is most suitably approximated by a crumpled globule build of Gaussian blobs at longer distances. We observe prominent cell-to-cell variability in the long-range contacts between either active genome loci or between Polycomb-bound regions, suggesting an important contribution of stochastic processes to the formation of the Drosophila 3D genome.},
}
@article {pmid33396256,
year = {2020},
author = {Decker, B and Liput, M and Abdellatif, H and Yergeau, D and Bae, Y and Jornet, JM and Stachowiak, EK and Stachowiak, MK},
title = {Global Genome Conformational Programming during Neuronal Development Is Associated with CTCF and Nuclear FGFR1-The Genome Archipelago Model.},
journal = {International journal of molecular sciences},
volume = {22},
number = {1},
pages = {},
pmid = {33396256},
issn = {1422-0067},
mesh = {Animals ; CCCTC-Binding Factor/genetics/*metabolism ; Cell Differentiation ; Cell Nucleus/*genetics ; Chromatin/genetics/*metabolism ; Chromosomes/genetics ; Embryonic Stem Cells/*cytology/metabolism ; *Genome ; Mice ; Molecular Conformation ; *Neurogenesis ; Receptor, Fibroblast Growth Factor, Type 1/genetics/*metabolism ; },
abstract = {During the development of mouse embryonic stem cells (ESC) to neuronal committed cells (NCC), coordinated changes in the expression of 2851 genes take place, mediated by the nuclear form of FGFR1. In this paper, widespread differences are demonstrated in the ESC and NCC inter- and intra-chromosomal interactions, chromatin looping, the formation of CTCF- and nFGFR1-linked Topologically Associating Domains (TADs) on a genome-wide scale and in exemplary HoxA-D loci. The analysis centered on HoxA cluster shows that blocking FGFR1 disrupts the loop formation. FGFR1 binding and genome locales are predictive of the genome interactions; likewise, chromatin interactions along with nFGFR1 binding are predictive of the genome function and correlate with genome regulatory attributes and gene expression. This study advances a topologically integrated genome archipelago model that undergoes structural transformations through the formation of nFGFR1-associated TADs. The makeover of the TAD islands serves to recruit distinct ontogenic programs during the development of the ESC to NCC.},
}
@article {pmid33382983,
year = {2021},
author = {Takemata, N and Bell, SD},
title = {Multi-scale architecture of archaeal chromosomes.},
journal = {Molecular cell},
volume = {81},
number = {3},
pages = {473-487.e6},
pmid = {33382983},
issn = {1097-4164},
support = {R01 GM135178/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Compartmentation ; Chromatin/*genetics ; Chromatin Assembly and Disassembly ; *Chromosomes, Archaeal ; DNA, Archaeal/*genetics ; Gene Expression Regulation, Archaeal ; Nucleotide Motifs ; Ribosomes/genetics/metabolism ; Sulfolobus acidocaldarius/*genetics/metabolism ; Sulfolobus solfataricus/*genetics/metabolism ; Transcription, Genetic ; },
abstract = {Chromosome conformation capture (3C) technologies have identified topologically associating domains (TADs) and larger A/B compartments as two salient structural features of eukaryotic chromosomes. These structures are sculpted by the combined actions of transcription and structural maintenance of chromosomes (SMC) superfamily proteins. Bacterial chromosomes fold into TAD-like chromosomal interaction domains (CIDs) but do not display A/B compartment-type organization. We reveal that chromosomes of Sulfolobus archaea are organized into CID-like topological domains in addition to previously described larger A/B compartment-type structures. We uncover local rules governing the identity of the topological domains and their boundaries. We also identify long-range loop structures and provide evidence of a hub-like structure that colocalizes genes involved in ribosome biogenesis. In addition to providing high-resolution descriptions of archaeal chromosome architectures, our data provide evidence of multiple modes of organization in prokaryotic chromosomes and yield insights into the evolution of eukaryotic chromosome conformation.},
}
@article {pmid33360765,
year = {2021},
author = {Rullens, PMJ and Kind, J},
title = {Attach and stretch: Emerging roles for genome-lamina contacts in shaping the 3D genome.},
journal = {Current opinion in cell biology},
volume = {70},
number = {},
pages = {51-57},
doi = {10.1016/j.ceb.2020.11.006},
pmid = {33360765},
issn = {1879-0410},
mesh = {Animals ; Cell Nucleus ; Chromatin ; *Genome ; Intermediate Filaments ; Nuclear Envelope ; *Nuclear Lamina ; },
abstract = {A large proportion of the metazoan genome is spatially segregated at the nuclear periphery through genomic contacts with the nuclear lamina, a thin meshwork of lamin filaments that lines the inner-nuclear membrane. Lamina-associated domains are believed to contribute to the regulation of gene transcription and to provide structural three-dimensional support to the organization of the genome in A and B compartments and topologically associating domains. In this review, we will evaluate recent work addressing the role of lamina-associated domains in three-dimensional genome organization and propose experimental frameworks that may expand our understanding of their interdependence.},
}
@article {pmid33334380,
year = {2020},
author = {Kruse, K and Hug, CB and Vaquerizas, JM},
title = {FAN-C: a feature-rich framework for the analysis and visualisation of chromosome conformation capture data.},
journal = {Genome biology},
volume = {21},
number = {1},
pages = {303},
pmid = {33334380},
issn = {1474-760X},
support = {MC_UP_1605/10/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Chromatin ; Chromosomes/*chemistry ; Computational Biology ; Embryonic Stem Cells ; Genomics ; High-Throughput Nucleotide Sequencing ; Humans ; *Molecular Conformation ; },
abstract = {Chromosome conformation capture data, particularly from high-throughput approaches such as Hi-C, are typically very complex to analyse. Existing analysis tools are often single-purpose, or limited in compatibility to a small number of data formats, frequently making Hi-C analyses tedious and time-consuming. Here, we present FAN-C, an easy-to-use command-line tool and powerful Python API with a broad feature set covering matrix generation, analysis, and visualisation for C-like data (https://github.com/vaquerizaslab/fanc). Due to its compatibility with the most prevalent Hi-C storage formats, FAN-C can be used in combination with a large number of existing analysis tools, thus greatly simplifying Hi-C matrix analysis.},
}
@article {pmid33284803,
year = {2020},
author = {Torosin, NS and Anand, A and Golla, TR and Cao, W and Ellison, CE},
title = {3D genome evolution and reorganization in the Drosophila melanogaster species group.},
journal = {PLoS genetics},
volume = {16},
number = {12},
pages = {e1009229},
pmid = {33284803},
issn = {1553-7404},
support = {R01 GM130698/GM/NIGMS NIH HHS/United States ; P40 OD018537/OD/NIH HHS/United States ; },
mesh = {Animals ; Chromatin/*genetics ; *Chromatin Assembly and Disassembly ; Chromosomes, Insect/*genetics ; Conserved Sequence ; Drosophila melanogaster ; *Evolution, Molecular ; Gene Rearrangement ; *Genome, Insect ; Transcription, Genetic ; },
abstract = {Topologically associating domains, or TADs, are functional units that organize chromosomes into 3D structures of interacting chromatin. TADs play an important role in regulating gene expression by constraining enhancer-promoter contacts and there is evidence that deletion of TAD boundaries leads to aberrant expression of neighboring genes. While the mechanisms of TAD formation have been well-studied, current knowledge on the patterns of TAD evolution across species is limited. Due to the integral role TADs play in gene regulation, their structure and organization is expected to be conserved during evolution. However, more recent research suggests that TAD structures diverge relatively rapidly. We use Hi-C chromosome conformation capture to measure evolutionary conservation of whole TADs and TAD boundary elements between D. melanogaster and D. triauraria, two early-branching species from the melanogaster species group which diverged ∼15 million years ago. We find that the majority of TADs have been reorganized since the common ancestor of D. melanogaster and D. triauraria, via a combination of chromosomal rearrangements and gain/loss of TAD boundaries. TAD reorganization between these two species is associated with a localized effect on gene expression, near the site of disruption. By separating TADs into subtypes based on their chromatin state, we find that different subtypes are evolving under different evolutionary forces. TADs enriched for broadly expressed, transcriptionally active genes are evolving rapidly, potentially due to positive selection, whereas TADs enriched for developmentally-regulated genes remain conserved, presumably due to their importance in restricting gene-regulatory element interactions. These results provide novel insight into the evolutionary dynamics of TADs and help to reconcile contradictory reports related to the evolutionary conservation of TADs and whether changes in TAD structure affect gene expression.},
}
@article {pmid33273453,
year = {2020},
author = {Guerrero-Martínez, JA and Ceballos-Chávez, M and Koehler, F and Peiró, S and Reyes, JC},
title = {TGFβ promotes widespread enhancer chromatin opening and operates on genomic regulatory domains.},
journal = {Nature communications},
volume = {11},
number = {1},
pages = {6196},
pmid = {33273453},
issn = {2041-1723},
mesh = {Animals ; Chromatin/*metabolism ; *Enhancer Elements, Genetic ; Gene Expression Regulation ; Genome ; HEK293 Cells ; Humans ; MCF-7 Cells ; Mice ; Multigene Family ; RNA, Messenger/genetics/metabolism ; Transforming Growth Factor beta/*metabolism ; },
abstract = {The Transforming Growth Factor-β (TGFβ) signaling pathway controls transcription by regulating enhancer activity. How TGFβ-regulated enhancers are selected and what chromatin changes are associated with TGFβ-dependent enhancers regulation are still unclear. Here we report that TGFβ treatment triggers fast and widespread increase in chromatin accessibility in about 80% of the enhancers of normal mouse mammary epithelial-gland cells, irrespective of whether they are activated, repressed or not regulated by TGFβ. This enhancer opening depends on both the canonical and non-canonical TGFβ pathways. Most TGFβ-regulated genes are located around enhancers regulated in the same way, often creating domains of several co-regulated genes that we term TGFβ regulatory domains (TRD). CRISPR-mediated inactivation of enhancers within TRDs impairs TGFβ-dependent regulation of all co-regulated genes, demonstrating that enhancer targeting is more promiscuous than previously anticipated. The area of TRD influence is restricted by topologically associating domains (TADs) borders, causing a bias towards co-regulation within TADs.},
}
@article {pmid33268790,
year = {2020},
author = {Sanders, JT and Freeman, TF and Xu, Y and Golloshi, R and Stallard, MA and Hill, AM and San Martin, R and Balajee, AS and McCord, RP},
title = {Radiation-induced DNA damage and repair effects on 3D genome organization.},
journal = {Nature communications},
volume = {11},
number = {1},
pages = {6178},
pmid = {33268790},
issn = {2041-1723},
support = {R35 GM133557/GM/NIGMS NIH HHS/United States ; },
mesh = {Ataxia Telangiectasia/genetics/metabolism/pathology ; Ataxia Telangiectasia Mutated Proteins/deficiency/*genetics ; Cell Cycle/genetics/*radiation effects ; Cell Line ; DNA/*genetics/metabolism ; DNA Damage ; *DNA Repair ; Fibroblasts/metabolism/pathology/radiation effects ; Gene Expression ; Genome, Human/*radiation effects ; High-Throughput Nucleotide Sequencing ; Histones/genetics/metabolism ; Humans ; Lymphocytes/metabolism/pathology/radiation effects ; Organ Specificity ; X-Rays ; },
abstract = {The three-dimensional structure of chromosomes plays an important role in gene expression regulation and also influences the repair of radiation-induced DNA damage. Genomic aberrations that disrupt chromosome spatial domains can lead to diseases including cancer, but how the 3D genome structure responds to DNA damage is poorly understood. Here, we investigate the impact of DNA damage response and repair on 3D genome folding using Hi-C experiments on wild type cells and ataxia telangiectasia mutated (ATM) patient cells. We irradiate fibroblasts, lymphoblasts, and ATM-deficient fibroblasts with 5 Gy X-rays and perform Hi-C at 30 minutes, 24 hours, or 5 days after irradiation. We observe that 3D genome changes after irradiation are cell type-specific, with lymphoblastoid cells generally showing more contact changes than irradiated fibroblasts. However, all tested repair-proficient cell types exhibit an increased segregation of topologically associating domains (TADs). This TAD boundary strengthening after irradiation is not observed in ATM deficient fibroblasts and may indicate the presence of a mechanism to protect 3D genome structure integrity during DNA damage repair.},
}
@article {pmid33239788,
year = {2020},
author = {Yang, H and Luan, Y and Liu, T and Lee, HJ and Fang, L and Wang, Y and Wang, X and Zhang, B and Jin, Q and Ang, KC and Xing, X and Wang, J and Xu, J and Song, F and Sriranga, I and Khunsriraksakul, C and Salameh, T and Li, D and Choudhary, MNK and Topczewski, J and Wang, K and Gerhard, GS and Hardison, RC and Wang, T and Cheng, KC and Yue, F},
title = {A map of cis-regulatory elements and 3D genome structures in zebrafish.},
journal = {Nature},
volume = {588},
number = {7837},
pages = {337-343},
pmid = {33239788},
issn = {1476-4687},
support = {U01 HG009391/HG/NHGRI NIH HHS/United States ; R01 HG009906/HG/NHGRI NIH HHS/United States ; R01 HG007175/HG/NHGRI NIH HHS/United States ; R01 DK107735/DK/NIDDK NIH HHS/United States ; U01 CA200060/CA/NCI NIH HHS/United States ; R01 ES024992/ES/NIEHS NIH HHS/United States ; R24 DK106766/DK/NIDDK NIH HHS/United States ; R25 DA027995/DA/NIDA NIH HHS/United States ; U24 ES026699/ES/NIEHS NIH HHS/United States ; R35 GM124820/GM/NIGMS NIH HHS/United States ; R01 HG007354/HG/NHGRI NIH HHS/United States ; },
mesh = {Animals ; Brain/metabolism ; Conserved Sequence/genetics ; DNA Methylation ; Enhancer Elements, Genetic/genetics ; Epigenesis, Genetic ; Evolution, Molecular ; Female ; Gene Expression Profiling ; Gene Regulatory Networks/genetics ; Genome/*genetics ; Heterochromatin/chemistry/genetics/metabolism ; Humans ; *Imaging, Three-Dimensional ; Male ; Mice ; *Molecular Imaging ; Organ Specificity ; Promoter Regions, Genetic/genetics ; Regulatory Sequences, Nucleic Acid/*genetics ; Single-Cell Analysis ; Species Specificity ; Zebrafish/*genetics ; },
abstract = {The zebrafish (Danio rerio) has been widely used in the study of human disease and development, and about 70% of the protein-coding genes are conserved between the two species[1]. However, studies in zebrafish remain constrained by the sparse annotation of functional control elements in the zebrafish genome. Here we performed RNA sequencing, assay for transposase-accessible chromatin using sequencing (ATAC-seq), chromatin immunoprecipitation with sequencing, whole-genome bisulfite sequencing, and chromosome conformation capture (Hi-C) experiments in up to eleven adult and two embryonic tissues to generate a comprehensive map of transcriptomes, cis-regulatory elements, heterochromatin, methylomes and 3D genome organization in the zebrafish Tübingen reference strain. A comparison of zebrafish, human and mouse regulatory elements enabled the identification of both evolutionarily conserved and species-specific regulatory sequences and networks. We observed enrichment of evolutionary breakpoints at topologically associating domain boundaries, which were correlated with strong histone H3 lysine 4 trimethylation (H3K4me3) and CCCTC-binding factor (CTCF) signals. We performed single-cell ATAC-seq in zebrafish brain, which delineated 25 different clusters of cell types. By combining long-read DNA sequencing and Hi-C, we assembled the sex-determining chromosome 4 de novo. Overall, our work provides an additional epigenomic anchor for the functional annotation of vertebrate genomes and the study of evolutionarily conserved elements of 3D genome organization.},
}
@article {pmid33229569,
year = {2020},
author = {Rodríguez-Carballo, E and Lopez-Delisle, L and Willemin, A and Beccari, L and Gitto, S and Mascrez, B and Duboule, D},
title = {Chromatin topology and the timing of enhancer function at the HoxD locus.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {117},
number = {49},
pages = {31231-31241},
pmid = {33229569},
issn = {1091-6490},
mesh = {Animals ; CCCTC-Binding Factor/*genetics ; Chromatin/genetics ; Chromatin Assembly and Disassembly/genetics ; Embryonic Development/*genetics ; Enhancer Elements, Genetic/*genetics ; Extremities/growth &amp; development ; Gene Expression Regulation, Developmental/genetics ; Genes, Homeobox/*genetics ; Limb Buds/growth &amp; development ; Mice ; },
abstract = {The HoxD gene cluster is critical for proper limb formation in tetrapods. In the emerging limb buds, different subgroups of Hoxd genes respond first to a proximal regulatory signal, then to a distal signal that organizes digits. These two regulations are exclusive from one another and emanate from two distinct topologically associating domains (TADs) flanking HoxD, both containing a range of appropriate enhancer sequences. The telomeric TAD (T-DOM) contains several enhancers active in presumptive forearm cells and is divided into two sub-TADs separated by a CTCF-rich boundary, which defines two regulatory submodules. To understand the importance of this particular regulatory topology to control Hoxd gene transcription in time and space, we either deleted or inverted this sub-TAD boundary, eliminated the CTCF binding sites, or inverted the entire T-DOM to exchange the respective positions of the two sub-TADs. The effects of such perturbations on the transcriptional regulation of Hoxd genes illustrate the requirement of this regulatory topology for the precise timing of gene activation. However, the spatial distribution of transcripts was eventually resumed, showing that the presence of enhancer sequences, rather than either their exact topology or a particular chromatin architecture, is the key factor. We also show that the affinity of enhancers to find their natural target genes can overcome the presence of both a strong TAD border and an unfavorable orientation of CTCF sites.},
}
@article {pmid33203573,
year = {2021},
author = {Eres, IE and Gilad, Y},
title = {A TAD Skeptic: Is 3D Genome Topology Conserved?.},
journal = {Trends in genetics : TIG},
volume = {37},
number = {3},
pages = {216-223},
pmid = {33203573},
issn = {0168-9525},
support = {R35 GM131726/GM/NIGMS NIH HHS/United States ; T32 GM007197/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromatin/genetics ; Chromatin Assembly and Disassembly/genetics ; Conserved Sequence/*genetics ; *Evolution, Molecular ; Genome, Human/genetics ; Genomics ; Humans ; Protein Domains/*genetics ; },
abstract = {The notion that topologically associating domains (TADs) are highly conserved across species is prevalent in the field of 3D genomics. However, what exactly is meant by 'highly conserved' and what are the actual comparative data that support this notion? To address these questions, we performed a historical review of the relevant literature and retraced numerous citation chains to reveal the primary data that were used as the basis for the widely accepted conclusion that TADs are highly conserved across evolution. A thorough review of the available evidence suggests the answer may be more complex than what is commonly presented.},
}
@article {pmid33182325,
year = {2020},
author = {Ehrlich, KC and Baribault, C and Ehrlich, M},
title = {Epigenetics of Muscle- and Brain-Specific Expression of KLHL Family Genes.},
journal = {International journal of molecular sciences},
volume = {21},
number = {21},
pages = {},
pmid = {33182325},
issn = {1422-0067},
support = {NS04885/NH/NIH HHS/United States ; },
mesh = {Adaptor Proteins, Signal Transducing/*genetics ; Adult ; Aged ; Brain/*metabolism ; Cells, Cultured ; Child, Preschool ; Chromatin/genetics ; DNA Methylation/genetics ; Enhancer Elements, Genetic/genetics ; Epigenesis, Genetic/*genetics ; Epigenomics/methods ; Exons/genetics ; Female ; Gene Expression Regulation/genetics ; Humans ; Male ; Middle Aged ; Muscle Proteins/*genetics ; Muscle, Skeletal/*metabolism ; Promoter Regions, Genetic/genetics ; Transcription, Genetic/genetics ; Up-Regulation/genetics ; },
abstract = {KLHL and the related KBTBD genes encode components of the Cullin-E3 ubiquitin ligase complex and typically target tissue-specific proteins for degradation, thereby affecting differentiation, homeostasis, metabolism, cell signaling, and the oxidative stress response. Despite their importance in cell function and disease (especially, KLHL40, KLHL41, KBTBD13, KEAP1, and ENC1), previous studies of epigenetic factors that affect transcription were predominantly limited to promoter DNA methylation. Using diverse tissue and cell culture whole-genome profiles, we examined 17 KLHL or KBTBD genes preferentially expressed in skeletal muscle or brain to identify tissue-specific enhancer and promoter chromatin, open chromatin (DNaseI hypersensitivity), and DNA hypomethylation. Sixteen of the 17 genes displayed muscle- or brain-specific enhancer chromatin in their gene bodies, and most exhibited specific intergenic enhancer chromatin as well. Seven genes were embedded in super-enhancers (particularly strong, tissue-specific clusters of enhancers). The enhancer chromatin regions typically displayed foci of DNA hypomethylation at peaks of open chromatin. In addition, we found evidence for an intragenic enhancer in one gene upregulating expression of its neighboring gene, specifically for KLHL40/HHATL and KLHL38/FBXO32 gene pairs. Many KLHL/KBTBD genes had tissue-specific promoter chromatin at their 5' ends, but surprisingly, two (KBTBD11 and KLHL31) had constitutively unmethylated promoter chromatin in their 3' exons that overlaps a retrotransposed KLHL gene. Our findings demonstrate the importance of expanding epigenetic analyses beyond the 5' ends of genes in studies of normal and abnormal gene regulation.},
}
@article {pmid33155082,
year = {2022},
author = {Chang, L and Li, M and Shao, S and Li, C and Ai, S and Xue, B and Hou, Y and Zhang, Y and Li, R and Fan, X and He, A and Li, C and Sun, Y},
title = {Nuclear peripheral chromatin-lamin B1 interaction is required for global integrity of chromatin architecture and dynamics in human cells.},
journal = {Protein &amp; cell},
volume = {13},
number = {4},
pages = {258-280},
pmid = {33155082},
issn = {1674-8018},
mesh = {*Chromatin ; Chromosomes ; Genome ; Humans ; *Lamin Type B/genetics ; },
abstract = {The eukaryotic genome is folded into higher-order conformation accompanied with constrained dynamics for coordinated genome functions. However, the molecular machinery underlying these hierarchically organized three-dimensional (3D) chromatin architecture and dynamics remains poorly understood. Here by combining imaging and sequencing, we studied the role of lamin B1 in chromatin architecture and dynamics. We found that lamin B1 depletion leads to detachment of lamina-associated domains (LADs) from the nuclear periphery accompanied with global chromatin redistribution and decompaction. Consequently, the inter-chromosomal as well as inter-compartment interactions are increased, but the structure of topologically associating domains (TADs) is not affected. Using live-cell genomic loci tracking, we further proved that depletion of lamin B1 leads to increased chromatin dynamics, owing to chromatin decompaction and redistribution toward nucleoplasm. Taken together, our data suggest that lamin B1 and chromatin interactions at the nuclear periphery promote LAD maintenance, chromatin compaction, genomic compartmentalization into chromosome territories and A/B compartments and confine chromatin dynamics, supporting their crucial roles in chromatin higher-order structure and chromatin dynamics.},
}
@article {pmid33154377,
year = {2020},
author = {Nora, EP and Caccianini, L and Fudenberg, G and So, K and Kameswaran, V and Nagle, A and Uebersohn, A and Hajj, B and Saux, AL and Coulon, A and Mirny, LA and Pollard, KS and Dahan, M and Bruneau, BG},
title = {Molecular basis of CTCF binding polarity in genome folding.},
journal = {Nature communications},
volume = {11},
number = {1},
pages = {5612},
pmid = {33154377},
issn = {2041-1723},
support = {R01 GM114190/GM/NIGMS NIH HHS/United States ; U54 DK107980/DK/NIDDK NIH HHS/United States ; UM1 HL098179/HL/NHLBI NIH HHS/United States ; },
mesh = {Amino Acid Motifs ; Animals ; Binding Sites ; CCCTC-Binding Factor/*chemistry/genetics/*metabolism ; Cell Cycle Proteins/chemistry/metabolism ; Cell Line ; Chromatin/metabolism ; Chromosomal Proteins, Non-Histone/chemistry/metabolism ; Chromosomes, Mammalian/*chemistry/genetics/metabolism ; Cricetinae ; Drosophila ; Mice ; Mutation ; Nucleotide Motifs ; Protein Binding ; Structure-Activity Relationship ; },
abstract = {Current models propose that boundaries of mammalian topologically associating domains (TADs) arise from the ability of the CTCF protein to stop extrusion of chromatin loops by cohesin. While the orientation of CTCF motifs determines which pairs of CTCF sites preferentially stabilize loops, the molecular basis of this polarity remains unclear. By combining ChIP-seq and single molecule live imaging we report that CTCF positions cohesin, but does not control its overall binding dynamics on chromatin. Using an inducible complementation system, we find that CTCF mutants lacking the N-terminus cannot insulate TADs properly. Cohesin remains at CTCF sites in this mutant, albeit with reduced enrichment. Given the orientation of CTCF motifs presents the N-terminus towards cohesin as it translocates from the interior of TADs, these observations explain how the orientation of CTCF binding sites translates into genome folding patterns.},
}
@article {pmid33151112,
year = {2020},
author = {Kong, N and Jung, I},
title = {Long-range chromatin interactions in pathogenic gene expression control.},
journal = {Transcription},
volume = {11},
number = {5},
pages = {211-216},
pmid = {33151112},
issn = {2154-1272},
mesh = {Chromatin/chemistry/*genetics/metabolism ; Disease/*genetics ; Gene Expression ; Humans ; },
abstract = {A large number of distal cis-regulatory elements (cREs) have been annotated in the human genome, which plays a central role in orchestrating spatiotemporal gene expression. Since many cREs regulate non-adjacent genes, long-range cRE-promoter interactions are an important factor in the functional characterization of the engaged cREs. In this regard, recent studies have demonstrated that identification of long-range target genes can decipher the effect of genetic mutations residing within cREs on abnormal gene expression. In addition, investigation of altered long-range cREs-promoter interactions induced by chromosomal rearrangements has revealed their critical roles in pathogenic gene expression. In this review, we briefly discuss how the analysis of 3D chromatin structure can help us understand the functional impact of cREs harboring disease-associated genetic variants and how chromosomal rearrangements disrupting topologically associating domains can lead to pathogenic gene expression.},
}
@article {pmid33101859,
year = {2020},
author = {Chu, X and Wang, J},
title = {Microscopic Chromosomal Structural and Dynamical Origin of Cell Differentiation and Reprogramming.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {7},
number = {20},
pages = {2001572},
pmid = {33101859},
issn = {2198-3844},
abstract = {As an essential and fundamental process of life, cell development involves large-scale reorganization of the 3D genome architecture, which forms the basis of gene regulation. Here, a landscape-switching model is developed to explore the microscopic chromosomal structural origin of embryonic stem cell (ESC) differentiation and somatic cell reprogramming. It is shown that chromosome structure exhibits significant compartment-switching in the unit of topologically associating domain. It is found that the chromosome during differentiation undergoes monotonic compaction with spatial repositioning of active and inactive chromosomal loci toward the chromosome surface and interior, respectively. In contrast, an overexpanded chromosome, which exhibits universal localization of loci at the chromosomal surface with erasing the structural characteristics formed in the somatic cells, is observed during reprogramming. An early distinct differentiation pathway from the ESC to the terminally differentiated cell, giving rise to early bifurcation on the Waddington landscape for the ESC differentiation is suggested. The theoretical model herein including the non-equilibrium effects, draws a picture of the highly irreversible cell differentiation and reprogramming processes, in line with the experiments. The predictions provide a physical understanding of cell differentiation and reprogramming from the chromosomal structural and dynamical perspective and can be tested by future experiments.},
}
@article {pmid33099628,
year = {2020},
author = {Li, Y and Gao, G and Lin, Y and Hu, S and Luo, Y and Wang, G and Jin, L and Wang, Q and Wang, J and Tang, Q and Li, M},
title = {Pacific Biosciences assembly with Hi-C mapping generates an improved, chromosome-level goose genome.},
journal = {GigaScience},
volume = {9},
number = {10},
pages = {},
pmid = {33099628},
issn = {2047-217X},
mesh = {Animals ; Chromosomes/genetics ; Female ; *Geese/genetics ; *Genome ; Genomics ; High-Throughput Nucleotide Sequencing ; Molecular Sequence Annotation ; },
abstract = {BACKGROUND: The domestic goose is an economically important and scientifically valuable waterfowl; however, a lack of high-quality genomic data has hindered research concerning its genome, genetics, and breeding. As domestic geese breeds derive from both the swan goose (Anser cygnoides) and the graylag goose (Anser anser), we selected a female Tianfu goose for genome sequencing. We generated a chromosome-level goose genome assembly by adopting a hybrid de novo assembly approach that combined Pacific Biosciences single-molecule real-time sequencing, high-throughput chromatin conformation capture mapping, and Illumina short-read sequencing.<br><br>FINDINGS: We generated a 1.11-Gb goose genome with contig and scaffold N50 values of 1.85 and 33.12 Mb, respectively. The assembly contains 39 pseudo-chromosomes (2n = 78) accounting for &#x223c;88.36% of the goose genome. Compared with previous goose assemblies, our assembly has more continuity, completeness, and accuracy; the annotation of core eukaryotic genes and universal single-copy orthologs has also been improved. We have identified 17,568 protein-coding genes and a repeat content of 8.67% (96.57 Mb) in this genome assembly. We also explored the spatial organization of chromatin and gene expression in the goose liver tissues, in terms of inter-pseudo-chromosomal interaction patterns, compartments, topologically associating domains, and promoter-enhancer interactions.<br><br>CONCLUSIONS: We present the first chromosome-level assembly of the goose genome. This will be a valuable resource for future genetic and genomic studies on geese.},
}
@article {pmid33091336,
year = {2020},
author = {Gu, B and Comerci, CJ and McCarthy, DG and Saurabh, S and Moerner, WE and Wysocka, J},
title = {Opposing Effects of Cohesin and Transcription on CTCF Organization Revealed by Super-resolution Imaging.},
journal = {Molecular cell},
volume = {80},
number = {4},
pages = {699-711.e7},
pmid = {33091336},
issn = {1097-4164},
support = {R35 GM118067/GM/NIGMS NIH HHS/United States ; R35 GM131757/GM/NIGMS NIH HHS/United States ; T32 GM120007/GM/NIGMS NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; },
mesh = {Animals ; CCCTC-Binding Factor/genetics/*metabolism ; Cell Cycle Proteins/genetics/*metabolism ; Cells, Cultured ; Chromatin/genetics/*metabolism ; Chromosomal Proteins, Non-Histone/genetics/*metabolism ; Chromosomes, Mammalian ; Embryonic Stem Cells/*cytology/metabolism ; Genetic Loci ; Genome ; Image Processing, Computer-Assisted ; Mice ; Microscopy, Fluorescence/*methods ; Proteins/genetics/*metabolism ; *Transcription, Genetic ; },
abstract = {CCCTC-binding factor (CTCF) and cohesin play critical roles in organizing mammalian genomes into topologically associating domains (TADs). Here, by combining genetic engineering with quantitative super-resolution stimulated emission depletion (STED) microscopy, we demonstrate that in living cells, CTCF forms clusters typically containing 2-8 molecules. A fraction of CTCF clusters, enriched for those with ≥3 molecules, are coupled with cohesin complexes with a characteristic physical distance suggestive of a defined molecular interaction. Acute degradation of the cohesin unloader WAPL or transcriptional inhibition (TI) result in increased CTCF clustering. Furthermore, the effect of TI on CTCF clusters is alleviated by the acute loss of the cohesin subunit SMC3. Our study provides quantitative characterization of CTCF clusters in living cells, uncovers the opposing effects of cohesin and transcription on CTCF clustering, and highlights the power of quantitative super-resolution microscopy as a tool to bridge the gap between biochemical and genomic methodologies in chromatin research.},
}
@article {pmid33090716,
year = {2020},
author = {Tinker, RJ and Burghel, GJ and Garg, S and Steggall, M and Cuvertino, S and Banka, S},
title = {Haploinsufficiency of ATP6V0C possibly underlies 16p13.3 deletions that cause microcephaly, seizures, and neurodevelopmental disorder.},
journal = {American journal of medical genetics. Part A},
volume = {},
number = {},
pages = {},
doi = {10.1002/ajmg.a.61905},
pmid = {33090716},
issn = {1552-4833},
abstract = {We recently contributed to the description of eight individuals with a novel condition caused by 16p13.3 microdeletions encompassing TBC1D24, ATP6V0C, and PDPK1 and resulting in epilepsy, microcephaly and neurodevelopmental problems. The phenotypic spectrum, the minimum overlapping region and the underlying disease mechanism for this disorder remain to be clarified. Here we report a 3.5-year-old male, with microcephaly, autism spectrum disorder and a de novo 16p13.3 microdeletion. We performed detailed in silico analysis to show that the minimum overlapping region for the condition is ~80Kb encompassing five protein coding genes. Analysis of loss of function constraint metrics, transcript-aware evaluation of the population variants, GeVIR scores, analysis of reported pathogenic point variants, detailed review of the known functions of gene products and their animal models showed that the haploinsufficiency of ATP6V0C likely underlies the phenotype of this condition. Protein-protein interaction network, gene phenology and analysis of topologically associating domain showed that it was unlikely that the disorder has an epistatic or regulatory basis. 16p13.3 deletions encompassing ATP6V0C cause a neurodevelopmental disorder. Our results broaden the phenotypic spectrum of this disorder and clarify the likely underlying disease mechanism for the condition.},
}
@article {pmid33077913,
year = {2020},
author = {Szabo, Q and Donjon, A and Jerković, I and Papadopoulos, GL and Cheutin, T and Bonev, B and Nora, EP and Bruneau, BG and Bantignies, F and Cavalli, G},
title = {Regulation of single-cell genome organization into TADs and chromatin nanodomains.},
journal = {Nature genetics},
volume = {52},
number = {11},
pages = {1151-1157},
pmid = {33077913},
issn = {1546-1718},
support = {P01 HL089707/HL/NHLBI NIH HHS/United States ; UM1 HL098179/HL/NHLBI NIH HHS/United States ; 788972/ERC_/European Research Council/International ; /WT_/Wellcome Trust/United Kingdom ; EP-C-15-010/EPA/EPA/United States ; 100136MA/Z/12/Z/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Animals ; Cell Differentiation/genetics ; Cell Line ; Chromatin/*chemistry ; Chromosome Painting ; Drosophila/genetics ; Embryonic Stem Cells/*ultrastructure ; In Situ Hybridization, Fluorescence ; Male ; Mice ; Mice, Inbred C57BL ; Molecular Conformation ; Nanostructures ; Nuclear Microscopy ; *Protein Domains ; },
abstract = {The genome folds into a hierarchy of three-dimensional structures within the nucleus. At the sub-megabase scale, chromosomes form topologically associating domains (TADs)[1-4]. However, how TADs fold in single cells is elusive. Here, we reveal TAD features inaccessible to cell population analysis by using super-resolution microscopy. TAD structures and physical insulation associated with their borders are variable between individual cells, yet chromatin intermingling is enriched within TADs compared to adjacent TADs in most cells. The spatial segregation of TADs is further exacerbated during cell differentiation. Favored interactions within TADs are regulated by cohesin and CTCF through distinct mechanisms: cohesin generates chromatin contacts and intermingling while CTCF prevents inter-TAD contacts. Furthermore, TADs are subdivided into discrete nanodomains, which persist in cells depleted of CTCF or cohesin, whereas disruption of nucleosome contacts alters their structural organization. Altogether, these results provide a physical basis for the folding of individual chromosomes at the nanoscale.},
}
@article {pmid33075237,
year = {2021},
author = {Paik, S and Maule, F and Gallo, M},
title = {Dysregulation of chromatin organization in pediatric and adult brain tumors: oncoepigenomic contributions to tumorigenesis and cancer stem cell properties.},
journal = {Genome},
volume = {64},
number = {4},
pages = {326-336},
doi = {10.1139/gen-2020-0097},
pmid = {33075237},
issn = {1480-3321},
mesh = {Adult ; Brain Neoplasms/*genetics ; Carcinogenesis/*genetics ; Cell Differentiation ; Child ; *Chromatin ; DNA Methylation ; Disease ; Epigenesis, Genetic ; Epigenomics ; Genome ; Humans ; Neoplasms ; *Neoplastic Stem Cells ; },
abstract = {The three-dimensional (3D) organization of the genome is a crucial enabler of cell fate, identity, and function. In this review, we will focus on the emerging role of altered 3D genome organization in the etiology of disease, with a special emphasis on brain cancers. We discuss how different genetic alterations can converge to disrupt the epigenome in childhood and adult brain tumors, by causing aberrant DNA methylation and by affecting the amounts and genomic distribution of histone post-translational modifications. We also highlight examples that illustrate how epigenomic alterations have the potential to affect 3D genome architecture in brain tumors. Finally, we will propose the concept of "epigenomic erosion" to explain the transition from stem-like cells to differentiated cells in hierarchically organized brain cancers.},
}
@article {pmid33073863,
year = {2020},
author = {Huang, Y and Neijts, R and de Laat, W},
title = {How chromosome topologies get their shape: views from proximity ligation and microscopy methods.},
journal = {FEBS letters},
volume = {594},
number = {21},
pages = {3439-3449},
doi = {10.1002/1873-3468.13961},
pmid = {33073863},
issn = {1873-3468},
mesh = {Animals ; Chromosomes/*chemistry/*metabolism ; Humans ; Microscopy/*methods ; Models, Molecular ; Molecular Conformation ; },
abstract = {The 3D organization of our genome is an important determinant for the transcriptional output of a gene in (patho)physiological contexts. The spatial organization of linear chromosomes within nucleus is dominantly inferred using two distinct approaches, chromosome conformation capture (3C) and DNA fluorescent in situ hybridization (DNA-FISH). While 3C and its derivatives score genomic interaction frequencies based on proximity ligation events, DNA-FISH methods measure physical distances between genomic loci. Despite these approaches probe different characteristics of chromosomal topologies, they provide a coherent picture of how chromosomes are organized in higher-order structures encompassing chromosome territories, compartments, and topologically associating domains. Yet, at the finer topological level of promoter-enhancer communication, the imaging-centered and the 3C methods give more divergent and sometimes seemingly paradoxical results. Here, we compare and contrast observations made applying visual DNA-FISH and molecular 3C approaches. We emphasize that the 3C approach, due to its inherently competitive ligation step, measures only 'relative' proximities. A 3C interaction enriched between loci, therefore does not necessarily translates into a decrease in absolute spatial distance. Hence, we advocate caution when modeling chromosome conformations.},
}
@article {pmid33060757,
year = {2020},
author = {Iwasaki, Y and Ikemura, T and Kurokawa, K and Okada, N},
title = {Implication of a new function of human tDNAs in chromatin organization.},
journal = {Scientific reports},
volume = {10},
number = {1},
pages = {17440},
pmid = {33060757},
issn = {2045-2322},
mesh = {A549 Cells ; Activating Transcription Factor 3/metabolism ; Amino Acid Motifs ; Chromatin/*chemistry ; Computational Biology ; Databases, Factual ; E1A-Associated p300 Protein/metabolism ; Genome, Human ; HeLa Cells ; Hep G2 Cells ; Humans ; K562 Cells ; Protein Domains ; RNA, Transfer/*metabolism ; Receptors, Cytoplasmic and Nuclear/metabolism ; Repressor Proteins/metabolism ; Synteny ; Transcription Factors/*metabolism ; Transcription Factors, TFIII/metabolism ; },
abstract = {Transfer RNA genes (tDNAs) are essential genes that encode tRNAs in all species. To understand new functions of tDNAs, other than that of encoding tRNAs, we used ENCODE data to examine binding characteristics of transcription factors (TFs) for all tDNA regions (489 loci) in the human genome. We divided the tDNAs into three groups based on the number of TFs that bound to them. At the two extremes were tDNAs to which many TFs bound (Group 1) and those to which no TFs bound (Group 3). Several TFs involved in chromatin remodeling such as ATF3, EP300 and TBL1XR1 bound to almost all Group 1 tDNAs. Furthermore, almost all Group 1 tDNAs included DNase I hypersensitivity sites and may thus interact with other chromatin regions through their bound TFs, and they showed highly conserved synteny across tetrapods. In contrast, Group 3 tDNAs did not possess these characteristics. These data suggest the presence of a previously uncharacterized function of these tDNAs. We also examined binding of CTCF to tDNAs and their involvement in topologically associating domains (TADs) and lamina-associated domains (LADs), which suggest a new perspective on the evolution and function of tDNAs.},
}
@article {pmid33028366,
year = {2020},
author = {Saha, P and Sowpati, DT and Soujanya, M and Srivastava, I and Mishra, RK},
title = {Interplay of pericentromeric genome organization and chromatin landscape regulates the expression of Drosophila melanogaster heterochromatic genes.},
journal = {Epigenetics &amp; chromatin},
volume = {13},
number = {1},
pages = {41},
pmid = {33028366},
issn = {1756-8935},
support = {EpiHed//Council&#xa0;of&#xa0;Scientific and Industrial Research, India/International ; JRF/SRF fellowship//University Grants Commission/International ; },
mesh = {Animals ; Centromere/genetics/*metabolism ; Chromobox Protein Homolog 5 ; Chromosomal Proteins, Non-Histone/metabolism ; Drosophila Proteins/metabolism ; Drosophila melanogaster ; *Epigenesis, Genetic ; Heterochromatin/genetics/*metabolism ; Histone-Lysine N-Methyltransferase/metabolism ; Histones/metabolism ; },
abstract = {BACKGROUND: Transcription of genes residing within constitutive heterochromatin is paradoxical to the tenets of epigenetic code. The regulatory mechanisms of Drosophila melanogaster heterochromatic gene transcription remain largely unknown. Emerging evidence suggests that genome organization and transcriptional regulation are inter-linked. However, the pericentromeric genome organization is relatively less studied. Therefore, we sought to characterize the pericentromeric genome organization and understand how this organization along with the pericentromeric factors influences heterochromatic gene expression.<br><br>RESULTS: Here, we characterized the pericentromeric genome organization in Drosophila melanogaster using 5C sequencing. Heterochromatic topologically associating domains (Het TADs) correlate with distinct epigenomic domains of active and repressed heterochromatic genes at the pericentromeres. These genes are known to depend on the heterochromatic landscape for their expression. However, HP1a or Su(var)3-9 RNAi has minimal effects on heterochromatic gene expression, despite causing significant changes in the global Het TAD organization. Probing further into this observation, we report the role of two other chromatin proteins enriched at the pericentromeres-dMES-4 and dADD1 in regulating the expression of a subset of heterochromatic genes.<br><br>CONCLUSIONS: Distinct pericentromeric genome organization and chromatin landscapes maintained by the interplay of heterochromatic factors (HP1a, H3K9me3, dMES-4 and dADD1) are sufficient to support heterochromatic gene expression despite the loss of global Het TAD structure. These findings open new avenues for future investigations into the mechanisms of heterochromatic gene expression.},
}
@article {pmid33022222,
year = {2020},
author = {de Bruijn, SE and Fiorentino, A and Ottaviani, D and Fanucchi, S and Melo, US and Corral-Serrano, JC and Mulders, T and Georgiou, M and Rivolta, C and Pontikos, N and Arno, G and Roberts, L and Greenberg, J and Albert, S and Gilissen, C and Aben, M and Rebello, G and Mead, S and Raymond, FL and Corominas, J and Smith, CEL and Kremer, H and Downes, S and Black, GC and Webster, AR and Inglehearn, CF and van den Born, LI and Koenekoop, RK and Michaelides, M and Ramesar, RS and Hoyng, CB and Mundlos, S and Mhlanga, MM and Cremers, FPM and Cheetham, ME and Roosing, S and Hardcastle, AJ},
title = {Structural Variants Create New Topological-Associated Domains and Ectopic Retinal Enhancer-Gene Contact in Dominant Retinitis Pigmentosa.},
journal = {American journal of human genetics},
volume = {107},
number = {5},
pages = {802-814},
pmid = {33022222},
issn = {1537-6605},
support = {MC_UU_00024/1/MRC_/Medical Research Council/United Kingdom ; 205041/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; MC_U123160651/MRC_/Medical Research Council/United Kingdom ; MR/R012121/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Adult ; Amino Acid Sequence ; Cell Differentiation ; Cellular Reprogramming ; Child ; Chromosome Mapping ; Chromosomes, Human, Pair 17/*chemistry ; Cohort Studies ; Enhancer Elements, Genetic ; Female ; Fibroblasts/metabolism/pathology ; Gene Expression ; Genes, Dominant ; Genome, Human ; Humans ; Induced Pluripotent Stem Cells/metabolism/pathology ; Male ; Nuclear Proteins/*genetics/metabolism ; Organoids/metabolism/pathology ; Phosphoric Diester Hydrolases/*genetics/metabolism ; Polymorphism, Genetic ; Primary Cell Culture ; Retinal Cone Photoreceptor Cells/*metabolism/pathology ; Retinitis Pigmentosa/diagnosis/*genetics/metabolism/pathology ; Transcription Factors/*genetics/metabolism ; Whole Genome Sequencing ; },
abstract = {The cause of autosomal-dominant retinitis pigmentosa (adRP), which leads to loss of vision and blindness, was investigated in families lacking a molecular diagnosis. A refined locus for adRP on Chr17q22 (RP17) was delineated through genotyping and genome sequencing, leading to the identification of structural variants (SVs) that segregate with disease. Eight different complex SVs were characterized in 22 adRP-affected families with >300 affected individuals. All RP17 SVs had breakpoints within a genomic region spanning YPEL2 to LINC01476. To investigate the mechanism of disease, we reprogrammed fibroblasts from affected individuals and controls into induced pluripotent stem cells (iPSCs) and differentiated them into photoreceptor precursor cells (PPCs) or retinal organoids (ROs). Hi-C was performed on ROs, and differential expression of regional genes and a retinal enhancer RNA at this locus was assessed by qPCR. The epigenetic landscape of the region, and Hi-C RO data, showed that YPEL2 sits within its own topologically associating domain (TAD), rich in enhancers with binding sites for retinal transcription factors. The Hi-C map of RP17 ROs revealed creation of a neo-TAD with ectopic contacts between GDPD1 and retinal enhancers, and modeling of all RP17 SVs was consistent with neo-TADs leading to ectopic retinal-specific enhancer-GDPD1 accessibility. qPCR confirmed increased expression of GDPD1 and increased expression of the retinal enhancer that enters the neo-TAD. Altered TAD structure resulting in increased retinal expression of GDPD1 is the likely convergent mechanism of disease, consistent with a dominant gain of function. Our study highlights the importance of SVs as a genomic mechanism in unsolved Mendelian diseases.},
}
@article {pmid33020667,
year = {2020},
author = {Akdemir, KC and Le, VT and Kim, JM and Killcoyne, S and King, DA and Lin, YP and Tian, Y and Inoue, A and Amin, SB and Robinson, FS and Nimmakayalu, M and Herrera, RE and Lynn, EJ and Chan, K and Seth, S and Klimczak, LJ and Gerstung, M and Gordenin, DA and O'Brien, J and Li, L and Deribe, YL and Verhaak, RG and Campbell, PJ and Fitzgerald, R and Morrison, AJ and Dixon, JR and Andrew Futreal, P},
title = {Somatic mutation distributions in cancer genomes vary with three-dimensional chromatin structure.},
journal = {Nature genetics},
volume = {52},
number = {11},
pages = {1178-1188},
pmid = {33020667},
issn = {1546-1718},
support = {DP5 OD023071/OD/NIH HHS/United States ; P30 CA016672/CA/NCI NIH HHS/United States ; ZIA ES103266/ImNIH/Intramural NIH HHS/United States ; P50 CA127001/CA/NCI NIH HHS/United States ; P30 CA014195/CA/NCI NIH HHS/United States ; },
mesh = {Cell Line, Tumor ; Chromatin/*chemistry ; Chromosomes, Human, X/genetics ; DNA Mismatch Repair ; DNA Mutational Analysis ; DNA, Neoplasm ; Datasets as Topic ; Female ; *Genome, Human ; Humans ; Male ; *Mutation ; Neoplasms/*genetics ; Protein Conformation ; Protein Domains ; Protein Folding ; X Chromosome Inactivation ; },
abstract = {Somatic mutations in driver genes may ultimately lead to the development of cancer. Understanding how somatic mutations accumulate in cancer genomes and the underlying factors that generate somatic mutations is therefore crucial for developing novel therapeutic strategies. To understand the interplay between spatial genome organization and specific mutational processes, we studied 3,000 tumor-normal-pair whole-genome datasets from 42 different human cancer types. Our analyses reveal that the change in somatic mutational load in cancer genomes is co-localized with topologically-associating-domain boundaries. Domain boundaries constitute a better proxy to track mutational load change than replication timing measurements. We show that different mutational processes lead to distinct somatic mutation distributions where certain processes generate mutations in active domains, and others generate mutations in inactive domains. Overall, the interplay between three-dimensional genome organization and active mutational processes has a substantial influence on the large-scale mutation-rate variations observed in human cancers.},
}
@article {pmid32987449,
year = {2021},
author = {Goel, VY and Hansen, AS},
title = {The macro and micro of chromosome conformation capture.},
journal = {Wiley interdisciplinary reviews. Developmental biology},
volume = {10},
number = {6},
pages = {e395},
pmid = {32987449},
issn = {1759-7692},
support = {R00 GM130896/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Nucleus ; *Chromatin/genetics ; *Chromosomes/genetics ; Genome ; Promoter Regions, Genetic ; },
abstract = {The 3D organization of the genome facilitates gene regulation, replication, and repair, making it a key feature of genomic function and one that remains to be properly understood. Over the past two decades, a variety of chromosome conformation capture (3C) methods have delineated genome folding from megabase-scale compartments and topologically associating domains (TADs) down to kilobase-scale enhancer-promoter interactions. Understanding the functional role of each layer of genome organization is a gateway to understanding cell state, development, and disease. Here, we discuss the evolution of 3C-based technologies for mapping 3D genome organization. We focus on genomics methods and provide a historical account of the development from 3C to Hi-C. We also discuss ChIP-based techniques that focus on 3D genome organization mediated by specific proteins, capture-based methods that focus on particular regions or regulatory elements, 3C-orthogonal methods that do not rely on restriction digestion and proximity ligation, and methods for mapping the DNA-RNA and RNA-RNA interactomes. We consider the biological discoveries that have come from these methods, examine the mechanistic contributions of CTCF, cohesin, and loop extrusion to genomic folding, and detail the 3D genome field's current understanding of nuclear architecture. Finally, we give special consideration to Micro-C as an emerging frontier in chromosome conformation capture and discuss recent Micro-C findings uncovering fine-scale chromatin organization in unprecedented detail. This article is categorized under: Gene Expression and Transcriptional Hierarchies > Regulatory Mechanisms Gene Expression and Transcriptional Hierarchies > Gene Networks and Genomics.},
}
@article {pmid32986691,
year = {2020},
author = {Xie, WJ and Qi, Y and Zhang, B},
title = {Characterizing chromatin folding coordinate and landscape with deep learning.},
journal = {PLoS computational biology},
volume = {16},
number = {9},
pages = {e1008262},
pmid = {32986691},
issn = {1553-7358},
support = {R35 GM133580/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromatin/chemistry/*metabolism ; Computer Simulation ; *Deep Learning ; Genome ; Histone Code ; Models, Biological ; Protein Conformation ; Thermodynamics ; },
abstract = {Genome organization is critical for setting up the spatial environment of gene transcription, and substantial progress has been made towards its high-resolution characterization. The underlying molecular mechanism for its establishment is much less understood. We applied a deep-learning approach, variational autoencoder (VAE), to analyze the fluctuation and heterogeneity of chromatin structures revealed by single-cell imaging and to identify a reaction coordinate for chromatin folding. This coordinate connects the seemingly random structures observed in individual cohesin-depleted cells as intermediate states along a folding pathway that leads to the formation of topologically associating domains (TAD). We showed that folding into wild-type-like structures remain energetically favorable in cohesin-depleted cells, potentially as a result of the phase separation between the two chromatin segments with active and repressive histone marks. The energetic stabilization, however, is not strong enough to overcome the entropic penalty, leading to the formation of only partially folded structures and the disappearance of TADs from contact maps upon averaging. Our study suggests that machine learning techniques, when combined with rigorous statistical mechanical analysis, are powerful tools for analyzing structural ensembles of chromatin.},
}
@article {pmid32970351,
year = {2021},
author = {Chan, WF and Coughlan, HD and Iannarella, N and Smyth, GK and Johanson, TM and Keenan, CR and Allan, RS},
title = {Identification and characterization of the long noncoding RNA Dreg1 as a novel regulator of Gata3.},
journal = {Immunology and cell biology},
volume = {99},
number = {3},
pages = {323-332},
doi = {10.1111/imcb.12408},
pmid = {32970351},
issn = {1440-1711},
mesh = {Chromatin ; Enhancer Elements, Genetic/genetics ; GATA3 Transcription Factor/genetics/metabolism ; Promoter Regions, Genetic ; *RNA, Long Noncoding/genetics ; },
abstract = {The eukaryotic genome is three-dimensionally segregated into discrete globules of topologically associating domains (TADs), within which numerous cis-regulatory elements such as enhancers and promoters interact to regulate gene expression. In this study, we identify a T-cell-specific sub-TAD containing the Gata3 locus, and reveal a previously uncharacterized long noncoding RNA (Dreg1) within a distant enhancer lying approximately 280 kb downstream of Gata3. Dreg1 expression is highly correlated with that of Gata3 during early immune system development and T helper type 2 cell differentiation. Inhibition and overexpression of Dreg1 suggest that it may be involved in the establishment, but not in the maintenance of Gata3 expression. Overall, we propose that Dreg1 is a novel regulator of Gata3 and may inform therapeutic strategies in diseases such allergy and lymphoma, where Gata3 has a pathological role.},
}
@article {pmid32968472,
year = {2019},
author = {Wang, YXR and Sarkar, P and Ursu, O and Kundaje, A and Bickel, PJ},
title = {NETWORK MODELLING OF TOPOLOGICAL DOMAINS USING HI-C DATA.},
journal = {The annals of applied statistics},
volume = {13},
number = {3},
pages = {1511-1536},
pmid = {32968472},
issn = {1932-6157},
support = {DP2 GM123485/GM/NIGMS NIH HHS/United States ; },
abstract = {Chromosome conformation capture experiments such as Hi-C are used to map the three-dimensional spatial organization of genomes. One specific feature of the 3D organization is known as topologically associating domains (TADs), which are densely interacting, contiguous chromatin regions playing important roles in regulating gene expression. A few algorithms have been proposed to detect TADs. In particular, the structure of Hi-C data naturally inspires application of community detection methods. However, one of the drawbacks of community detection is that most methods take exchangeability of the nodes in the network for granted; whereas the nodes in this case, that is, the positions on the chromosomes, are not exchangeable. We propose a network model for detecting TADs using Hi-C data that takes into account this nonexchangeability. in addition, our model explicitly makes use of cell-type specific CTCF binding sites as biological covariates and can be used to identify conserved TADs across multiple cell types. The model leads to a likelihood objective that can be efficiently optimized via relaxation. We also prove that when suitably initialized, this model finds the underlying TAD structure with high probability. using simulated data, we show the advantages of our method and the caveats of popular community detection methods, such as spectral clustering, in this application. Applying our method to real Hi-C data, we demonstrate the domains identified have desirable epigenetic features and compare them across different cell types.},
}
@article {pmid32968280,
year = {2020},
author = {Mitter, M and Gasser, C and Takacs, Z and Langer, CCH and Tang, W and Jessberger, G and Beales, CT and Neuner, E and Ameres, SL and Peters, JM and Goloborodko, A and Micura, R and Gerlich, DW},
title = {Conformation of sister chromatids in the replicated human genome.},
journal = {Nature},
volume = {586},
number = {7827},
pages = {139-144},
pmid = {32968280},
issn = {1476-4687},
support = {P 27947/FWF_/Austrian Science Fund FWF/Austria ; 281198/ERC_/European Research Council/International ; F 8002/FWF_/Austrian Science Fund FWF/Austria ; 693949/ERC_/European Research Council/International ; F 8011/FWF_/Austrian Science Fund FWF/Austria ; P 31691/FWF_/Austrian Science Fund FWF/Austria ; },
mesh = {Cell Cycle Proteins/metabolism ; Chromatids/*chemistry/genetics/metabolism ; Chromosomal Proteins, Non-Histone/metabolism ; *Chromosome Pairing ; DNA/analysis/biosynthesis ; *DNA Replication ; Genome, Human/*genetics ; Heterochromatin/chemistry/genetics/metabolism ; Humans ; *Nucleic Acid Conformation ; },
abstract = {The three-dimensional organization of the genome supports regulated gene expression, recombination, DNA repair, and chromosome segregation during mitosis. Chromosome conformation capture (Hi-C)[1,2] analysis has revealed a complex genomic landscape of internal chromosomal structures in vertebrate cells[3-7], but the identical sequence of sister chromatids has made it difficult to determine how they topologically interact in replicated chromosomes. Here we describe sister-chromatid-sensitive Hi-C (scsHi-C), which is based on labelling of nascent DNA with 4-thio-thymidine and nucleoside conversion chemistry. Genome-wide conformation maps of human chromosomes reveal that sister-chromatid pairs interact most frequently at the boundaries of topologically associating domains (TADs). Continuous loading of a dynamic cohesin pool separates sister-chromatid pairs inside TADs and is required to focus sister-chromatid contacts at TAD boundaries. We identified a subset of TADs that are overall highly paired and are characterized by facultative heterochromatin and insulated topological domains that form separately within individual sister chromatids. The rich pattern of sister-chromatid topologies and our scsHi-C technology will make it possible to investigate how physical interactions between identical DNA molecules contribute to DNA repair, gene expression, chromosome segregation, and potentially other biological processes.},
}
@article {pmid32967822,
year = {2020},
author = {Miron, E and Oldenkamp, R and Brown, JM and Pinto, DMS and Xu, CS and Faria, AR and Shaban, HA and Rhodes, JDP and Innocent, C and de Ornellas, S and Hess, HF and Buckle, V and Schermelleh, L},
title = {Chromatin arranges in chains of mesoscale domains with nanoscale functional topography independent of cohesin.},
journal = {Science advances},
volume = {6},
number = {39},
pages = {},
pmid = {32967822},
issn = {2375-2548},
support = {MC_UU_00016/1/MRC_/Medical Research Council/United Kingdom ; MR/K01577X/1/MRC_/Medical Research Council/United Kingdom ; MR/N00969X/1/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; },
abstract = {Three-dimensional (3D) chromatin organization plays a key role in regulating mammalian genome function; however, many of its physical features at the single-cell level remain underexplored. Here, we use live- and fixed-cell 3D super-resolution and scanning electron microscopy to analyze structural and functional nuclear organization in somatic cells. We identify chains of interlinked ~200- to 300-nm-wide chromatin domains (CDs) composed of aggregated nucleosomes that can overlap with individual topologically associating domains and are distinct from a surrounding RNA-populated interchromatin compartment. High-content mapping uncovers confinement of cohesin and active histone modifications to surfaces and enrichment of repressive modifications toward the core of CDs in both hetero- and euchromatic regions. This nanoscale functional topography is temporarily relaxed in postreplicative chromatin but remarkably persists after ablation of cohesin. Our findings establish CDs as physical and functional modules of mesoscale genome organization.},
}
@article {pmid32948616,
year = {2020},
author = {Fu, AX and Lui, KN and Tang, CS and Ng, RK and Lai, FP and Lau, ST and Li, Z and Garcia-Barcelo, MM and Sham, PC and Tam, PK and Ngan, ES and Yip, KY},
title = {Whole-genome analysis of noncoding genetic variations identifies multiscale regulatory element perturbations associated with Hirschsprung disease.},
journal = {Genome research},
volume = {30},
number = {11},
pages = {1618-1632},
pmid = {32948616},
issn = {1549-5469},
mesh = {Class II Phosphatidylinositol 3-Kinases/genetics/metabolism ; *Enhancer Elements, Genetic ; Genetic Variation ; Hirschsprung Disease/*genetics ; Humans ; Introns ; NFI Transcription Factors/metabolism ; *Promoter Regions, Genetic ; Proto-Oncogene Proteins c-ret/genetics ; Whole Genome Sequencing ; ras Guanine Nucleotide Exchange Factors/genetics ; },
abstract = {It is widely recognized that noncoding genetic variants play important roles in many human diseases, but there are multiple challenges that hinder the identification of functional disease-associated noncoding variants. The number of noncoding variants can be many times that of coding variants; many of them are not functional but in linkage disequilibrium with the functional ones; different variants can have epistatic effects; different variants can affect the same genes or pathways in different individuals; and some variants are related to each other not by affecting the same gene but by affecting the binding of the same upstream regulator. To overcome these difficulties, we propose a novel analysis framework that considers convergent impacts of different genetic variants on protein binding, which provides multiscale information about disease-associated perturbations of regulatory elements, genes, and pathways. Applying it to our whole-genome sequencing data of 918 short-segment Hirschsprung disease patients and matched controls, we identify various novel genes not detected by standard single-variant and region-based tests, functionally centering on neural crest migration and development. Our framework also identifies upstream regulators whose binding is influenced by the noncoding variants. Using human neural crest cells, we confirm cell stage-specific regulatory roles of three top novel regulatory elements on our list, respectively in the RET, RASGEF1A, and PIK3C2B loci. In the PIK3C2B regulatory element, we further show that a noncoding variant found only in the patients affects the binding of the gliogenesis regulator NFIA, with a corresponding up-regulation of multiple genes in the same topologically associating domain.},
}
@article {pmid32896099,
year = {2021},
author = {Serna-Pujol, N and Salinas-Pena, M and Mugianesi, F and Lopez-Anguita, N and Torrent-Llagostera, F and Izquierdo-Bouldstridge, A and Marti-Renom, MA and Jordan, A},
title = {TADs enriched in histone H1.2 strongly overlap with the B compartment, inaccessible chromatin, and AT-rich Giemsa bands.},
journal = {The FEBS journal},
volume = {288},
number = {6},
pages = {1989-2013},
doi = {10.1111/febs.15549},
pmid = {32896099},
issn = {1742-4658},
mesh = {*Azure Stains ; Base Composition/*genetics ; Breast Neoplasms/genetics/metabolism/pathology ; Cell Line, Tumor ; Chromatin/*genetics/metabolism ; Chromatin Assembly and Disassembly/*genetics ; Epigenesis, Genetic ; Epigenomics/methods ; Gene Expression Profiling/methods ; Gene Expression Regulation, Neoplastic ; Histones/*genetics/metabolism ; Humans ; },
abstract = {Giemsa staining of metaphase chromosomes results in a characteristic banding useful for identification of chromosomes and its alterations. We have investigated in silico whether Giemsa bands (G bands) correlate with epigenetic and topological features of the interphase genome. Staining of G-positive bands decreases with GC content; nonetheless, G-negative bands are GC heterogeneous. High GC bands are enriched in active histone marks, RNA polymerase II, and SINEs and associate with gene richness, gene expression, and early replication. Low GC bands are enriched in repressive marks, lamina-associated domains, and LINEs. Histone H1 variants distribute heterogeneously among G bands: H1X is enriched at high GC bands and H1.2 is abundant at low GC, compacted bands. According to epigenetic features and H1 content, G bands can be organized in clusters useful to compartmentalize the genome. Indeed, we have obtained Hi-C chromosome interaction maps and compared topologically associating domains (TADs) and A/B compartments to G banding. TADs with high H1.2/H1X ratio strongly overlap with B compartment, late replicating, and inaccessible chromatin and low GC bands. We propose that GC content is a strong driver of chromatin compaction and 3D genome organization, that Giemsa staining recapitulates this organization denoted by high-throughput techniques, and that H1 variants distribute at distinct chromatin domains. DATABASES: Hi-C data on T47D breast cancer cells have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO Series accession number GSE147627.},
}
@article {pmid32820401,
year = {2021},
author = {Forcato, M and Bicciato, S},
title = {Computational Analysis of Hi-C Data.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {2157},
number = {},
pages = {103-125},
doi = {10.1007/978-1-0716-0664-3_7},
pmid = {32820401},
issn = {1940-6029},
mesh = {Chromatin/*chemistry/*metabolism ; Computational Biology/*methods ; Humans ; Nucleic Acid Conformation ; },
abstract = {The chromatin organization in the 3D nuclear space is essential for genome functionality. This spatial organization encompasses different topologies at diverse scale lengths with chromosomes occupying distinct volumes and individual chromosomes folding into compartments, inside which the chromatin fiber is packed in large domains (as the topologically associating domains, TADs) and forms short-range interactions (as enhancer-promoter loops). The widespread adoption of high-throughput techniques derived from chromosome conformation capture (3C) has been instrumental in investigating the nuclear organization of chromatin. In particular, Hi-C has the potential to achieve the most comprehensive characterization of chromatin 3D structures, as in principle it can detect any pair of restriction fragments connected as a result of ligation by proximity. However, the analysis of the enormous amount of genomic data produced by Hi-C techniques requires the application of complex, multistep computational procedures that may constitute a difficult task also for expert computational biologists. In this chapter, we describe the computational analysis of Hi-C data obtained from the lymphoblastoid cell line GM12878, detailing the processing of raw data, the generation and normalization of the Hi-C contact map, the detection of TADs and chromatin interactions, and their visualization and annotation.},
}
@article {pmid32820398,
year = {2021},
author = {Di Stefano, M and Castillo, D and Serra, F and Farabella, I and Goodstadt, MN and Marti-Renom, MA},
title = {Analysis, Modeling, and Visualization of Chromosome Conformation Capture Experiments.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {2157},
number = {},
pages = {35-63},
doi = {10.1007/978-1-0716-0664-3_4},
pmid = {32820398},
issn = {1940-6029},
mesh = {Animals ; Chromatin/genetics/metabolism ; Chromosomes, Human/genetics/*metabolism ; Genome, Human/genetics/physiology ; Humans ; },
abstract = {Chromatin Conformation Capture techniques have unveiled several layers of chromosome organization such as the segregation in compartments, the folding in topologically associating domains (TADs), and site-specific looping interactions. The discovery of this genome hierarchical organization emerged from the computational analysis of chromatin capture data. With the increasing availability of such data, automatic pipelines for the robust comparison, grouping, and classification of multiple experiments are needed. Here we present a pipeline based on the TADbit framework that emphasizes reproducibility, automation, quality check, and statistical robustness. This comprehensive modular pipeline covers all the steps from the sequencing products to the visualization of reconstructed 3D models of the chromatin.},
}
@article {pmid32806598,
year = {2020},
author = {Nath, N and Hagenau, L and Weiss, S and Tzvetkova, A and Jensen, LR and Kaderali, L and Port, M and Scherthan, H and Kuss, AW},
title = {Genome-Wide DNA Alterations in X-Irradiated Human Gingiva Fibroblasts.},
journal = {International journal of molecular sciences},
volume = {21},
number = {16},
pages = {},
pmid = {32806598},
issn = {1422-0067},
mesh = {Chromosomes, Human, Pair 19/genetics ; DNA/*genetics/*radiation effects ; DNA Copy Number Variations/genetics ; Databases, Genetic ; Fibroblasts/*pathology/*radiation effects ; *Genome, Human ; Gingiva/*cytology ; Humans ; INDEL Mutation/genetics ; Translocation, Genetic ; X-Rays ; },
abstract = {While ionizing radiation (IR) is a powerful tool in medical diagnostics, nuclear medicine, and radiology, it also is a serious threat to the integrity of genetic material. Mutagenic effects of IR to the human genome have long been the subject of research, yet still comparatively little is known about the genome-wide effects of IR exposure on the DNA-sequence level. In this study, we employed high throughput sequencing technologies to investigate IR-induced DNA alterations in human gingiva fibroblasts (HGF) that were acutely exposed to 0.5, 2, and 10 Gy of 240 kV X-radiation followed by repair times of 16 h or 7 days before whole-genome sequencing (WGS). Our analysis of the obtained WGS datasets revealed patterns of IR-induced variant (SNV and InDel) accumulation across the genome, within chromosomes as well as around the borders of topologically associating domains (TADs). Chromosome 19 consistently accumulated the highest SNVs and InDels events. Translocations showed variable patterns but with recurrent chromosomes of origin (e.g., Chr7 and Chr16). IR-induced InDels showed a relative increase in number relative to SNVs and a characteristic signature with respect to the frequency of triplet deletions in areas without repetitive or microhomology features. Overall experimental conditions and datasets the majority of SNVs per genome had no or little predicted functional impact with a maximum of 62, showing damaging potential. A dose-dependent effect of IR was surprisingly not apparent. We also observed a significant reduction in transition/transversion (Ti/Tv) ratios for IR-dependent SNVs, which could point to a contribution of the mismatch repair (MMR) system that strongly favors the repair of transitions over transversions, to the IR-induced DNA-damage response in human cells. Taken together, our results show the presence of distinguishable characteristic patterns of IR-induced DNA-alterations on a genome-wide level and implicate DNA-repair mechanisms in the formation of these signatures.},
}
@article {pmid32805187,
year = {2020},
author = {Zhang, X and Lei, F and Wang, XM and Deng, KQ and Ji, YX and Zhang, Y and Li, H and Zhang, XD and Lu, Z and Zhang, P},
title = {NULP1 Alleviates Cardiac Hypertrophy by Suppressing NFAT3 Transcriptional Activity.},
journal = {Journal of the American Heart Association},
volume = {9},
number = {16},
pages = {e016419},
pmid = {32805187},
issn = {2047-9980},
mesh = {Animals ; Basic Helix-Loop-Helix Transcription Factors/deficiency/genetics/*metabolism ; Cardiomegaly/diagnostic imaging/genetics/*metabolism/therapy ; Echocardiography ; Gene Deletion ; Humans ; Immunoprecipitation/methods ; Mice ; Mice, Knockout ; Mice, Transgenic ; Myocytes, Cardiac/metabolism ; NFATC Transcription Factors/antagonists &amp; inhibitors/genetics/*metabolism ; Oligopeptides/pharmacology ; Phosphoric Monoester Hydrolases/metabolism ; Rats ; Rats, Sprague-Dawley ; Repressor Proteins/deficiency/genetics/*metabolism ; Transcription, Genetic ; },
abstract = {Background The development of pathological cardiac hypertrophy involves the coordination of a series of transcription activators and repressors, while their interplay to trigger pathological gene reprogramming remains unclear. NULP1 (nuclear localized protein 1) is a member of the basic helix-loop-helix family of transcription factors and its biological functions in pathological cardiac hypertrophy are barely understood. Methods and Results Immunoblot and immunostaining analyses showed that NULP1 expression was consistently reduced in the failing hearts of patients and hypertrophic mouse hearts and rat cardiomyocytes. Nulp1 knockout exacerbates aortic banding-induced cardiac hypertrophy pathology, which was significantly blunted by transgenic overexpression of Nulp1. Signal pathway screening revealed the nuclear factor of activated T cells (NFAT) pathway to be dramatically suppressed by NULP1. Coimmunoprecipitation showed that NULP1 directly interacted with the topologically associating domain of NFAT3 via its C-terminal region, which was sufficient to suppress NFAT3 transcriptional activity. Inactivation of the NFAT pathway by VIVIT peptides in vivo rescued the aggravated pathogenesis of cardiac hypertrophy resulting from Nulp1 deficiency. Conclusions NULP1 is an endogenous suppressor of NFAT3 signaling under hypertrophic stress and thus negatively regulates the pathogenesis of cardiac hypertrophy. Targeting overactivated NFAT by NULP1 may be a novel therapeutic strategy for the treatment of pathological cardiac hypertrophy and heart failure.},
}
@article {pmid32782014,
year = {2020},
author = {Nanni, L and Ceri, S and Logie, C},
title = {Spatial patterns of CTCF sites define the anatomy of TADs and their boundaries.},
journal = {Genome biology},
volume = {21},
number = {1},
pages = {197},
pmid = {32782014},
issn = {1474-760X},
mesh = {CCCTC-Binding Factor/*metabolism ; *Genome, Human ; Humans ; },
abstract = {BACKGROUND: Topologically associating domains (TADs) are genomic regions of self-interaction. Additionally, it is known that TAD boundaries are enriched in CTCF binding sites. In turn, CTCF sites are known to be asymmetric, whereby the convergent configuration of a pair of CTCF sites leads to the formation of a chromatin loop in vivo. However, to date, it has been unclear how to reconcile TAD structure with CTCF-based chromatin loops.<br><br>RESULTS: We approach this problem by analysing CTCF binding site strengths and classifying clusters of CTCF sites along the genome on the basis of their relative orientation. Analysis of CTCF site orientation classes as a function of their spatial distribution along the human genome reveals that convergent CTCF site clusters are depleted while divergent CTCF clusters are enriched in the 5- to 100-kb range. We then analyse the distribution of CTCF binding sites as a function of TAD boundary conservation across seven primary human blood cell types. This reveals divergent CTCF site enrichment at TAD boundaries. Furthermore, convergent arrays of CTCF sites separate the left and right sections of TADs that harbour internal CTCF sites, resulting in unequal TAD 'halves'.<br><br>CONCLUSIONS: The orientation-based CTCF binding site cluster classification that we present reconciles TAD boundaries and CTCF site clusters in a mechanistically elegant fashion. This model suggests that the emergent structure of nuclear chromatin in the form of TADs relies on the obligate alternation of divergent and convergent CTCF site clusters that occur at different length scales along the genome.},
}
@article {pmid32767399,
year = {2020},
author = {Khazeem, MM and Cowell, IG and Harkin, LF and Casement, JW and Austin, CA},
title = {Transcription of carbonyl reductase 1 is regulated by DNA topoisomerase II beta.},
journal = {FEBS letters},
volume = {594},
number = {20},
pages = {3395-3405},
doi = {10.1002/1873-3468.13904},
pmid = {32767399},
issn = {1873-3468},
mesh = {Carbonyl Reductase (NADPH)/*genetics/metabolism ; Cell Line ; DNA Topoisomerases, Type II/*metabolism ; Epigenesis, Genetic ; Gene Expression Profiling ; *Gene Expression Regulation ; Genome, Human ; Humans ; Promoter Regions, Genetic ; *Transcription, Genetic ; },
abstract = {DNA topoisomerase II beta (TOP2B) has a role in transcriptional regulation. Here, to further investigate transcriptional regulation by TOP2B, we used RNA-sequencing and real-time PCR to analyse the differential gene expression profiles of wild-type and two independent TOP2B-null pre-B Nalm-6 cell lines, one generated by targeted insertion and the other using CRISPR-Cas9 gene editing. We identified carbonyl reductase 1 (CBR1) among the most significantly downregulated genes in these TOP2B-null cells. Reduced CBR1 expression was accompanied by loss of binding of the transcription factors USF2 and MAX to the CBR1 promoter. We describe possible mechanisms by which loss of TOP2B results in CBR1 downregulation. To our knowledge, this is the first report of a link between TOP2B and CBR1.},
}
@article {pmid32746892,
year = {2020},
author = {Heurteau, A and Perrois, C and Depierre, D and Fosseprez, O and Humbert, J and Schaak, S and Cuvier, O},
title = {Insulator-based loops mediate the spreading of H3K27me3 over distant micro-domains repressing euchromatin genes.},
journal = {Genome biology},
volume = {21},
number = {1},
pages = {193},
pmid = {32746892},
issn = {1474-760X},
mesh = {Animals ; Cell Line ; DNA-Binding Proteins/*metabolism ; Drosophila ; Drosophila Proteins/*metabolism ; Eye Proteins/*metabolism ; Genome, Insect ; Heterochromatin/*metabolism ; Histone Code ; Histone Methyltransferases/*metabolism ; },
}
@article {pmid32680543,
year = {2020},
author = {Matthews, BJ and Waxman, DJ},
title = {Impact of 3D genome organization, guided by cohesin and CTCF looping, on sex-biased chromatin interactions and gene expression in mouse liver.},
journal = {Epigenetics &amp; chromatin},
volume = {13},
number = {1},
pages = {30},
pmid = {32680543},
issn = {1756-8935},
support = {R01 DK121998/DK/NIDDK NIH HHS/United States ; DK121998/DK/NIDDK NIH HHS/United States ; DK33765/DK/NIDDK NIH HHS/United States ; DGE-1247312//National Science Foundation/International ; },
mesh = {Animals ; CCCTC-Binding Factor/chemistry/metabolism ; Cell Cycle Proteins/metabolism ; Chromatin/*metabolism ; Chromatin Assembly and Disassembly ; Chromosomal Proteins, Non-Histone/metabolism ; Enhancer Elements, Genetic ; Female ; *Genome ; Liver/*metabolism ; Male ; Mice ; *Sex ; },
abstract = {Several thousand sex-differential distal enhancers have been identified in mouse liver; however, their links to sex-biased genes and the impact of any sex-differences in nuclear organization and chromatin interactions are unknown. To address these issues, we first characterized 1847 mouse liver genomic regions showing significant sex differential occupancy by cohesin and CTCF, two key 3D nuclear organizing factors. These sex-differential binding sites were primarily distal to sex-biased genes but rarely generated sex-differential TAD (topologically associating domain) or intra-TAD loop anchors, and were sometimes found in TADs without sex-biased genes. A substantial subset of sex-biased cohesin-non-CTCF binding sites, but not sex-biased cohesin-and-CTCF binding sites, overlapped sex-biased enhancers. Cohesin depletion reduced the expression of male-biased genes with distal, but not proximal, sex-biased enhancers by >10-fold, implicating cohesin in long-range enhancer interactions regulating sex-biased genes. Using circularized chromosome conformation capture-based sequencing (4C-seq), we showed that sex differences in distal sex-biased enhancer-promoter interactions are common. Intra-TAD loops with sex-independent cohesin-and-CTCF anchors conferred sex specificity to chromatin interactions indirectly, by insulating sex-biased enhancer-promoter contacts and by bringing sex-biased genes into closer proximity to sex-biased enhancers. Furthermore, sex-differential chromatin interactions involving sex-biased gene promoters, enhancers, and lncRNAs were associated with sex-biased binding of cohesin and/or CTCF. These studies elucidate how 3D genome organization impacts sex-biased gene expression in a non-reproductive tissue through both direct and indirect effects of cohesin and CTCF looping on distal enhancer interactions with sex-differentially expressed genes.},
}
@article {pmid32663239,
year = {2020},
author = {Liang, M and Soomro, A and Tasneem, S and Abatti, LE and Alizada, A and Yuan, X and Uusküla-Reimand, L and Antounians, L and Alvi, SA and Paterson, AD and Rivard, G&#xc9; and Scott, IC and Mitchell, JA and Hayward, CPM and Wilson, MD},
title = {Enhancer-gene rewiring in the pathogenesis of Quebec platelet disorder.},
journal = {Blood},
volume = {136},
number = {23},
pages = {2679-2690},
pmid = {32663239},
issn = {1528-0020},
support = {201603PJT-364832/CAPMC/CIHR/Canada ; },
mesh = {Animals ; *Enhancer Elements, Genetic ; *Factor V Deficiency/genetics/metabolism/pathology ; Female ; *Gene Duplication ; *Gene Expression Regulation ; Humans ; Megakaryocytes/*metabolism/pathology ; *Membrane Proteins/biosynthesis/genetics ; Zebrafish ; },
abstract = {Quebec platelet disorder (QPD) is an autosomal dominant bleeding disorder with a unique, platelet-dependent, gain-of-function defect in fibrinolysis, without systemic fibrinolysis. The hallmark feature of QPD is a >100-fold overexpression of PLAU, specifically in megakaryocytes. This overexpression leads to a >100-fold increase in platelet stores of urokinase plasminogen activator (PLAU/uPA); subsequent plasmin-mediated degradation of diverse α-granule proteins; and platelet-dependent, accelerated fibrinolysis. The causative mutation is a 78-kb tandem duplication of PLAU. How this duplication causes megakaryocyte-specific PLAU overexpression is unknown. To investigate the mechanism that causes QPD, we used epigenomic profiling, comparative genomics, and chromatin conformation capture approaches to study PLAU regulation in cultured megakaryocytes from participants with QPD and unaffected controls. QPD duplication led to ectopic interactions between PLAU and a conserved megakaryocyte enhancer found within the same topologically associating domain (TAD). Our results support a unique disease mechanism whereby the reorganization of sub-TAD genome architecture results in a dramatic, cell-type-specific blood disorder phenotype.},
}
@article {pmid32619215,
year = {2020},
author = {Danieli, A and Papantonis, A},
title = {Spatial genome architecture and the emergence of malignancy.},
journal = {Human molecular genetics},
volume = {29},
number = {R2},
pages = {R197-R204},
doi = {10.1093/hmg/ddaa128},
pmid = {32619215},
issn = {1460-2083},
mesh = {*Chromatin Assembly and Disassembly ; Chromosomes, Human/*chemistry/genetics ; Genome, Human ; Humans ; Neoplasms/etiology/*pathology ; *Promoter Regions, Genetic ; },
abstract = {Human chromosomes are large spatially and hierarchically structured entities, the integrity of which needs to be preserved throughout the lifespan of the cell and in conjunction with cell cycle progression. Preservation of chromosomal structure is important for proper deployment of cell type-specific gene expression programs. Thus, aberrations in the integrity and structure of chromosomes will predictably lead to disease, including cancer. Here, we provide an updated standpoint with respect to chromatin misfolding and the emergence of various cancer types. We discuss recent studies implicating the disruption of topologically associating domains, switching between active and inactive compartments, rewiring of promoter-enhancer interactions in malignancy as well as the effects of single nucleotide polymorphisms in non-coding regions involved in long-range regulatory interactions. In light of these findings, we argue that chromosome conformation studies may now also be useful for patient diagnosis and drug target discovery.},
}
@article {pmid32579944,
year = {2020},
author = {Zhang, K and Wu, DY and Zheng, H and Wang, Y and Sun, QR and Liu, X and Wang, LY and Xiong, WJ and Wang, Q and Rhodes, JDP and Xu, K and Li, L and Lin, Z and Yu, G and Xia, W and Huang, B and Du, Z and Yao, Y and Nasmyth, KA and Klose, RJ and Miao, YL and Xie, W},
title = {Analysis of Genome Architecture during SCNT Reveals a Role of Cohesin in Impeding Minor ZGA.},
journal = {Molecular cell},
volume = {79},
number = {2},
pages = {234-250.e9},
doi = {10.1016/j.molcel.2020.06.001},
pmid = {32579944},
issn = {1097-4164},
support = {209400/Z/17/Z/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Animals ; Cell Cycle Proteins/*physiology ; Cell Line ; Cell Nucleus ; Chromatin/*physiology ; Chromatin Assembly and Disassembly ; Chromosomal Proteins, Non-Histone/*physiology ; Computational Biology/methods ; Datasets as Topic ; Embryonic Development ; Female ; Male ; Mice ; Mice, Inbred C57BL ; *Nuclear Transfer Techniques ; Zygote/*physiology ; },
abstract = {Somatic cell nuclear transfer (SCNT) can reprogram a somatic nucleus to a totipotent state. However, the re-organization of 3D chromatin structure in this process remains poorly understood. Using low-input Hi-C, we revealed that, during SCNT, the transferred nucleus first enters a mitotic-like state (premature chromatin condensation). Unlike fertilized embryos, SCNT embryos show stronger topologically associating domains (TADs) at the 1-cell stage. TADs become weaker at the 2-cell stage, followed by gradual consolidation. Compartments A/B are markedly weak in 1-cell SCNT embryos and become increasingly strengthened afterward. By the 8-cell stage, somatic chromatin architecture is largely reset to embryonic patterns. Unexpectedly, we found cohesin represses minor zygotic genome activation (ZGA) genes (2-cell-specific genes) in pluripotent and differentiated cells, and pre-depleting cohesin in donor cells facilitates minor ZGA and SCNT. These data reveal multi-step reprogramming of 3D chromatin architecture during SCNT and support dual roles of cohesin in TAD formation and minor ZGA repression.},
}
@article {pmid32572210,
year = {2020},
author = {Luppino, JM and Park, DS and Nguyen, SC and Lan, Y and Xu, Z and Yunker, R and Joyce, EF},
title = {Cohesin promotes stochastic domain intermingling to ensure proper regulation of boundary-proximal genes.},
journal = {Nature genetics},
volume = {52},
number = {8},
pages = {840-848},
pmid = {32572210},
issn = {1546-1718},
support = {R35 GM128903/GM/NIGMS NIH HHS/United States ; T32 GM008216/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Cycle Proteins/*genetics ; Cell Line, Tumor ; Chromatin/genetics ; Chromosomal Proteins, Non-Histone/*genetics ; Genome, Human/*genetics ; HCT116 Cells ; Humans ; Protein Binding/*genetics ; Regulatory Sequences, Nucleic Acid/*genetics ; Transcription, Genetic/genetics ; },
abstract = {The human genome can be segmented into topologically associating domains (TADs), which have been proposed to spatially sequester genes and regulatory elements through chromatin looping. Interactions between TADs have also been suggested, presumably because of variable boundary positions across individual cells. However, the nature, extent and consequence of these dynamic boundaries remain unclear. Here, we combine high-resolution imaging with Oligopaint technology to quantify the interaction frequencies across both weak and strong boundaries. We find that chromatin intermingling across population-defined boundaries is widespread but that the extent of permissibility is locus-specific. Cohesin depletion, which abolishes domain formation at the population level, does not induce ectopic interactions but instead reduces interactions across all boundaries tested. In contrast, WAPL or CTCF depletion increases inter-domain contacts in a cohesin-dependent manner. Reduced chromatin intermingling due to cohesin loss affects the topology and transcriptional bursting frequencies of genes near boundaries. We propose that cohesin occasionally bypasses boundaries to promote incorporation of boundary-proximal genes into neighboring domains.},
}
@article {pmid32568101,
year = {2020},
author = {Chen, SL and Hu, F and Wang, DW and Qin, ZY and Liang, Y and Dai, YJ},
title = {Prognosis and regulation of an adenylyl cyclase network in acute myeloid leukemia.},
journal = {Aging},
volume = {12},
number = {12},
pages = {11864-11877},
pmid = {32568101},
issn = {1945-4589},
mesh = {Adenylyl Cyclases/*genetics/metabolism ; Antineoplastic Combined Chemotherapy Protocols/pharmacology/therapeutic use ; Apoptosis/genetics ; Biomarkers, Tumor/*genetics/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Computational Biology ; Datasets as Topic ; Drug Screening Assays, Antitumor ; Drug Synergism ; Gene Expression Profiling ; *Gene Expression Regulation, Leukemic ; Gene Regulatory Networks/drug effects/genetics ; Humans ; Kaplan-Meier Estimate ; Leukemia, Myeloid, Acute/*genetics/mortality/pathology ; MAP Kinase Signaling System/drug effects/genetics ; Mutation ; Prognosis ; Protein Interaction Maps/drug effects/genetics ; Protein Kinase Inhibitors/pharmacology/therapeutic use ; },
abstract = {We explored the roles of adenylyl cyclases (ADCYs) in acute myeloid leukemia (AML). Expression ADCYs in AML and their effect on prognosis was analyzed using data from Oncomine, GEPIA and cBioPortal databases. Frequently altered neighbor genes (FANGs) of ADCYs were detected using the 3D Genome Browser, after which the functions of these FANGs were predicted using Metascape tools. Cell viability and apoptosis were assessed using CCK-8 and Annexin V-FITC/PI kits. Expression levels of ADCYs were higher in AML cells lines and in bone marrow-derived mononuclear cells from AML patients than in control cells, and were predictive of a poor prognosis. A total of 58 ADCY FANGs were identified from the topologically associating domains on the basis of the Hi-C data. Functional analysis of these FANGs revealed abnormal activation of the MAPK signaling pathway. Drug sensitivity tests showed that fasudil plus trametinib or sapanisertib had a synergistic effect suppressing AML cell viability and increasing apoptosis. These findings suggest that dysregulation of ADCY expression leads to altered signaling in the MAPK pathway in AML and that the ADCY expression profile may be predictive of prognosis in AML patients.},
}
@article {pmid32554599,
year = {2020},
author = {Maharjan, M and McKowen, JK and Hart, CM},
title = {Overlapping but Distinct Sequences Play Roles in the Insulator and Promoter Activities of the Drosophila BEAF-Dependent scs' Insulator.},
journal = {Genetics},
volume = {215},
number = {4},
pages = {1003-1012},
pmid = {32554599},
issn = {1943-2631},
mesh = {Animals ; Chromatin/*genetics ; Chromosomes/*genetics ; DNA-Binding Proteins/*genetics/metabolism ; Drosophila Proteins/*genetics/metabolism ; Drosophila melanogaster/*genetics/growth &amp; development/metabolism ; Eye Proteins/*genetics/metabolism ; Female ; *Insulator Elements ; *Promoter Regions, Genetic ; },
abstract = {Chromatin domain insulators are thought to help partition the genome into genetic units called topologically associating domains (TADs). In Drosophila, TADs are often separated by inter-TAD regions containing active housekeeping genes and associated insulator binding proteins. This raises the question of whether insulator binding proteins are involved primarily in chromosomal TAD architecture or gene activation, or if these two activities are linked. The Boundary Element-Associated Factor of 32 kDa (BEAF-32, or BEAF for short) is usually found in inter-TADs. BEAF was discovered based on binding to the scs' insulator, and is important for the insulator activity of scs' and other BEAF binding sites. There are divergent promoters in scs' with a BEAF binding site by each. Here, we dissect the scs' insulator to identify DNA sequences important for insulator and promoter activity, focusing on the half of scs' with a high affinity BEAF binding site. We find that the BEAF binding site is important for both insulator and promoter activity, as is another sequence we refer to as LS4. Aside from that, different sequences play roles in insulator and promoter activity. So while there is overlap and BEAF is important for both, insulator and promoter activity can be separated.},
}
@article {pmid32514124,
year = {2020},
author = {Stik, G and Vidal, E and Barrero, M and Cuartero, S and Vila-Casadesús, M and Mendieta-Esteban, J and Tian, TV and Choi, J and Berenguer, C and Abad, A and Borsari, B and le Dily, F and Cramer, P and Marti-Renom, MA and Stadhouders, R and Graf, T},
title = {CTCF is dispensable for immune cell transdifferentiation but facilitates an acute inflammatory response.},
journal = {Nature genetics},
volume = {52},
number = {7},
pages = {655-661},
pmid = {32514124},
issn = {1546-1718},
mesh = {Antigens, Differentiation/metabolism ; B-Lymphocytes/*physiology ; CCCTC-Binding Factor/genetics/*physiology ; Cell Line, Tumor ; Cell Proliferation/physiology ; Chromatin/physiology ; Gene Expression Regulation ; Humans ; Macrophages/*physiology ; Molecular Conformation ; Myelopoiesis/genetics/*physiology ; Protein Conformation ; },
abstract = {Three-dimensional organization of the genome is important for transcriptional regulation[1-7]. In mammals, CTCF and the cohesin complex create submegabase structures with elevated internal chromatin contact frequencies, called topologically associating domains (TADs)[8-12]. Although TADs can contribute to transcriptional regulation, ablation of TAD organization by disrupting CTCF or the cohesin complex causes modest gene expression changes[13-16]. In contrast, CTCF is required for cell cycle regulation[17], embryonic development and formation of various adult cell types[18]. To uncouple the role of CTCF in cell-state transitions and cell proliferation, we studied the effect of CTCF depletion during the conversion of human leukemic B cells into macrophages with minimal cell division. CTCF depletion disrupts TAD organization but not cell transdifferentiation. In contrast, CTCF depletion in induced macrophages impairs the full-blown upregulation of inflammatory genes after exposure to endotoxin. Our results demonstrate that CTCF-dependent genome topology is not strictly required for a functional cell-fate conversion but facilitates a rapid and efficient response to an external stimulus.},
}
@article {pmid32499403,
year = {2020},
author = {Kang, H and Shokhirev, MN and Xu, Z and Chandran, S and Dixon, JR and Hetzer, MW},
title = {Dynamic regulation of histone modifications and long-range chromosomal interactions during postmitotic transcriptional reactivation.},
journal = {Genes &amp; development},
volume = {34},
number = {13-14},
pages = {913-930},
pmid = {32499403},
issn = {1549-5477},
support = {DP5 OD023071/OD/NIH HHS/United States ; P30 CA014195/CA/NCI NIH HHS/United States ; R01 GM126829/GM/NIGMS NIH HHS/United States ; R01 NS096786/NS/NINDS NIH HHS/United States ; },
mesh = {Animals ; Cell Cycle Checkpoints/genetics ; Chromatin/*metabolism ; Chromosomes/genetics/metabolism ; Enhancer Elements, Genetic ; Genome/genetics ; Histone Code/*genetics ; Histones/*metabolism ; Humans ; Mitosis/*genetics ; Promoter Regions, Genetic ; Protein Binding ; Protein Processing, Post-Translational/*genetics ; Time Factors ; Transcriptional Activation/*genetics ; },
abstract = {During mitosis, transcription of genomic DNA is dramatically reduced, before it is reactivated during nuclear reformation in anaphase/telophase. Many aspects of the underlying principles that mediate transcriptional memory and reactivation in the daughter cells remain unclear. Here, we used ChIP-seq on synchronized cells at different stages after mitosis to generate genome-wide maps of histone modifications. Combined with EU-RNA-seq and Hi-C analyses, we found that during prometaphase, promoters, enhancers, and insulators retain H3K4me3 and H3K4me1, while losing H3K27ac. Enhancers globally retaining mitotic H3K4me1 or locally retaining mitotic H3K27ac are associated with cell type-specific genes and their transcription factors for rapid transcriptional activation. As cells exit mitosis, promoters regain H3K27ac, which correlates with transcriptional reactivation. Insulators also gain H3K27ac and CCCTC-binding factor (CTCF) in anaphase/telophase. This increase of H3K27ac in anaphase/telophase is required for posttranscriptional activation and may play a role in the establishment of topologically associating domains (TADs). Together, our results suggest that the genome is reorganized in a sequential order, in which histone methylations occur first in prometaphase, histone acetylation, and CTCF in anaphase/telophase, transcription in cytokinesis, and long-range chromatin interactions in early G1. We thus provide insights into the histone modification landscape that allows faithful reestablishment of the transcriptional program and TADs during cell division.},
}
@article {pmid32486876,
year = {2020},
author = {Papanicolaou, N and Bonetti, A},
title = {The New Frontier of Functional Genomics: From Chromatin Architecture and Noncoding RNAs to Therapeutic Targets.},
journal = {SLAS discovery : advancing life sciences R &amp; D},
volume = {25},
number = {6},
pages = {568-580},
pmid = {32486876},
issn = {2472-5560},
mesh = {Chromatin/*genetics ; Genome, Human ; Genome-Wide Association Study ; *Genomics ; Humans ; Molecular Targeted Therapy/*trends ; Promoter Regions, Genetic/genetics ; RNA, Untranslated/*genetics ; },
abstract = {Common diseases are complex, multifactorial disorders whose pathogenesis is influenced by the interplay of genetic predisposition and environmental factors. Genome-wide association studies have interrogated genetic polymorphisms across genomes of individuals to test associations between genotype and susceptibility to specific disorders, providing insights into the genetic architecture of several complex disorders. However, genetic variants associated with the susceptibility to common diseases are often located in noncoding regions of the genome, such as tissue-specific enhancers or long noncoding RNAs, suggesting that regulatory elements might play a relevant role in human diseases. Enhancers are cis-regulatory genomic sequences that act in concert with promoters to regulate gene expression in a precise spatiotemporal manner. They can be located at a considerable distance from their cognate target promoters, increasing the difficulty of their identification. Genomes are organized in domains of chromatin folding, namely topologically associating domains (TADs). Identification of enhancer-promoter interactions within TADs has revealed principles of cell-type specificity across several organisms and tissues. The vast majority of mammalian genomes are pervasively transcribed, accounting for a previously unappreciated complexity of the noncoding RNA fraction. Particularly, long noncoding RNAs have emerged as key players for the establishment of chromatin architecture and regulation of gene expression. In this perspective, we describe the new advances in the fields of transcriptomics and genome organization, focusing on the role of noncoding genomic variants in the predisposition of common diseases. Finally, we propose a new framework for the identification of the next generation of pharmacological targets for common human diseases.},
}
@article {pmid32483172,
year = {2020},
author = {Oudelaar, AM and Beagrie, RA and Gosden, M and de Ornellas, S and Georgiades, E and Kerry, J and Hidalgo, D and Carrelha, J and Shivalingam, A and El-Sagheer, AH and Telenius, JM and Brown, T and Buckle, VJ and Socolovsky, M and Higgs, DR and Hughes, JR},
title = {Dynamics of the 4D genome during in vivo lineage specification and differentiation.},
journal = {Nature communications},
volume = {11},
number = {1},
pages = {2722},
pmid = {32483172},
issn = {2041-1723},
support = {G1000801/MRC_/Medical Research Council/United Kingdom ; MR/N00969X/1/MRC_/Medical Research Council/United Kingdom ; MC_UU_00016/MRC_/Medical Research Council/United Kingdom ; MC_UU_12009/15/MRC_/Medical Research Council/United Kingdom ; R01 DK100915/DK/NIDDK NIH HHS/United States ; MC_UU_00016/12/MRC_/Medical Research Council/United Kingdom ; BB/R008655/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; MC_PC_15069/MRC_/Medical Research Council/United Kingdom ; BB/M025624/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/J001694/2/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; MC_U137961145/MRC_/Medical Research Council/United Kingdom ; //Wellcome Trust/United Kingdom ; 209181/Z/17/Z/WT_/Wellcome Trust/United Kingdom ; MC_UU_12009/4/MRC_/Medical Research Council/United Kingdom ; MC_UU_00016/1/MRC_/Medical Research Council/United Kingdom ; MC_UU_00016/4/MRC_/Medical Research Council/United Kingdom ; MC_UU_12009/13/MRC_/Medical Research Council/United Kingdom ; MC_U137961144/MRC_/Medical Research Council/United Kingdom ; MC_UU_00016/14/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Animals ; Cell Differentiation/*genetics ; Cells, Cultured ; Chromatin/genetics ; Chromosomes, Mammalian/genetics ; Enhancer Elements, Genetic/*genetics ; Female ; Gene Expression Profiling/methods ; *Gene Expression Regulation, Developmental ; Genome/*genetics ; Hematopoietic Stem Cells/cytology/metabolism ; Mice ; Mice, Inbred C57BL ; Mouse Embryonic Stem Cells/cytology/metabolism ; Promoter Regions, Genetic/*genetics ; Stem Cells/cytology/*metabolism ; },
abstract = {Mammalian gene expression patterns are controlled by regulatory elements, which interact within topologically associating domains (TADs). The relationship between activation of regulatory elements, formation of structural chromatin interactions and gene expression during development is unclear. Here, we present Tiled-C, a low-input chromosome conformation capture (3C) technique. We use this approach to study chromatin architecture at high spatial and temporal resolution through in vivo mouse erythroid differentiation. Integrated analysis of chromatin accessibility and single-cell expression data shows that regulatory elements gradually become accessible within pre-existing TADs during early differentiation. This is followed by structural re-organization within the TAD and formation of specific contacts between enhancers and promoters. Our high-resolution data show that these enhancer-promoter interactions are not established prior to gene expression, but formed gradually during differentiation, concomitant with progressive upregulation of gene activity. Together, these results provide new insight into the close, interdependent relationship between chromatin architecture and gene regulation during development.},
}
@article {pmid32473574,
year = {2020},
author = {Sparks, TM and Harabula, I and Pombo, A},
title = {Evolving methodologies and concepts in 4D nucleome research.},
journal = {Current opinion in cell biology},
volume = {64},
number = {},
pages = {105-111},
pmid = {32473574},
issn = {1879-0410},
support = {U54 DK107977/DK/NIDDK NIH HHS/United States ; },
mesh = {Animals ; Chromatin/metabolism ; Genome ; Genomics ; Humans ; Nucleosomes/*metabolism ; *Research ; },
abstract = {The genome requires tight regulation in space and time to maintain viable cell functions. Advances in our understanding of the 3D genome show a complex hierarchical network of structures, involving compartments, membraneless bodies, topologically associating domains, lamina associated domains, protein- or RNA-mediated loops, enhancer-promoter contacts, and accessible chromatin regions, with chromatin state regulation through epigenetic and transcriptional mechanisms. Further technology developments are poised to increase genomic resolution, dissect single-cell behaviors, including in vivo dynamics of genome folding, and provide mechanistic perspectives that identify further 3D genome players by integrating multiomics information. We highlight recent key developments in 4D nucleome methodologies and give a perspective on their future directions.},
}
@article {pmid32470376,
year = {2020},
author = {Melo, US and Schöpflin, R and Acuna-Hidalgo, R and Mensah, MA and Fischer-Zirnsak, B and Holtgrewe, M and Klever, MK and Türkmen, S and Heinrich, V and Pluym, ID and Matoso, E and Bernardo de Sousa, S and Louro, P and Hülsemann, W and Cohen, M and Dufke, A and Latos-Bieleńska, A and Vingron, M and Kalscheuer, V and Quintero-Rivera, F and Spielmann, M and Mundlos, S},
title = {Hi-C Identifies Complex Genomic Rearrangements and TAD-Shuffling in Developmental Diseases.},
journal = {American journal of human genetics},
volume = {106},
number = {6},
pages = {872-884},
pmid = {32470376},
issn = {1537-6605},
mesh = {Chromatin Assembly and Disassembly/genetics ; Chromosome Breakpoints ; Chromosomes, Human/*genetics ; Cohort Studies ; Developmental Disabilities/*genetics ; Genome, Human/*genetics ; Humans ; *Molecular Conformation ; SOX9 Transcription Factor/genetics ; Segmental Duplications, Genomic/genetics ; Translocation, Genetic/*genetics ; },
abstract = {Genome-wide analysis methods, such as array comparative genomic hybridization (CGH) and whole-genome sequencing (WGS), have greatly advanced the identification of structural variants (SVs) in the human genome. However, even with standard high-throughput sequencing techniques, complex rearrangements with multiple breakpoints are often difficult to resolve, and predicting their effects on gene expression and phenotype remains a challenge. Here, we address these problems by using high-throughput chromosome conformation capture (Hi-C) generated from cultured cells of nine individuals with developmental disorders (DDs). Three individuals had previously been identified as harboring duplications at the SOX9 locus and six had been identified with translocations. Hi-C resolved the positions of the duplications and was instructive in interpreting their distinct pathogenic effects, including the formation of new topologically associating domains (neo-TADs). Hi-C was very sensitive in detecting translocations, and it revealed previously unrecognized complex rearrangements at the breakpoints. In several cases, we observed the formation of fused-TADs promoting ectopic enhancer-promoter interactions that were likely to be involved in the disease pathology. In summary, we show that Hi-C is a sensible method for the detection of complex SVs in a clinical setting. The results help interpret the possible pathogenic effects of the SVs in individuals with DDs.},
}
@article {pmid32460018,
year = {2020},
author = {Lazar, JE and Stehling-Sun, S and Nandakumar, V and Wang, H and Chee, DR and Howard, NP and Acosta, R and Dunn, D and Diegel, M and Neri, F and Castillo, A and Ibarrientos, S and Lee, K and Lescano, N and Van Biber, B and Nelson, J and Halow, J and Sandstrom, R and Bates, D and Urnov, FD and Stamatoyannopoulos, JA and Funnell, APW},
title = {Global Regulatory DNA Potentiation by SMARCA4 Propagates to Selective Gene Expression Programs via Domain-Level Remodeling.},
journal = {Cell reports},
volume = {31},
number = {8},
pages = {107676},
doi = {10.1016/j.celrep.2020.107676},
pmid = {32460018},
issn = {2211-1247},
support = {UM1 HG009444/HG/NHGRI NIH HHS/United States ; U54 HG007010/HG/NHGRI NIH HHS/United States ; },
mesh = {Chromatin Assembly and Disassembly/*genetics ; DNA/*genetics ; DNA Helicases/*metabolism ; Gene Expression/*genetics ; Humans ; Nuclear Proteins/*metabolism ; Transcription Factors/*metabolism ; },
abstract = {The human genome encodes millions of regulatory elements, of which only a small fraction are active within a given cell type. Little is known about the global impact of chromatin remodelers on regulatory DNA landscapes and how this translates to gene expression. We use precision genome engineering to reawaken homozygously inactivated SMARCA4, a central ATPase of the human SWI/SNF chromatin remodeling complex, in lung adenocarcinoma cells. Here, we combine DNase I hypersensitivity, histone modification, and transcriptional profiling to show that SMARCA4 dramatically increases both the number and magnitude of accessible chromatin sites genome-wide, chiefly by unmasking sites of low regulatory factor occupancy. By contrast, transcriptional changes are concentrated within well-demarcated remodeling domains wherein expression of specific genes is gated by both distal element activation and promoter chromatin configuration. Our results provide a perspective on how global chromatin remodeling activity is translated to gene expression via regulatory DNA.},
}
@article {pmid32439634,
year = {2020},
author = {Boyle, S and Flyamer, IM and Williamson, I and Sengupta, D and Bickmore, WA and Illingworth, RS},
title = {A central role for canonical PRC1 in shaping the 3D nuclear landscape.},
journal = {Genes &amp; development},
volume = {34},
number = {13-14},
pages = {931-949},
pmid = {32439634},
issn = {1549-5477},
support = {MC_UU_00007/2/MRC_/Medical Research Council/United Kingdom ; MR/S007644/1/MRC_/Medical Research Council/United Kingdom ; MR/K017047/1/MRC_/Medical Research Council/United Kingdom ; BBSRC_BB/H008500/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; },
mesh = {Animals ; CCCTC-Binding Factor/metabolism ; Cell Nucleus/*genetics ; Embryo, Mammalian ; Genome/*genetics ; Mice ; Mouse Embryonic Stem Cells ; Polycomb Repressive Complex 1/*genetics/*metabolism ; Polycomb-Group Proteins/metabolism ; Protein Binding ; Ubiquitin-Protein Ligases/genetics/metabolism ; },
abstract = {Polycomb group (PcG) proteins silence gene expression by chemically and physically modifying chromatin. A subset of PcG target loci are compacted and cluster in the nucleus; a conformation that is thought to contribute to gene silencing. However, how these interactions influence gross nuclear organization and their relationship with transcription remains poorly understood. Here we examine the role of Polycomb-repressive complex 1 (PRC1) in shaping 3D genome organization in mouse embryonic stem cells (mESCs). Using a combination of imaging and Hi-C analyses, we show that PRC1-mediated long-range interactions are independent of CTCF and can bridge sites at a megabase scale. Impairment of PRC1 enzymatic activity does not directly disrupt these interactions. We demonstrate that PcG targets coalesce in vivo, and that developmentally induced expression of one of the target loci disrupts this spatial arrangement. Finally, we show that transcriptional activation and the loss of PRC1-mediated interactions are separable events. These findings provide important insights into the function of PRC1, while highlighting the complexity of this regulatory system.},
}
@article {pmid32424124,
year = {2020},
author = {Chen, CH and Zheng, R and Tokheim, C and Dong, X and Fan, J and Wan, C and Tang, Q and Brown, M and Liu, JS and Meyer, CA and Liu, XS},
title = {Determinants of transcription factor regulatory range.},
journal = {Nature communications},
volume = {11},
number = {1},
pages = {2472},
pmid = {32424124},
issn = {2041-1723},
support = {U24 CA237617/CA/NCI NIH HHS/United States ; },
mesh = {Acetylation ; Animals ; Cell Line ; Chromatin/metabolism ; *Gene Expression Regulation ; Genome-Wide Association Study ; Histones/metabolism ; Lysine/metabolism ; Mice ; Models, Genetic ; Polymorphism, Single Nucleotide/genetics ; Protein Binding/genetics ; Quantitative Trait Loci/genetics ; Transcription Factors/*metabolism ; Transcription Initiation Site ; },
abstract = {Characterization of the genomic distances over which transcription factor (TF) binding influences gene expression is important for inferring target genes from TF chromatin immunoprecipitation followed by sequencing (ChIP-seq) data. Here we systematically examine the relationship between thousands of TF and histone modification ChIP-seq data sets with thousands of gene expression profiles. We develop a model for integrating these data, which reveals two classes of TFs with distinct ranges of regulatory influence, chromatin-binding preferences, and auto-regulatory properties. We find that the regulatory range of the same TF bound within different topologically associating domains (TADs) depend on intrinsic TAD properties such as local gene density and G/C content, but also on the TAD chromatin states. Our results suggest that considering TF type, binding distance to gene locus, as well as chromatin context is important in identifying implicated TFs from GWAS SNPs.},
}
@article {pmid32403166,
year = {2020},
author = {Sumiyama, K and Tanave, A},
title = {The regulatory landscape of the Dlx gene system in branchial arches: Shared characteristics among Dlx bigene clusters and evolution.},
journal = {Development, growth &amp; differentiation},
volume = {62},
number = {5},
pages = {355-362},
doi = {10.1111/dgd.12671},
pmid = {32403166},
issn = {1440-169X},
mesh = {Animals ; Branchial Region/*metabolism ; *Evolution, Molecular ; Gene Expression Regulation, Developmental/*genetics ; Homeodomain Proteins/*genetics/metabolism ; Humans ; Multigene Family/*genetics ; Transcription Factors/*genetics/metabolism ; },
abstract = {The mammalian Dlx genes encode homeobox-type transcription factors and are physically organized as convergent bigene clusters. The paired Dlx genes share tissue specificity in the expression profile. Genetic regulatory mechanisms, such as intergenic enhancer sharing between paired Dlx genes, have been proposed to explain this conservation of bigene structure. All mammalian Dlx genes have expression and function in developing craniofacial structures, especially in the first and second pharyngeal arches (branchial arches). Each Dlx cluster (Dlx1/2, Dlx3/4, and Dlx5/6) has overlapping, nested expression in the branchial arches which is called the "Dlx code" and plays a key role in organizing craniofacial structure and evolution. Here we summarize cis-regulatory studies on branchial arch expression of the three Dlx bigene clusters and show some shared characteristics among the clusters, including cis-regulatory motifs, TAD (Topologically Associating Domain) boundaries, CTCF loops, and distal enhancer landscapes, together with a molecular condensate model for activation of the Dlx bigene cluster.},
}
@article {pmid32385148,
year = {2020},
author = {Bian, Q and Anderson, EC and Yang, Q and Meyer, BJ},
title = {Histone H3K9 methylation promotes formation of genome compartments in Caenorhabditis elegans via chromosome compaction and perinuclear anchoring.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {117},
number = {21},
pages = {11459-11470},
pmid = {32385148},
issn = {1091-6490},
support = {R01 GM030702/GM/NIGMS NIH HHS/United States ; R35 GM131845/GM/NIGMS NIH HHS/United States ; S10 OD018174/OD/NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; },
mesh = {Animals ; Caenorhabditis elegans/*genetics/metabolism ; Caenorhabditis elegans Proteins/genetics/metabolism ; Cell Nucleus/genetics/metabolism ; Chromosomal Proteins, Non-Histone/genetics/metabolism ; Chromosomes/genetics/*metabolism ; Gene Expression Regulation ; Genome ; Heterochromatin/genetics/metabolism ; Histone-Lysine N-Methyltransferase/genetics/metabolism ; Histones/genetics/*metabolism ; Lysine/genetics/*metabolism ; Methylation ; Mutation ; X Chromosome/genetics/metabolism ; },
abstract = {Genomic regions preferentially associate with regions of similar transcriptional activity, partitioning genomes into active and inactive compartments within the nucleus. Here we explore mechanisms controlling genome compartment organization in Caenorhabditis elegans and investigate roles for compartments in regulating gene expression. Distal arms of C. elegans chromosomes, which are enriched for heterochromatic histone modifications H3K9me1/me2/me3, interact with each other both in cis and in trans, while interacting less frequently with central regions, leading to genome compartmentalization. Arms are anchored to the nuclear periphery via the nuclear envelope protein CEC-4, which binds to H3K9me. By performing genome-wide chromosome conformation capture experiments (Hi-C), we showed that eliminating H3K9me1/me2/me3 through mutations in the methyltransferase genes met-2 and set-25 significantly impaired formation of inactive Arm and active Center compartments. cec-4 mutations also impaired compartmentalization, but to a lesser extent. We found that H3K9me promotes compartmentalization through two distinct mechanisms: Perinuclear anchoring of chromosome arms via CEC-4 to promote their cis association, and an anchoring-independent mechanism that compacts individual chromosome arms. In both met-2 set-25 and cec-4 mutants, no dramatic changes in gene expression were found for genes that switched compartments or for genes that remained in their original compartment, suggesting that compartment strength does not dictate gene-expression levels. Furthermore, H3K9me, but not perinuclear anchoring, also contributes to formation of another prominent feature of chromosome organization, megabase-scale topologically associating domains on X established by the dosage compensation condensin complex. Our results demonstrate that H3K9me plays crucial roles in regulating genome organization at multiple levels.},
}
@article {pmid32384149,
year = {2020},
author = {Yang, M and Safavi, S and Woodward, EL and Duployez, N and Olsson-Arvidsson, L and Ungerbäck, J and Sigvardsson, M and Zaliova, M and Zuna, J and Fioretos, T and Johansson, B and Nord, KH and Paulsson, K},
title = {13q12.2 deletions in acute lymphoblastic leukemia lead to upregulation of FLT3 through enhancer hijacking.},
journal = {Blood},
volume = {136},
number = {8},
pages = {946-956},
pmid = {32384149},
issn = {1528-0020},
mesh = {Cell Line ; Chromatin Assembly and Disassembly/genetics/physiology ; Chromosome Deletion ; Chromosome Disorders/complications/*genetics ; Chromosomes, Human, Pair 13/genetics ; Cohort Studies ; DNA Copy Number Variations/genetics ; Enhancer Elements, Genetic/*genetics ; Gene Expression Regulation, Leukemic ; Humans ; Microarray Analysis ; Polymorphism, Single Nucleotide ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*genetics ; RNA-Seq ; Up-Regulation/genetics ; Whole Genome Sequencing ; fms-Like Tyrosine Kinase 3/*genetics ; },
abstract = {Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene in 13q12.2 are among the most common driver events in acute leukemia, leading to increased cell proliferation and survival through activation of the phosphatidylinositol 3-kinase/AKT-, RAS/MAPK-, and STAT5-signaling pathways. In this study, we examine the pathogenetic impact of somatic hemizygous 13q12.2 microdeletions in B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) using 5 different patient cohorts (in total including 1418 cases). The 13q12.2 deletions occur immediately 5' of FLT3 and involve the PAN3 locus. By detailed analysis of the 13q12.2 segment, we show that the deletions lead to loss of a topologically associating domain border and an enhancer of FLT3. This results in increased cis interactions between the FLT3 promoter and another enhancer located distally to the deletion breakpoints, with subsequent allele-specific upregulation of FLT3 expression, expected to lead to ligand-independent activation of the receptor and downstream signaling. The 13q12.2 deletions are highly enriched in the high-hyperdiploid BCP ALL subtype (frequency 3.9% vs 0.5% in other BCP ALL) and in cases that subsequently relapsed. Taken together, our study describes a novel mechanism of FLT3 involvement in leukemogenesis by upregulation via chromatin remodeling and enhancer hijacking. These data further emphasize the role of FLT3 as a driver gene in BCP ALL.},
}
@article {pmid32334414,
year = {2020},
author = {Pérez-Rico, YA and Barillot, E and Shkumatava, A},
title = {Demarcation of Topologically Associating Domains Is Uncoupled from Enriched CTCF Binding in Developing Zebrafish.},
journal = {iScience},
volume = {23},
number = {5},
pages = {101046},
pmid = {32334414},
issn = {2589-0042},
abstract = {CCCTC-binding factor (CTCF) is a conserved architectural protein that plays crucial roles in gene regulation and three-dimensional (3D) chromatin organization. To better understand mechanisms and evolution of vertebrate genome organization, we analyzed genome occupancy of CTCF in zebrafish utilizing an endogenously epitope-tagged CTCF knock-in allele. Zebrafish CTCF shares similar facets with its mammalian counterparts, including binding to enhancers, active promoters and repeat elements, and bipartite sequence motifs of its binding sites. However, we found that in vivo CTCF binding is not enriched at boundaries of topologically associating domains (TADs) in developing zebrafish, whereas TAD demarcation by chromatin marks did not differ from mammals. Our data suggest that general mechanisms underlying 3D chromatin organization, and in particular the involvement of CTCF in this process, differ between distant vertebrate species.},
}
@article {pmid32324846,
year = {2020},
author = {Zhang, Z and Wang, Q and Liu, Y and Sun, Q and Li, H and Czajkowsky, DM and Shao, Z},
title = {Massive reorganization of the genome during primary monocyte differentiation into macrophage.},
journal = {Acta biochimica et biophysica Sinica},
volume = {52},
number = {5},
pages = {546-553},
doi = {10.1093/abbs/gmaa026},
pmid = {32324846},
issn = {1745-7270},
mesh = {*Cell Differentiation ; Female ; *Genome, Human ; Humans ; Macrophages/cytology/*metabolism ; Male ; Monocytes/cytology/*metabolism ; },
abstract = {Monocyte-to-macrophage trans-differentiation has long been studied to better understand this immunological response and aspects of developmental processes more generally. A key question is the nature of the corresponding changes in chromatin conformation and its relationship to the transcriptome during this process. This question is especially intriguing since this trans-differentiation is not associated with progression through mitosis, often considered a necessary step for gross changes in chromosomal structure. Here, we characterized the transcriptional and genomic structural changes during macrophage development of primary human monocytes using RNA-seq and in situ Hi-C. We found that, during this transition, the genome architecture undergoes a massive remodeling to a degree not observed before between structured genomes, with changes in ~90% of the topologically associating domains (TADs). These changes in the TADs are associated with changed expression of immunological genes. These structural changes, however, differ extensively from those described recently in a study of the leukemia cell line, THP-1. Furthermore, up-regulation of the AP-1 family of genes that effected functionally important changes in the genomic structure during the differentiation of the THP-1 cells was not corroborated with the primary cells. Taken together, our results provide a comprehensive characterization of the changes in genomic structure during the monocyte-to-macrophage transition, establish a framework for the elucidation of processes underlying differentiation without proliferation, and demonstrate the importance of verifying with primary cells the mechanisms discovered with cultured cells.},
}
@article {pmid32315832,
year = {2020},
author = {Luo, Z and Wang, X and Jiang, H and Wang, R and Chen, J and Chen, Y and Xu, Q and Cao, J and Gong, X and Wu, J and Yang, Y and Li, W and Han, C and Cheng, CY and Rosenfeld, MG and Sun, F and Song, X},
title = {Reorganized 3D Genome Structures Support Transcriptional Regulation in Mouse Spermatogenesis.},
journal = {iScience},
volume = {23},
number = {4},
pages = {101034},
pmid = {32315832},
issn = {2589-0042},
abstract = {Three-dimensional chromatin structures undergo dynamic reorganization during mammalian spermatogenesis; however, their impacts on gene regulation remain unclear. Here, we focused on understanding the structure-function regulation of meiotic chromosomes by Hi-C and other omics techniques in mouse spermatogenesis across five stages. Beyond confirming recent reports regarding changes in compartmentalization and reorganization of topologically associating domains (TADs), we further demonstrated that chromatin loops are present prior to and after, but not at, the pachytene stage. By integrating Hi-C and RNA-seq data, we showed that the switching of A/B compartments between spermatogenic stages is tightly associated with meiosis-specific mRNAs and piRNAs expression. Moreover, our ATAC-seq data indicated that chromatin accessibility per se is not responsible for the TAD and loop diminishment at pachytene. Additionally, our ChIP-seq data demonstrated that CTCF and cohesin remain bound at TAD boundary regions throughout meiosis, suggesting that dynamic reorganization of TADs does not require CTCF and cohesin clearance.},
}
@article {pmid32313950,
year = {2020},
author = {Kantidze, OL and Razin, SV},
title = {Weak interactions in higher-order chromatin organization.},
journal = {Nucleic acids research},
volume = {48},
number = {9},
pages = {4614-4626},
pmid = {32313950},
issn = {1362-4962},
mesh = {Chromatin/*chemistry ; DNA, Superhelical ; RNA ; Static Electricity ; },
abstract = {The detailed principles of the hierarchical folding of eukaryotic chromosomes have been revealed during the last two decades. Along with structures composing three-dimensional (3D) genome organization (chromatin compartments, topologically associating domains, chromatin loops, etc.), the molecular mechanisms that are involved in their establishment and maintenance have been characterized. Generally, protein-protein and protein-DNA interactions underlie the spatial genome organization in eukaryotes. However, it is becoming increasingly evident that weak interactions, which exist in biological systems, also contribute to the 3D genome. Here, we provide a snapshot of our current understanding of the role of the weak interactions in the establishment and maintenance of the 3D genome organization. We discuss how weak biological forces, such as entropic forces operating in crowded solutions, electrostatic interactions of the biomolecules, liquid-liquid phase separation, DNA supercoiling, and RNA environment participate in chromosome segregation into structural and functional units and drive intranuclear functional compartmentalization.},
}
@article {pmid32301703,
year = {2020},
author = {Amândio, AR and Lopez-Delisle, L and Bolt, CC and Mascrez, B and Duboule, D},
title = {A complex regulatory landscape involved in the development of mammalian external genitals.},
journal = {eLife},
volume = {9},
number = {},
pages = {},
pmid = {32301703},
issn = {2050-084X},
support = {NICHD F32HD0935/NH/NIH HHS/United States ; 310030B_138662/SNSF_/Swiss National Science Foundation/Switzerland ; 588029/ERC_/European Research Council/International ; },
mesh = {Animals ; CCCTC-Binding Factor/metabolism ; Chromatin/*metabolism ; Enhancer Elements, Genetic/*genetics ; Genes, Homeobox/genetics ; Genitalia/*metabolism ; Mammals/*genetics ; Mice ; Multigene Family/genetics ; Promoter Regions, Genetic ; },
abstract = {Developmental genes are often controlled by large regulatory landscapes matching topologically associating domains (TADs). In various contexts, the associated chromatin backbone is modified by specific enhancer-enhancer and enhancer-promoter interactions. We used a TAD flanking the mouse HoxD cluster to study how these regulatory architectures are formed and deconstructed once their function achieved. We describe this TAD as a functional unit, with several regulatory sequences acting together to elicit a transcriptional response. With one exception, deletion of these sequences didn't modify the transcriptional outcome, a result at odds with a conventional view of enhancer function. The deletion and inversion of a CTCF site located near these regulatory sequences did not affect transcription of the target gene. Slight modifications were nevertheless observed, in agreement with the loop extrusion model. We discuss these unexpected results considering both conventional and alternative explanations relying on the accumulation of poorly specific factors within the TAD backbone.},
}
@article {pmid32299027,
year = {2020},
author = {Noordermeer, D and Feil, R},
title = {Differential 3D chromatin organization and gene activity in genomic imprinting.},
journal = {Current opinion in genetics &amp; development},
volume = {61},
number = {},
pages = {17-24},
doi = {10.1016/j.gde.2020.03.004},
pmid = {32299027},
issn = {1879-0380},
mesh = {Alleles ; Allelic Imbalance/genetics ; Animals ; CCCTC-Binding Factor/*genetics ; Chromatin/*genetics/ultrastructure ; CpG Islands/genetics ; DNA Methylation/genetics ; Gene Expression Regulation/genetics ; Genomic Imprinting/*genetics ; Histones/genetics ; Humans ; RNA, Long Noncoding/*genetics ; },
abstract = {Genomic imprinting gives rise to parent-of-origin dependent allelic gene expression. Most imprinted genes cluster in domains where differentially methylated regions (DMRs)-carrying CpG methylation on one parental allele-regulate their activity. Several imprinted DMRs bind CTCF on the non-methylated allele. CTCF structures TADs ('Topologically Associating Domains'), which are structural units of transcriptional regulation. Recent investigations show that imprinted domains are embedded within TADs that are similar on both parental chromosomes. Within these TADs, however, allelic subdomains are structured by combinations of mono-allelic and bi-allelic CTCF binding that guide imprinted expression. This emerging view indicates that imprinted chromosomal domains should be considered at the overarching TAD level, and questions how CTCF integrates with other regulatory proteins and lncRNAs to achieve imprinted transcriptional programs.},
}
@article {pmid32286279,
year = {2020},
author = {Chen, M and Zhu, Q and Li, C and Kou, X and Zhao, Y and Li, Y and Xu, R and Yang, L and Yang, L and Gu, L and Wang, H and Liu, X and Jiang, C and Gao, S},
title = {Chromatin architecture reorganization in murine somatic cell nuclear transfer embryos.},
journal = {Nature communications},
volume = {11},
number = {1},
pages = {1813},
pmid = {32286279},
issn = {2041-1723},
mesh = {Animals ; Cellular Reprogramming ; Chromatin/*metabolism ; Embryo, Mammalian/*metabolism ; Embryonic Development ; Enhancer Elements, Genetic/genetics ; Gene Expression Regulation, Developmental ; Genome ; Histones/metabolism ; Lysine/metabolism ; Metaphase ; Methylation ; Mice ; *Nuclear Transfer Techniques ; Promoter Regions, Genetic/genetics ; Zygote/metabolism ; },
abstract = {The oocyte cytoplasm can reprogram the somatic cell nucleus into a totipotent state, but with low efficiency. The spatiotemporal chromatin organization of somatic cell nuclear transfer (SCNT) embryos remains elusive. Here, we examine higher order chromatin structures of mouse SCNT embryos using a low-input Hi-C method. We find that donor cell chromatin transforms to the metaphase state rapidly after SCNT along with the dissolution of typical 3D chromatin structure. Intriguingly, the genome undergoes a mitotic metaphase-like to meiosis metaphase II-like transition following activation. Subsequently, weak chromatin compartments and topologically associating domains (TADs) emerge following metaphase exit. TADs are further removed until the 2-cell stage before being progressively reestablished. Obvious defects including stronger TAD boundaries, aberrant super-enhancer and promoter interactions are found in SCNT embryos. These defects are partially caused by inherited H3K9me3, and can be rescued by Kdm4d overexpression. These observations provide insight into chromatin architecture reorganization during SCNT embryo development.},
}
@article {pmid32241291,
year = {2020},
author = {Wang, G and Meng, Q and Xia, B and Zhang, S and Lv, J and Zhao, D and Li, Y and Wang, X and Zhang, L and Cooke, JP and Cao, Q and Chen, K},
title = {TADsplimer reveals splits and mergers of topologically associating domains for epigenetic regulation of transcription.},
journal = {Genome biology},
volume = {21},
number = {1},
pages = {84},
pmid = {32241291},
issn = {1474-760X},
support = {P50 CA180995/CA/NCI NIH HHS/United States ; R01 HL133254/HL/NHLBI NIH HHS/United States ; HL133254/NH/NIH HHS/United States ; GM125632/NH/NIH HHS/United States ; R01 CA208257/CA/NCI NIH HHS/United States ; R01 GM125632/GM/NIGMS NIH HHS/United States ; },
mesh = {*Algorithms ; Animals ; Cell Line, Tumor ; Chromatin/metabolism ; *Chromosomes, Mammalian ; *Epigenesis, Genetic ; Epigenomics/methods ; Histone Code ; Humans ; Mice ; Sequence Analysis, DNA ; *Transcription, Genetic ; },
abstract = {We present TADsplimer, the first computational tool to systematically detect topologically associating domain (TAD) splits and mergers across the genome between Hi-C samples. TADsplimer recaptures splits and mergers of TADs with high accuracy in simulation analyses and defines hundreds of TAD splits and mergers between pairs of different cell types, such as endothelial cells and fibroblasts. Our work reveals a key role for TAD remodeling in epigenetic regulation of transcription and delivers the first tool for the community to perform dynamic analysis of TAD splits and mergers in numerous biological and disease models.},
}
@article {pmid32240449,
year = {2020},
author = {Pontvianne, F and Grob, S},
title = {Three-dimensional nuclear organization in Arabidopsis thaliana.},
journal = {Journal of plant research},
volume = {133},
number = {4},
pages = {479-488},
pmid = {32240449},
issn = {1618-0860},
mesh = {Animals ; *Arabidopsis/genetics ; *Cell Nucleus/genetics ; Chromatin ; },
abstract = {In recent years, the study of plant three-dimensional nuclear architecture received increasing attention. Enabled by technological advances, our knowledge on nuclear architecture has greatly increased and we can now access large data sets describing its manifold aspects. The principles of nuclear organization in plants do not significantly differ from those in animals. Plant nuclear organization comprises various scales, ranging from gene loops to topologically associating domains to nuclear compartmentalization. However, whether plant three-dimensional chromosomal features also exert similar functions as in animals is less clear. This review discusses recent advances in the fields of three-dimensional chromosome folding and nuclear compartmentalization and describes a novel silencing mechanism, which is closely linked to nuclear architecture.},
}
@article {pmid32213324,
year = {2020},
author = {Krietenstein, N and Abraham, S and Venev, SV and Abdennur, N and Gibcus, J and Hsieh, TS and Parsi, KM and Yang, L and Maehr, R and Mirny, LA and Dekker, J and Rando, OJ},
title = {Ultrastructural Details of Mammalian Chromosome Architecture.},
journal = {Molecular cell},
volume = {78},
number = {3},
pages = {554-565.e7},
pmid = {32213324},
issn = {1097-4164},
support = {R01 GM114190/GM/NIGMS NIH HHS/United States ; U54 DK107980/DK/NIDDK NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; },
mesh = {Animals ; CCCTC-Binding Factor/metabolism ; Cells, Cultured ; Chromatin/chemistry ; Chromosomes, Human/*ultrastructure ; Chromosomes, Mammalian/ultrastructure ; Embryonic Stem Cells/cytology ; Fibroblasts/cytology ; Humans ; Male ; Mammals/genetics ; Nucleosomes/metabolism/ultrastructure ; Signal-To-Noise Ratio ; },
abstract = {Over the past decade, 3C-related methods have provided remarkable insights into chromosome folding in vivo. To overcome the limited resolution of prior studies, we extend a recently developed Hi-C variant, Micro-C, to map chromosome architecture at nucleosome resolution in human ESCs and fibroblasts. Micro-C robustly captures known features of chromosome folding including compartment organization, topologically associating domains, and interactions between CTCF binding sites. In addition, Micro-C provides a detailed map of nucleosome positions and localizes contact domain boundaries with nucleosomal precision. Compared to Hi-C, Micro-C exhibits an order of magnitude greater dynamic range, allowing the identification of ∼20,000 additional loops in each cell type. Many newly identified peaks are localized along extrusion stripes and form transitive grids, consistent with their anchors being pause sites impeding cohesin-dependent loop extrusion. Our analyses comprise the highest-resolution maps of chromosome folding in human cells to date, providing a valuable resource for studies of chromosome organization.},
}
@article {pmid32213323,
year = {2020},
author = {Hsieh, TS and Cattoglio, C and Slobodyanyuk, E and Hansen, AS and Rando, OJ and Tjian, R and Darzacq, X},
title = {Resolving the 3D Landscape of Transcription-Linked Mammalian Chromatin Folding.},
journal = {Molecular cell},
volume = {78},
number = {3},
pages = {539-553.e8},
pmid = {32213323},
issn = {1097-4164},
support = {R00 GM130896/GM/NIGMS NIH HHS/United States ; 003061/HHMI/Howard Hughes Medical Institute/United States ; U01 EB021236/EB/NIBIB NIH HHS/United States ; U54 DK107980/DK/NIDDK NIH HHS/United States ; S10 RR029668/RR/NCRR NIH HHS/United States ; S10 RR027303/RR/NCRR NIH HHS/United States ; K99 GM130896/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; CCCTC-Binding Factor/genetics ; Chromatin/*chemistry/genetics/*metabolism ; Chromatin Assembly and Disassembly/*genetics ; DNA Polymerase II/genetics/metabolism ; Embryonic Stem Cells/physiology ; Enhancer Elements, Genetic ; Gene Expression Regulation ; Genome Components ; Mice ; Promoter Regions, Genetic ; Transcription Factors/genetics/metabolism ; *Transcription, Genetic ; },
abstract = {Whereas folding of genomes at the large scale of epigenomic compartments and topologically associating domains (TADs) is now relatively well understood, how chromatin is folded at finer scales remains largely unexplored in mammals. Here, we overcome some limitations of conventional 3C-based methods by using high-resolution Micro-C to probe links between 3D genome organization and transcriptional regulation in mouse stem cells. Combinatorial binding of transcription factors, cofactors, and chromatin modifiers spatially segregates TAD regions into various finer-scale structures with distinct regulatory features including stripes, dots, and domains linking promoters-to-promoters (P-P) or enhancers-to-promoters (E-P) and bundle contacts between Polycomb regions. E-P stripes extending from the edge of domains predominantly link co-expressed loci, often in the absence of CTCF and cohesin occupancy. Acute inhibition of transcription disrupts these gene-related folding features without altering higher-order chromatin structures. Our study uncovers previously obscured finer-scale genome organization, establishing functional links between chromatin folding and gene regulation.},
}
@article {pmid32203470,
year = {2020},
author = {Kloetgen, A and Thandapani, P and Ntziachristos, P and Ghebrechristos, Y and Nomikou, S and Lazaris, C and Chen, X and Hu, H and Bakogianni, S and Wang, J and Fu, Y and Boccalatte, F and Zhong, H and Paietta, E and Trimarchi, T and Zhu, Y and Van Vlierberghe, P and Inghirami, GG and Lionnet, T and Aifantis, I and Tsirigos, A},
title = {Three-dimensional chromatin landscapes in T cell acute lymphoblastic leukemia.},
journal = {Nature genetics},
volume = {52},
number = {4},
pages = {388-400},
pmid = {32203470},
issn = {1546-1718},
support = {R01 CA133379/CA/NCI NIH HHS/United States ; R01 CA194923/CA/NCI NIH HHS/United States ; R01 CA228135/CA/NCI NIH HHS/United States ; R01 CA149655/CA/NCI NIH HHS/United States ; R01 GM127538/GM/NIGMS NIH HHS/United States ; R01 CA216421/CA/NCI NIH HHS/United States ; R01 CA202025/CA/NCI NIH HHS/United States ; UG1 CA233332/CA/NCI NIH HHS/United States ; U54 CA193419/CA/NCI NIH HHS/United States ; R35 CA220499/CA/NCI NIH HHS/United States ; P01 CA229086/CA/NCI NIH HHS/United States ; P30 CA016087/CA/NCI NIH HHS/United States ; 639784/ERC_/European Research Council/International ; U10 CA180820/CA/NCI NIH HHS/United States ; R00 CA188293/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; CCCTC-Binding Factor/genetics ; Carcinogenesis/genetics ; Cell Line, Tumor ; Chromatin/*genetics ; Enhancer Elements, Genetic/genetics ; Epigenesis, Genetic/genetics ; Humans ; Jurkat Cells ; Mice ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/*genetics ; Promoter Regions, Genetic/genetics ; T-Lymphocytes/*physiology ; },
abstract = {Differences in three-dimensional (3D) chromatin architecture can influence the integrity of topologically associating domains (TADs) and rewire specific enhancer-promoter interactions, impacting gene expression and leading to human disease. Here we investigate the 3D chromatin architecture in T cell acute lymphoblastic leukemia (T-ALL) by using primary human leukemia specimens and examine the dynamic responses of this architecture to pharmacological agents. Systematic integration of matched in situ Hi-C, RNA-seq and CTCF ChIP-seq datasets revealed widespread differences in intra-TAD chromatin interactions and TAD boundary insulation in T-ALL. Our studies identify and focus on a TAD 'fusion' event associated with absence of CTCF-mediated insulation, enabling direct interactions between the MYC promoter and a distal super-enhancer. Moreover, our data also demonstrate that small-molecule inhibitors targeting either oncogenic signal transduction or epigenetic regulation can alter specific 3D interactions found in leukemia. Overall, our study highlights the impact, complexity and dynamic nature of 3D chromatin architecture in human acute leukemia.},
}
@article {pmid32199341,
year = {2020},
author = {Ibrahim, DM and Mundlos, S},
title = {The role of 3D chromatin domains in gene regulation: a multi-facetted view on genome organization.},
journal = {Current opinion in genetics &amp; development},
volume = {61},
number = {},
pages = {1-8},
doi = {10.1016/j.gde.2020.02.015},
pmid = {32199341},
issn = {1879-0380},
mesh = {Animals ; Chromatin/*genetics/ultrastructure ; Chromatin Assembly and Disassembly/genetics ; *Evolution, Molecular ; Gene Expression Regulation/genetics ; Genome/*genetics ; Humans ; Mice ; },
abstract = {The causal relationship between 3D chromatin domains and gene regulation has been of considerable debate in recent years. Initial Hi-C studies profiling the 3D chromatin structure of the genome described evolutionarily conserved Topologically Associating Domains (TADs) that correlated with gene expression. Subsequent evidence from mouse models and human disease directly linked TADs to gene regulation. However, a number of focused genetic and genome-wide studies questioned the relevance of 3D chromatin domains for orchestrating gene expression, ultimately yielding a more multi-layered view of 3D chromatin structure and gene regulation. We review the evidence for and against the importance of 3D chromatin structure for gene regulation and argue for a more comprehensive classification of regulatory chromatin domains that integrates 3D chromatin structure with genomic, functional, and evolutionary conservation.},
}
@article {pmid32193349,
year = {2020},
author = {Carstens, S and Nilges, M and Habeck, M},
title = {Bayesian inference of chromatin structure ensembles from population-averaged contact data.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {117},
number = {14},
pages = {7824-7830},
pmid = {32193349},
issn = {1091-6490},
mesh = {*Bayes Theorem ; Chromatin/genetics/*ultrastructure ; Chromosomes/genetics/*ultrastructure ; Genome, Human/*genetics ; Humans ; Molecular Conformation ; },
abstract = {Mounting experimental evidence suggests a role for the spatial organization of chromatin in crucial processes of the cell nucleus such as transcription regulation. Chromosome conformation capture techniques allow us to characterize chromatin structure by mapping contacts between chromosomal loci on a genome-wide scale. The most widespread modality is to measure contact frequencies averaged over a population of cells. Single-cell variants exist, but suffer from low contact numbers and have not yet gained the same resolution as population methods. While intriguing biological insights have already been garnered from ensemble-averaged data, information about three-dimensional (3D) genome organization in the underlying individual cells remains largely obscured because the contact maps show only an average over a huge population of cells. Moreover, computational methods for structure modeling of chromatin have mostly focused on fitting a single consensus structure, thereby ignoring any cell-to-cell variability in the model itself. Here, we propose a fully Bayesian method to infer ensembles of chromatin structures and to determine the optimal number of states in a principled, objective way. We illustrate our approach on simulated data and compute multistate models of chromatin from chromosome conformation capture carbon copy (5C) data. Comparison with independent data suggests that the inferred ensembles represent the underlying sample population faithfully. Harnessing the rich information contained in multistate models, we investigate cell-to-cell variability of chromatin organization into topologically associating domains, thus highlighting the ability of our approach to deliver insights into chromatin organization of great biological relevance.},
}
@article {pmid32191860,
year = {2020},
author = {Shinkai, S and Sugawara, T and Miura, H and Hiratani, I and Onami, S},
title = {Microrheology for Hi-C Data Reveals the Spectrum of the Dynamic 3D Genome Organization.},
journal = {Biophysical journal},
volume = {118},
number = {9},
pages = {2220-2228},
pmid = {32191860},
issn = {1542-0086},
mesh = {Animals ; Cell Nucleus ; *Chromatin/genetics ; *Chromosomes/genetics ; DNA ; Mice ; Mouse Embryonic Stem Cells ; },
abstract = {The one-dimensional information of genomic DNA is hierarchically packed inside the eukaryotic cell nucleus and organized in a three-dimensional (3D) space. Genome-wide chromosome conformation capture (Hi-C) methods have uncovered the 3D genome organization and revealed multiscale chromatin domains of compartments and topologically associating domains (TADs). Moreover, single-nucleosome live-cell imaging experiments have revealed the dynamic organization of chromatin domains caused by stochastic thermal fluctuations. However, the mechanism underlying the dynamic regulation of such hierarchical and structural chromatin units within the microscale thermal medium remains unclear. Microrheology is a way to measure dynamic viscoelastic properties coupling between thermal microenvironment and mechanical response. Here, we propose a new, to our knowledge, microrheology for Hi-C data to analyze the dynamic compliance property as a measure of rigidness and flexibility of genomic regions along with the time evolution. Our method allows the conversion of an Hi-C matrix into the spectrum of the dynamic rheological property along the genomic coordinate of a single chromosome. To demonstrate the power of the technique, we analyzed Hi-C data during the neural differentiation of mouse embryonic stem cells. We found that TAD boundaries behave as more rigid nodes than the intra-TAD regions. The spectrum clearly shows the dynamic viscoelasticity of chromatin domain formation at different timescales. Furthermore, we characterized the appearance of synchronous and liquid-like intercompartment interactions in differentiated cells. Together, our microrheology data derived from Hi-C data provide physical insights into the dynamics of the 3D genome organization.},
}
@article {pmid32165395,
year = {2020},
author = {Luo, Z and Hu, T and Jiang, H and Wang, R and Xu, Q and Zhang, S and Cao, J and Song, X},
title = {Rearrangement of macronucleus chromosomes correspond to TAD-like structures of micronucleus chromosomes in Tetrahymena thermophila.},
journal = {Genome research},
volume = {30},
number = {3},
pages = {406-414},
pmid = {32165395},
issn = {1549-5469},
mesh = {Centromere ; Chromatin/*chemistry ; Chromosomes/*chemistry ; Macronucleus/*genetics ; Meiosis/genetics ; Micronucleus, Germline/*genetics ; Tetrahymena thermophila/*genetics ; },
abstract = {The somatic macronucleus (MAC) and germline micronucleus (MIC) of Tetrahymena thermophila differ in chromosome numbers, sizes, functions, transcriptional activities, and cohesin complex location. However, the higher-order chromatin organization in T. thermophila is still largely unknown. Here, we explored the higher-order chromatin organization in the two distinct nuclei of T. thermophila using the Hi-C and HiChIP methods. We found that the meiotic crescent MIC has a specific chromosome interaction pattern, with all the telomeres or centromeres on the five MIC chromosomes clustering together, respectively, which is also helpful to identify the midpoints of centromeres in the MIC. We revealed that the MAC chromosomes lack A/B compartments, topologically associating domains (TADs), and chromatin loops. The MIC chromosomes have TAD-like structures but not A/B compartments and chromatin loops. The boundaries of the TAD-like structures in the MIC are highly consistent with the chromatin breakage sequence (CBS) sites, suggesting that each TAD-like structure of the MIC chromosomes develops into one MAC chromosome during MAC development, which provides a mechanism of the formation of MAC chromosomes during conjugation. Overall, we demonstrated the distinct higher-order chromatin organization in the two nuclei of the T. thermophila and suggest that the higher-order chromatin structures may play important roles during the development of the MAC chromosomes.},
}
@article {pmid32160531,
year = {2020},
author = {Santana, JF and Parida, M and Long, A and Wankum, J and Lilienthal, AJ and Nukala, KM and Manak, JR},
title = {The Dm-Myb Oncoprotein Contributes to Insulator Function and Stabilizes Repressive H3K27me3 PcG Domains.},
journal = {Cell reports},
volume = {30},
number = {10},
pages = {3218-3228.e5},
pmid = {32160531},
issn = {2211-1247},
support = {T32 GM008629/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Cell Cycle Proteins/*chemistry/*metabolism ; Drosophila Proteins/*chemistry/*metabolism ; Drosophila melanogaster/*metabolism ; Histones/*metabolism ; Insulator Elements/*genetics ; Lysine/*metabolism ; Methylation ; Oncogene Proteins/*metabolism ; Polycomb-Group Proteins/*chemistry ; Protein Binding ; Protein Domains ; Protein Stability ; Proto-Oncogene Proteins c-myb/*chemistry/*metabolism ; RNA Polymerase II/metabolism ; Transcription Initiation Site ; },
abstract = {Drosophila Myb (Dm-Myb) encodes a protein that plays a key role in regulation of mitotic phase genes. Here, we further refine its role in the context of a developing tissue as a potentiator of gene expression required for proper RNA polymerase II (RNA Pol II) function and efficient H3K4 methylation at promoters. In contrast to its role in gene activation, Myb is also required for repression of many genes, although no specific mechanism for this role has been proposed. We now reveal a critical role for Myb in contributing to insulator function, in part by promoting binding of insulator proteins BEAF-32 and CP190 and stabilizing H3K27me3 Polycomb-group (PcG) domains. In the absence of Myb, H3K27me3 is markedly reduced throughout the genome, leading to H3K4me3 spreading and gene derepression. Finally, Myb is enriched at boundaries that demarcate chromatin environments, including chromatin loop anchors. These results reveal functions of Myb that extend beyond transcriptional regulation.},
}
@article {pmid32116548,
year = {2020},
author = {Van der Veen, DR and Laing, EE and Bae, SE and Johnston, JD and Dijk, DJ and Archer, SN},
title = {A Topological Cluster of Differentially Regulated Genes in Mice Lacking PER3.},
journal = {Frontiers in molecular neuroscience},
volume = {13},
number = {},
pages = {15},
pmid = {32116548},
issn = {1662-5099},
support = {BB/E003672/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/F020309/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/F022883/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; },
abstract = {Polymorphisms in the human circadian clock gene PERIOD3 (PER3) are associated with a wide variety of phenotypes such as diurnal preference, delayed sleep phase disorder, sleep homeostasis, cognitive performance, bipolar disorder, type 2 diabetes, cardiac regulation, cancer, light sensitivity, hormone and cytokine secretion, and addiction. However, the molecular mechanisms underlying these phenotypic associations remain unknown. Per3 knockout mice (Per3[-/-]) have phenotypes related to activity, sleep homeostasis, anhedonia, metabolism, and behavioral responses to light. Using a protocol that induces behavioral differences in response to light in wild type and Per3[-/-] mice, we compared genome-wide expression in the eye and hypothalamus in the two genotypes. Differentially expressed transcripts were related to inflammation, taste, olfactory and melatonin receptors, lipid metabolism, cell cycle, ubiquitination, and hormones, as well as receptors and channels related to sleep regulation. Differentially expressed transcripts in both tissues co-localized with Per3 on an ∼8Mbp region of distal chromosome 4. The most down-regulated transcript is Prdm16, which is involved in adipocyte differentiation and may mediate altered body mass accumulation in Per3[-/-] mice. eQTL analysis with BXD mouse strains showed that the expression of some of these transcripts and also others co-localized at distal chromosome 4, is correlated with brain tissue expression levels of Per3 with a highly significant linkage to genetic variation in that region. These data identify a cluster of transcripts on mouse distal chromosome 4 that are co-regulated with Per3 and whose expression levels correlate with those of Per3. This locus lies within a topologically associating domain island that contains many genes with functional links to several of the diverse non-circadian phenotypes associated with polymorphisms in human PER3.},
}
@article {pmid32113985,
year = {2020},
author = {Ji, L and Huo, X and Zhang, Y and Yan, Z and Wang, Q and Wen, B},
title = {TOPORS, a tumor suppressor protein, contributes to the maintenance of higher-order chromatin architecture.},
journal = {Biochimica et biophysica acta. Gene regulatory mechanisms},
volume = {1863},
number = {5},
pages = {194518},
doi = {10.1016/j.bbagrm.2020.194518},
pmid = {32113985},
issn = {1876-4320},
mesh = {Animals ; Cell Line ; Chromatin/*chemistry/metabolism ; Chromatin Assembly and Disassembly ; Mice ; Nuclear Lamina/metabolism ; Promyelocytic Leukemia Protein/metabolism ; Protein Binding ; Transcriptome ; Ubiquitin-Protein Ligases/genetics/*metabolism ; },
abstract = {In the nucleus, chromosomes are hierarchically folded into active (A) and inactive (B) compartments composed of topologically associating domains (TADs). Genomic regions interact with nuclear lamina, termed lamina-associated domains (LADs). However, the molecular mechanisms underlying these 3D chromatin architectures remain incompletely understood. Here, we investigated the role of a potential tumor suppressor, TOP1 Binding Arginine/Serine Rich Protein (TOPORS), in genome organization. In mouse hepatocytes, chromatin interactions between A and B compartments increase and compartmentalization strength is reduced significantly upon Topors knockdown. Correspondingly, strength of TAD boundaries located at A/B borders is weakened. In the absence of TOPORS, chromatin-lamina interactions decrease and the coverage of LADs reduces from 53.31% to 46.52%. Interestingly, these changes in 3D genome are associated with PML nuclear bodies and PML-associated domains (PADs). Moreover, chromatin accessibility is altered predominantly at intergenic regions upon Topors knockdown, including a subset of enhancers. These alterations of chromatin are concordant with transcriptome changes, which are associated with carcinogenesis. Collectively, our findings demonstrate that TOPORS functions as a regulator in chromatin structure, providing novel insight into the architectural roles of tumor suppressors in higher-order genome organization.},
}
@article {pmid32110488,
year = {2020},
author = {Sjakste, T and Leonova, E and Petrovs, R and Trapina, I and Röder, MS and Sjakste, N},
title = {Tight DNA-protein complexes isolated from barley seedlings are rich in potential guanine quadruplex sequences.},
journal = {PeerJ},
volume = {8},
number = {},
pages = {e8569},
pmid = {32110488},
issn = {2167-8359},
abstract = {BACKGROUND: The concept of chromatin domains attached to the nuclear matrix is being revisited, with nucleus described as a set of topologically associating domains. The significance of the tightly bound to DNA proteins (TBP), a protein group that remains attached to DNA after its deproteinization should be also revisited, as the existence of these interactions is in good agreement with the concept of the topologically associating domain. The work aimed to characterize the DNA component of TBP isolated from barley seedlings.<br><br>METHODS: The tight DNA-protein complexes from the first leaves, coleoptiles, and roots of barley seedlings were isolated by purification with chromatography on nitrocellulose or exhaustive digestion of DNA with DNase I. Cloning and transformation were performed using pMOSBBlue Blunt Ended Cloning Kit. Inserts were amplified by PCR, and sequencing was performed on the MegaBace 1000 Sequencing System. The BLAST search was performed using sequence databases at NCBI, CR-EST, and TREP and Ensembl Plants databases. Comparison to MAR/SAR sequences was performed using http://smartdb.bioinf.med.uni-goettingen.de/cgi-bin/SMARtDB/smar.cgi database. The prediction of G quadruplexes (GQ) was performed with the aid of R-studio library pqsfinder. CD spectra were recorded on a Chirascan CS/3D spectrometer.<br><br>RESULTS: Although the barley genome is AT-rich (43% of GC pairs), most DNA fragments associated with TBP were GC-rich (up to 70% in some fractions). Both fractionation procedures yielded a high proportion of CT-motif sequences presented predominantly by the 16-bp CC(TCTCCC)2 TC fragment present in clones derived from the TBP-bound DNA and absent in free DNA. BLAST analysis revealed alignment with different barley repeats. Some clones, however, aligned with both nuclear and chloroplast structural genes. Alignments with MAR/SAR motifs were very few. The analysis produced by the pqsfinder program revealed numerous potential quadruplex-forming sites in the TBP-bound sequences. A set of oligonucleotides containing sites of possible GQs were designed and ordered. Three of them represented the minus strand of the CT-repeat. Two were derived from sequences of two clones of nitrocellulose retained fraction from leaves and contained GC-rich motifs different from the CT motif. Circular dichroism spectroscopy revealed profound changes in spectra when oligonucleotides were incubated with 100 mM KCl. There was either an increase of positive band in the area of 260 nm or the formation of a positive band at 290 nm. In the former case, changes are typical for parallel G-quadruplexes and, in the latter, 3&#xa0;+&#xa0;1 structures.<br><br>DISCUSSION: The G-quadruplexes anchor proteins are probably involved in the maintenance of the topologically associated domain structure.},
}
@article {pmid32109364,
year = {2020},
author = {Yokoshi, M and Segawa, K and Fukaya, T},
title = {Visualizing the Role of Boundary Elements in Enhancer-Promoter Communication.},
journal = {Molecular cell},
volume = {78},
number = {2},
pages = {224-235.e5},
doi = {10.1016/j.molcel.2020.02.007},
pmid = {32109364},
issn = {1097-4164},
mesh = {Animals ; Chromosomes/genetics ; Drosophila/genetics/growth &amp; development ; Embryo, Nonmammalian ; Embryonic Development/*genetics ; *Enhancer Elements, Genetic ; *Promoter Regions, Genetic ; *Transcription, Genetic ; },
abstract = {Formation of self-associating loop domains is a fundamental organizational feature of metazoan genomes. Here, we employed quantitative live-imaging methods to visualize impacts of higher-order chromosome topology on enhancer-promoter communication in developing Drosophila embryos. Evidence is provided that distal enhancers effectively produce transcriptional bursting from target promoters over distances when they are flanked with boundary elements. Importantly, neither inversion nor deletion of a boundary element abrogates this "enhancer-assisting activity," suggesting that they can facilitate intra-domain enhancer-promoter interaction and production of transcriptional bursting independently of topologically associating domain (TAD) formation. In contrast, domain-skipping activity of distal enhancers was lost after disruption of topological domains. This observation raises a possibility that intra-domain and inter-domain enhancer-promoter interactions are differentially regulated by chromosome topology.},
}
@article {pmid32101721,
year = {2020},
author = {Lazaris, C and Aifantis, I and Tsirigos, A},
title = {On Epigenetic Plasticity and Genome Topology.},
journal = {Trends in cancer},
volume = {6},
number = {3},
pages = {177-180},
doi = {10.1016/j.trecan.2020.01.006},
pmid = {32101721},
issn = {2405-8025},
mesh = {Cell Transformation, Neoplastic/genetics ; Chromatin/genetics/ultrastructure ; *Epigenomics ; *Gene Expression Regulation, Neoplastic/genetics ; *Genome, Human ; Humans ; Models, Genetic ; Neoplasms/*genetics ; Oncogenes ; Transcription, Genetic ; },
abstract = {Mounting evidence links genetic lesions with genome topology alterations and aberrant gene activation. However, the role of epigenetic plasticity remains elusive. Emerging studies implicate DNA methylation, transcriptional elongation, long noncoding RNAs (lncRNAs), and CCCTC-binding factor (CTCF)-RNA interactions, but systematic approaches are needed to fully decipher the role of epigenetic plasticity in genome integrity and function.},
}
@article {pmid32086528,
year = {2020},
author = {Li, Y and Liao, Z and Luo, H and Benyoucef, A and Kang, Y and Lai, Q and Dovat, S and Miller, B and Chepelev, I and Li, Y and Zhao, K and Brand, M and Huang, S},
title = {Alteration of CTCF-associated chromatin neighborhood inhibits TAL1-driven oncogenic transcription program and leukemogenesis.},
journal = {Nucleic acids research},
volume = {48},
number = {6},
pages = {3119-3133},
pmid = {32086528},
issn = {1362-4962},
support = {R01 CA204044/CA/NCI NIH HHS/United States ; R01 DK110108/DK/NIDDK NIH HHS/United States ; MOP-343603//CIHR/Canada ; },
mesh = {Binding Sites/genetics ; CCCTC-Binding Factor/*genetics ; Carcinogenesis/*genetics ; Chromatin/genetics ; DNA-Binding Proteins/genetics ; Enhancer Elements, Genetic/genetics ; Gene Expression Regulation, Neoplastic ; Genome, Human/genetics ; Histone Code/genetics ; Humans ; Jurkat Cells ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/*genetics/pathology ; Protein Binding/genetics ; T-Cell Acute Lymphocytic Leukemia Protein 1/*genetics ; Transcription, Genetic/genetics ; },
abstract = {Aberrant activation of the TAL1 is associated with up to 60% of T-ALL cases and is involved in CTCF-mediated genome organization within the TAL1 locus, suggesting that CTCF boundary plays a pathogenic role in T-ALL. Here, we show that -31-Kb CTCF binding site (-31CBS) serves as chromatin boundary that defines topologically associating domain (TAD) and enhancer/promoter interaction required for TAL1 activation. Deleted or inverted -31CBS impairs TAL1 expression in a context-dependent manner. Deletion of -31CBS reduces chromatin accessibility and blocks long-range interaction between the +51 erythroid enhancer and TAL1 promoter-1 leading to inhibition of TAL1 expression in erythroid cells, but not T-ALL cells. However, in TAL1-expressing T-ALL cells, the leukemia-prone TAL1 promoter-IV specifically interacts with the +19 stem cell enhancer located 19 Kb downstream of TAL1 and this interaction is disrupted by the -31CBS inversion in T-ALL cells. Inversion of -31CBS in Jurkat cells alters chromatin accessibility, histone modifications and CTCF-mediated TAD leading to inhibition of TAL1 expression and TAL1-driven leukemogenesis. Thus, our data reveal that -31CBS acts as critical regulator to define +19-enhancer and the leukemic prone promoter IV interaction for TAL1 activation in T-ALL. Manipulation of CTCF boundary can alter TAL1 TAD and oncogenic transcription networks in leukemogenesis.},
}
@article {pmid32083658,
year = {2020},
author = {Soler-Vila, P and Cuscó, P and Farabella, I and Di Stefano, M and Marti-Renom, MA},
title = {Hierarchical chromatin organization detected by TADpole.},
journal = {Nucleic acids research},
volume = {48},
number = {7},
pages = {e39},
pmid = {32083658},
issn = {1362-4962},
mesh = {Algorithms ; Animals ; Chromatin/*chemistry ; Mice ; *Software ; },
abstract = {The rapid development of Chromosome Conformation Capture (3C-based techniques), as well as imaging together with bioinformatics analyses, has been fundamental for unveiling that chromosomes are organized into the so-called topologically associating domains or TADs. While TADs appear as nested patterns in the 3C-based interaction matrices, the vast majority of available TAD callers are based on the hypothesis that TADs are individual and unrelated chromatin structures. Here we introduce TADpole, a computational tool designed to identify and analyze the entire hierarchy of TADs in intra-chromosomal interaction matrices. TADpole combines principal component analysis and constrained hierarchical clustering to provide a set of significant hierarchical chromatin levels in a genomic region of interest. TADpole is robust to data resolution, normalization strategy and sequencing depth. Domain borders defined by TADpole are enriched in main architectural proteins (CTCF and cohesin complex subunits) and in the histone mark H3K4me3, while their domain bodies, depending on their activation-state, are enriched in either H3K36me3 or H3K27me3, highlighting that TADpole is able to distinguish functional TAD units. Additionally, we demonstrate that TADpole's hierarchical annotation, together with the new DiffT score, allows for detecting significant topological differences on Capture Hi-C maps between wild-type and genetically engineered mouse.},
}
@article {pmid32060283,
year = {2020},
author = {Arzate-Mejía, RG and Josué Cerecedo-Castillo, A and Guerrero, G and Furlan-Magaril, M and Recillas-Targa, F},
title = {In situ dissection of domain boundaries affect genome topology and gene transcription in Drosophila.},
journal = {Nature communications},
volume = {11},
number = {1},
pages = {894},
pmid = {32060283},
issn = {2041-1723},
mesh = {Animals ; Chromatin/genetics/metabolism ; Drosophila Proteins/genetics/metabolism ; Drosophila melanogaster/*genetics/metabolism ; *Genome, Insect ; RNA Polymerase II/genetics/metabolism ; *Transcription, Genetic ; },
abstract = {Chromosomes are organized into high-frequency chromatin interaction domains called topologically associating domains (TADs), which are separated from each other by domain boundaries. The molecular mechanisms responsible for TAD formation are not yet fully understood. In Drosophila, it has been proposed that transcription is fundamental for TAD organization while the participation of genetic sequences bound by architectural proteins (APs) remains controversial. Here, we investigate the contribution of domain boundaries to TAD organization and the regulation of gene expression at the Notch gene locus in Drosophila. We find that deletion of domain boundaries results in TAD fusion and long-range topological defects that are accompanied by loss of APs and RNA Pol II chromatin binding as well as defects in transcription. Together, our results provide compelling evidence of the contribution of discrete genetic sequences bound by APs and RNA Pol II in the partition of the genome into TADs and in the regulation of gene expression in Drosophila.},
}
@article {pmid32036200,
year = {2020},
author = {Ibrahim, DM and Mundlos, S},
title = {Three-dimensional chromatin in disease: What holds us together and what drives us apart?.},
journal = {Current opinion in cell biology},
volume = {64},
number = {},
pages = {1-9},
doi = {10.1016/j.ceb.2020.01.003},
pmid = {32036200},
issn = {1879-0410},
mesh = {Animals ; Chromatin/*chemistry ; Enhancer Elements, Genetic/genetics ; Gene Expression Regulation ; Genome ; Humans ; *Imaging, Three-Dimensional ; Promoter Regions, Genetic ; },
abstract = {Recent advances in understanding spatial genome organization inside the nucleus have shown that chromatin is compartmentalized into megabase-scale units known as topologically associating domains (TADs). In further studies, TADs were linked to differing transcriptional activity, suggesting that they might provide a scaffold for gene regulation by promoting enhancer-promoter interaction and by insulating regulatory activities. One strong argument for this hypothesis was provided by the effects of disease-causing structural variations in congenital disease and cancer. By rearranging TADs, these mutations result in a rewiring of enhancer-promoter contacts, consecutive gene misexpression, and ultimately disease. However, not all rearrangements are equally effective in creating these effects. Here, we review several recent studies aiming to understand the mechanisms by which disease-causing mutations achieve gene misregulation. We will discuss which regulatory effects are to be expected by different disease mutations and how this new knowledge can be used for diagnostics in the clinic.},
}
@article {pmid32024999,
year = {2020},
author = {Akdemir, KC and Le, VT and Chandran, S and Li, Y and Verhaak, RG and Beroukhim, R and Campbell, PJ and Chin, L and Dixon, JR and Futreal, PA and , and , },
title = {Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer.},
journal = {Nature genetics},
volume = {52},
number = {3},
pages = {294-305},
pmid = {32024999},
issn = {1546-1718},
support = {DP5 OD023071/OD/NIH HHS/United States ; R01 CA095175/CA/NCI NIH HHS/United States ; R01 CA217991/CA/NCI NIH HHS/United States ; P30 CA014195/CA/NCI NIH HHS/United States ; R35 GM127029/GM/NIGMS NIH HHS/United States ; P30 CA016672/CA/NCI NIH HHS/United States ; },
mesh = {Chromatin/*genetics ; Gene Expression Regulation, Neoplastic ; Gene Rearrangement/*genetics ; Genome, Human/*genetics ; *Genomic Structural Variation ; Humans ; Neoplasms/*genetics ; },
abstract = {Chromatin is folded into successive layers to organize linear DNA. Genes within the same topologically associating domains (TADs) demonstrate similar expression and histone-modification profiles, and boundaries separating different domains have important roles in reinforcing the stability of these features. Indeed, domain disruptions in human cancers can lead to misregulation of gene expression. However, the frequency of domain disruptions in human cancers remains unclear. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumor types, we analyzed 288,457 somatic structural variations (SVs) to understand the distributions and effects of SVs across TADs. Notably, SVs can lead to the fusion of discrete TADs, and complex rearrangements markedly change chromatin folding maps in the cancer genomes. Notably, only 14% of the boundary deletions resulted in a change in expression in nearby genes of more than twofold.},
}
@article {pmid32014867,
year = {2020},
author = {Bolt, CC and Duboule, D},
title = {The regulatory landscapes of developmental genes.},
journal = {Development (Cambridge, England)},
volume = {147},
number = {3},
pages = {},
pmid = {32014867},
issn = {1477-9129},
support = {F32 HD093555/HD/NICHD NIH HHS/United States ; },
mesh = {Animals ; Chromatin/genetics/metabolism ; DNA/genetics/metabolism ; Enhancer Elements, Genetic/genetics ; Evolution, Molecular ; *Gene Expression Regulation, Developmental ; *Genes, Developmental ; Genetic Loci ; Humans ; Mice ; Promoter Regions, Genetic ; Transcription Factors/genetics/metabolism ; *Transcription, Genetic ; },
abstract = {Regulatory landscapes have been defined in vertebrates as large DNA segments containing diverse enhancer sequences that produce coherent gene transcription. These genomic platforms integrate multiple cellular signals and hence can trigger pleiotropic expression of developmental genes. Identifying and evaluating how these chromatin regions operate may be difficult as the underlying regulatory mechanisms can be as unique as the genes they control. In this brief article and accompanying poster, we discuss some of the ways in which regulatory landscapes operate, illustrating these mechanisms using genes important for vertebrate development as examples. We also highlight some of the techniques available to researchers for analysing regulatory landscapes.},
}
@article {pmid32009153,
year = {2020},
author = {Kumar, V and Leclerc, S and Taniguchi, Y},
title = {BHi-Cect: a top-down algorithm for identifying the multi-scale hierarchical structure of chromosomes.},
journal = {Nucleic acids research},
volume = {48},
number = {5},
pages = {e26},
pmid = {32009153},
issn = {1362-4962},
mesh = {*Algorithms ; Cell Line ; Chromatin Assembly and Disassembly ; Chromosome Mapping ; Chromosomes, Human/*chemistry/ultrastructure ; DNA/*genetics/metabolism ; Fibroblasts/cytology/metabolism ; Genetic Loci ; Humans ; Multigene Family ; },
abstract = {High-throughput chromosome conformation capture (Hi-C) technology enables the investigation of genome-wide interactions among chromosome loci. Current algorithms focus on topologically associating domains (TADs), that are contiguous clusters along the genome coordinate, to describe the hierarchical structure of chromosomes. However, high resolution Hi-C displays a variety of interaction patterns beyond what current TAD detection methods can capture. Here, we present BHi-Cect, a novel top-down algorithm that finds clusters by considering every locus with no assumption of genomic contiguity using spectral clustering. Our results reveal that the hierarchical structure of chromosome is organized as 'enclaves', which are complex interwoven clusters at both local and global scales. We show that the nesting of local clusters within global clusters characterizing enclaves, is associated with the epigenomic activity found on the underlying DNA. Furthermore, we show that the hierarchical nesting that links different enclaves integrates their respective function. BHi-Cect provides means to uncover the general principles guiding chromatin architecture.},
}
@article {pmid31971237,
year = {2020},
author = {Brackley, CA and Marenduzzo, D},
title = {Bridging-induced microphase separation: photobleaching experiments, chromatin domains and the need for active reactions.},
journal = {Briefings in functional genomics},
volume = {19},
number = {2},
pages = {111-118},
doi = {10.1093/bfgp/elz032},
pmid = {31971237},
issn = {2041-2657},
mesh = {Chromatin/*chemistry/*metabolism ; *Photobleaching ; Protein Processing, Post-Translational ; },
abstract = {We review the mechanism and consequences of the 'bridging-induced attraction', a generic biophysical principle that underpins some existing models for chromosome organization in 3D. This attraction, which was revealed in polymer physics-inspired computer simulations, is a generic clustering tendency arising in multivalent chromatin-binding proteins, and it provides an explanation for the biogenesis of nuclear bodies and transcription factories via microphase separation. Including post-translational modification reactions involving these multivalent proteins can account for the fast dynamics of the ensuing clusters, as is observed via microscopy and photobleaching experiments. The clusters found in simulations also give rise to chromatin domains that conform well with the observation of A/B compartments in HiC experiments.},
}
@article {pmid31968256,
year = {2020},
author = {Rhodes, JDP and Feldmann, A and Hernández-Rodríguez, B and Díaz, N and Brown, JM and Fursova, NA and Blackledge, NP and Prathapan, P and Dobrinic, P and Huseyin, MK and Szczurek, A and Kruse, K and Nasmyth, KA and Buckle, VJ and Vaquerizas, JM and Klose, RJ},
title = {Cohesin Disrupts Polycomb-Dependent Chromosome Interactions in Embryonic Stem Cells.},
journal = {Cell reports},
volume = {30},
number = {3},
pages = {820-835.e10},
pmid = {31968256},
issn = {2211-1247},
support = {294401/ERC_/European Research Council/International ; /BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; MC_UU_00016/1/MRC_/Medical Research Council/United Kingdom ; //Wellcome Trust/United Kingdom ; 209400/Z/17/Z/WT_/Wellcome Trust/United Kingdom ; MC_UP_1605/10/MRC_/Medical Research Council/United Kingdom ; 26747/CRUK_/Cancer Research UK/United Kingdom ; 107935/Z/15/Z/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Animals ; CCCTC-Binding Factor/metabolism ; Cell Cycle Proteins/*metabolism ; Cell Line ; Chromatin/metabolism ; Chromosomal Proteins, Non-Histone/*metabolism ; Chromosomes/*metabolism ; Embryonic Stem Cells/*metabolism ; Gene Expression Regulation ; Male ; Mice ; Polycomb-Group Proteins/*metabolism ; },
abstract = {How chromosome organization is related to genome function remains poorly understood. Cohesin, loop extrusion, and CCCTC-binding factor (CTCF) have been proposed to create topologically associating domains (TADs) to regulate gene expression. Here, we examine chromosome conformation in embryonic stem cells lacking cohesin and find, as in other cell types, that cohesin is required to create TADs and regulate A/B compartmentalization. However, in the absence of cohesin, we identify a series of long-range chromosomal interactions that persist. These correspond to regions of the genome occupied by the polycomb repressive system and are dependent on PRC1. Importantly, we discover that cohesin counteracts these polycomb-dependent interactions, but not interactions between super-enhancers. This disruptive activity is independent of CTCF and insulation and appears to modulate gene repression by the polycomb system. Therefore, we discover that cohesin disrupts polycomb-dependent chromosome interactions to modulate gene expression in embryonic stem cells.},
}
@article {pmid31960372,
year = {2020},
author = {Hu, G},
title = {Evaluation of 3D Chromatin Interactions Using Hi-C.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {2117},
number = {},
pages = {65-78},
pmid = {31960372},
issn = {1940-6029},
support = {U54 GM104942/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Cell Line ; Chromatin/*chemistry/*metabolism ; Computational Biology/*methods ; Epigenomics ; High-Throughput Nucleotide Sequencing ; Mice ; Molecular Conformation ; Mouse Embryonic Stem Cells/*chemistry ; Software ; },
abstract = {The invention of Hi-C has greatly facilitated 3D genome research through an unbiased probing of 3D chromatin interactions. It produces enormous amount of sequencing data that capture multiscale chromatin conformation structures. In the last decade, numerous computational methods have been developed to analyze Hi-C data and predict A/B compartments, topologically associating domains (TADs), and significant chromatin contacts. This chapter introduced the iHiC package that provides several utilities to facilitate Hi-C data analysis with public software and demonstrated its application to a Hi-C dataset generated for mouse embryonic stem (ES) cells.},
}
@article {pmid31956095,
year = {2020},
author = {Yang, K and Xue, Z and Lv, X},
title = {Molecular mechanism of the 3D genome structure and function regulation during cell terminal differentiation.},
journal = {Yi chuan = Hereditas},
volume = {42},
number = {1},
pages = {32-44},
doi = {10.16288/j.yczz.19-270},
pmid = {31956095},
issn = {0253-9772},
mesh = {*Cell Differentiation ; Chromatin/*chemistry ; *Chromatin Assembly and Disassembly ; *Genome ; Genomics ; },
abstract = {The eukaryotic chromatin is folded into highly complex three-dimensional (3D) structures, which plays an important role in the precise regulation of gene expression and normal physiological function. During differentiation and terminal maturation, cells usually undergo dramatic morphology and gene expression changes, accompanied by significant changes in the 3D structure of the genome. In this review, we provide a comprehensive view of the spatial hierarchical organization of the genome, including chromosome territories, A/B compartment, topologically associating domains (TADs) and looping, focusing on recent progresses in the dynamic 3D genomic structural changes and functional regulation during cell differentiation and terminal maturation. In the end, we summarize the unsolved issues as well as prospects of the 3D genome research in cell differentiation and maturation.},
}
@article {pmid31949157,
year = {2020},
author = {Achinger-Kawecka, J and Valdes-Mora, F and Luu, PL and Giles, KA and Caldon, CE and Qu, W and Nair, S and Soto, S and Locke, WJ and Yeo-Teh, NS and Gould, CM and Du, Q and Smith, GC and Ramos, IR and Fernandez, KF and Hoon, DS and Gee, JMW and Stirzaker, C and Clark, SJ},
title = {Epigenetic reprogramming at estrogen-receptor binding sites alters 3D chromatin landscape in endocrine-resistant breast cancer.},
journal = {Nature communications},
volume = {11},
number = {1},
pages = {320},
pmid = {31949157},
issn = {2041-1723},
mesh = {Antineoplastic Agents, Hormonal/pharmacology ; *Binding Sites ; Breast Neoplasms/*genetics/metabolism ; CCCTC-Binding Factor/chemistry/metabolism ; Chromatin/chemistry/genetics/*metabolism ; DNA Methylation ; *Epigenesis, Genetic/drug effects ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; MCF-7 Cells ; Neoplasm Proteins/genetics ; Promoter Regions, Genetic/drug effects ; Protein Interaction Domains and Motifs ; Receptors, Estrogen/*chemistry/*metabolism ; Whole Genome Sequencing ; },
abstract = {Endocrine therapy resistance frequently develops in estrogen receptor positive (ER+) breast cancer, but the underlying molecular mechanisms are largely unknown. Here, we show that 3-dimensional (3D) chromatin interactions both within and between topologically associating domains (TADs) frequently change in ER+ endocrine-resistant breast cancer cells and that the differential interactions are enriched for resistance-associated genetic variants at CTCF-bound anchors. Ectopic chromatin interactions are preferentially enriched at active enhancers and promoters and ER binding sites, and are associated with altered expression of ER-regulated genes, consistent with dynamic remodelling of ER pathways accompanying the development of endocrine resistance. We observe that loss of 3D chromatin interactions often occurs coincidently with hypermethylation and loss of ER binding. Alterations in active A and inactive B chromosomal compartments are also associated with decreased ER binding and atypical interactions and gene expression. Together, our results suggest that 3D epigenome remodelling is a key mechanism underlying endocrine resistance in ER+ breast cancer.},
}
@article {pmid31937349,
year = {2020},
author = {Cameron, CJ and Dostie, J and Blanchette, M},
title = {HIFI: estimating DNA-DNA interaction frequency from Hi-C data at restriction-fragment resolution.},
journal = {Genome biology},
volume = {21},
number = {1},
pages = {11},
pmid = {31937349},
issn = {1474-760X},
support = {MOP-142451//CIHR/Canada ; },
mesh = {*Algorithms ; Animals ; *Chromosomes ; DNA/*metabolism ; *Genome ; Humans ; Mice ; *Restriction Mapping ; },
abstract = {Hi-C is a popular technique to map three-dimensional chromosome conformation. In principle, Hi-C's resolution is only limited by the size of restriction fragments. However, insufficient sequencing depth forces researchers to artificially reduce the resolution of Hi-C matrices at a loss of biological interpretability. We present the Hi-C Interaction Frequency Inference (HIFI) algorithms that accurately estimate restriction-fragment resolution Hi-C matrices by exploiting dependencies between neighboring fragments. Cross-validation experiments and comparisons to 5C data and known regulatory interactions demonstrate HIFI's superiority to existing approaches. In addition, HIFI's restriction-fragment resolution reveals a new role for active regulatory regions in structuring topologically associating domains.},
}
@article {pmid31925403,
year = {2020},
author = {Beagan, JA and Phillips-Cremins, JE},
title = {On the existence and functionality of topologically associating domains.},
journal = {Nature genetics},
volume = {52},
number = {1},
pages = {8-16},
pmid = {31925403},
issn = {1546-1718},
support = {1DP2MH11024701//U.S. Department of Health &amp; Human Services | NIH | National Institute of Mental Health (NIMH)/International ; R01 MH120269/MH/NIMH NIH HHS/United States ; 1R011MH120269//U.S. Department of Health &amp; Human Services | NIH | National Institute of Mental Health (NIMH)/International ; DP2 MH110247/MH/NIMH NIH HHS/United States ; 1U01HL12999801//U.S. Department of Health &amp; Human Services | NIH | Office of Strategic Coordination (OSC)/International ; R01 NS114226/NS/NINDS NIH HHS/United States ; U01 HL129998/HL/NHLBI NIH HHS/United States ; },
mesh = {Animals ; Cell Compartmentation ; Chromatin Assembly and Disassembly/*genetics ; *Gene Expression Regulation ; *Genome ; Humans ; Models, Biological ; *Transcription, Genetic ; },
abstract = {Genomes across a wide range of eukaryotic organisms fold into higher-order chromatin domains. Topologically associating domains (TADs) were originally discovered empirically in low-resolution Hi-C heat maps representing ensemble average interaction frequencies from millions of cells. Here, we discuss recent advances in high-resolution Hi-C, single-cell imaging experiments, and functional genetic studies, which provide an increasingly complex view of the genome's hierarchical structure-function relationship. On the basis of these new findings, we update the definitions of distinct classes of chromatin domains according to emerging knowledge of their structural, mechanistic and functional properties.},
}
@article {pmid31911579,
year = {2020},
author = {Khoury, A and Achinger-Kawecka, J and Bert, SA and Smith, GC and French, HJ and Luu, PL and Peters, TJ and Du, Q and Parry, AJ and Valdes-Mora, F and Taberlay, PC and Stirzaker, C and Statham, AL and Clark, SJ},
title = {Constitutively bound CTCF sites maintain 3D chromatin architecture and long-range epigenetically regulated domains.},
journal = {Nature communications},
volume = {11},
number = {1},
pages = {54},
pmid = {31911579},
issn = {2041-1723},
mesh = {Binding Sites ; CCCTC-Binding Factor/genetics/*metabolism ; Chromatin/chemistry/genetics/*metabolism ; DNA/genetics/metabolism ; *Epigenesis, Genetic ; Humans ; Promoter Regions, Genetic ; Protein Binding ; Protein Domains ; },
abstract = {The architectural protein CTCF is a mediator of chromatin conformation, but how CTCF binding to DNA is orchestrated to maintain long-range gene expression is poorly understood. Here we perform RNAi knockdown to reduce CTCF levels and reveal a shared subset of CTCF-bound sites are robustly resistant to protein depletion. The 'persistent' CTCF sites are enriched at domain boundaries and chromatin loops constitutive to all cell types. CRISPR-Cas9 deletion of 2 persistent CTCF sites at the boundary between a long-range epigenetically active (LREA) and silenced (LRES) region, within the Kallikrein (KLK) locus, results in concordant activation of all 8 KLK genes within the LRES region. CTCF genome-wide depletion results in alteration in Topologically Associating Domain (TAD) structure, including the merging of TADs, whereas TAD boundaries are not altered where persistent sites are maintained. We propose that the subset of essential CTCF sites are involved in cell-type constitutive, higher order chromatin architecture.},
}
@article {pmid31910870,
year = {2020},
author = {Kentepozidou, E and Aitken, SJ and Feig, C and Stefflova, K and Ibarra-Soria, X and Odom, DT and Roller, M and Flicek, P},
title = {Clustered CTCF binding is an evolutionary mechanism to maintain topologically associating domains.},
journal = {Genome biology},
volume = {21},
number = {1},
pages = {5},
pmid = {31910870},
issn = {1474-760X},
support = {202878/Z/16/Z//Wellcome Trust/United Kingdom ; 615584/ERC_/European Research Council/International ; WT202878/B/16/Z/WT_/Wellcome Trust/United Kingdom ; WT202878/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; 20412/CRUK_/Cancer Research UK/United Kingdom ; WT106563/Z/14/WT_/Wellcome Trust/United Kingdom ; WT108749/Z/15/Z/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Animals ; CCCTC-Binding Factor/*genetics/*metabolism ; Chromatin/*metabolism ; Chromatin Immunoprecipitation Sequencing ; *Evolution, Molecular ; Genome ; Mice/*genetics ; },
abstract = {BACKGROUND: CTCF binding contributes to the establishment of a higher-order genome structure by demarcating the boundaries of large-scale topologically associating domains (TADs). However, despite the importance and conservation of TADs, the role of CTCF binding in their evolution and stability remains elusive.<br><br>RESULTS: We carry out an experimental and computational study that exploits the natural genetic variation across five closely related species to assess how CTCF binding patterns stably fixed by evolution in each species contribute to the establishment and evolutionary dynamics of TAD boundaries. We perform CTCF ChIP-seq in multiple mouse species to create genome-wide binding profiles and associate them with TAD boundaries. Our analyses reveal that CTCF binding is maintained at TAD boundaries by a balance of selective constraints and dynamic evolutionary processes. Regardless of their conservation across species, CTCF binding sites at TAD boundaries are subject to stronger sequence and functional constraints compared to other CTCF sites. TAD boundaries frequently harbor dynamically evolving clusters containing both evolutionarily old and young CTCF sites as a result of the repeated acquisition of new species-specific sites close to conserved ones. The overwhelming majority of clustered CTCF sites colocalize with cohesin and are significantly closer to gene transcription start sites than nonclustered CTCF sites, suggesting that CTCF clusters particularly contribute to cohesin stabilization and transcriptional regulation.<br><br>CONCLUSIONS: Dynamic conservation of CTCF site clusters is an apparently important feature of CTCF binding evolution that is critical to the functional stability of a higher-order chromatin structure.},
}
@article {pmid31909304,
year = {2019},
author = {Liu, CF and Tang, WHW},
title = {Epigenetics in Cardiac Hypertrophy and Heart Failure.},
journal = {JACC. Basic to translational science},
volume = {4},
number = {8},
pages = {976-993},
pmid = {31909304},
issn = {2452-302X},
abstract = {Heart failure (HF) is a complex syndrome affecting millions of people around the world. Over the past decade, the therapeutic potential of targeting epigenetic regulators in HF has been discussed extensively. Recent advances in next-generation sequencing techniques have contributed substantial progress in our understanding of the role of DNA methylation, post-translational modifications of histones, adenosine triphosphate (ATP)-dependent chromatin conformation and remodeling, and non-coding RNAs in HF pathophysiology. In this review, we summarize epigenomic studies on human and animal models in HF.},
}
@article {pmid31887284,
year = {2020},
author = {Chang, LH and Ghosh, S and Noordermeer, D},
title = {TADs and Their Borders: Free Movement or Building a Wall?.},
journal = {Journal of molecular biology},
volume = {432},
number = {3},
pages = {643-652},
doi = {10.1016/j.jmb.2019.11.025},
pmid = {31887284},
issn = {1089-8638},
mesh = {Animals ; CCCTC-Binding Factor/metabolism ; Chromatin/*chemistry/*metabolism ; Macromolecular Substances/*chemistry/*metabolism ; Mammals ; Microscopy, Ultraviolet ; *Molecular Conformation ; Protein Binding ; },
abstract = {The tridimensional (3D) organization of mammalian genomes combines structures from different length scales. Within this organization, Topologically Associating Domains (TADs) are visible in Hi-C heat maps at the sub-megabase scale. The integrity of TADs is important for correct gene expression, but in a context-dependent and variable manner. The correct structure and function of TADs require the binding of the CTCF protein at both borders, which appears to block an active and dynamic mechanism of "Cohesin-mediated loop extrusion." As a result, mammalian TADs appear as so-called "loop domains" in Hi-C data, which are the focus of this review. Here, we present a reanalysis of TADs from three "golden-standard" mammalian Hi-C data sets. Despite the prominent presence of TADs in Hi-C heat maps from all studies, we find consistently that regions within these domains are only moderately insulated from their surroundings. Moreover, single-cell Hi-C and superresolution microscopy have revealed that the structure of TADs and the position of their borders can vary from cell to cell. The function of TADs as units of gene regulation may thus require additional aspects, potentially incorporating the mechanism of loop extrusion as well. Recent developments in single-cell and multi-contact genomics and superresolution microscopy assays will be instrumental to link TAD formation and structure to their function in transcriptional regulation.},
}
@article {pmid31884969,
year = {2019},
author = {Foissac, S and Djebali, S and Munyard, K and Vialaneix, N and Rau, A and Muret, K and Esquerré, D and Zytnicki, M and Derrien, T and Bardou, P and Blanc, F and Cabau, C and Crisci, E and Dhorne-Pollet, S and Drouet, F and Faraut, T and Gonzalez, I and Goubil, A and Lacroix-Lamandé, S and Laurent, F and Marthey, S and Marti-Marimon, M and Momal-Leisenring, R and Mompart, F and Quéré, P and Robelin, D and Cristobal, MS and Tosser-Klopp, G and Vincent-Naulleau, S and Fabre, S and Pinard-Van der Laan, MH and Klopp, C and Tixier-Boichard, M and Acloque, H and Lagarrigue, S and Giuffra, E},
title = {Multi-species annotation of transcriptome and chromatin structure in domesticated animals.},
journal = {BMC biology},
volume = {17},
number = {1},
pages = {108},
pmid = {31884969},
issn = {1741-7007},
mesh = {Animals ; Animals, Domestic/*genetics ; Cattle ; Chickens ; Chromatin/*genetics ; Goats ; *Molecular Sequence Annotation ; Phylogeny ; Sus scrofa ; *Transcriptome ; },
abstract = {BACKGROUND: Comparative genomics studies are central in identifying the coding and non-coding elements associated with complex traits, and the functional annotation of genomes is a critical step to decipher the genotype-to-phenotype relationships in livestock animals. As part of the Functional Annotation of Animal Genomes (FAANG) action, the FR-AgENCODE project aimed to create reference functional maps of domesticated animals by profiling the landscape of transcription (RNA-seq), chromatin accessibility (ATAC-seq) and conformation (Hi-C) in species representing ruminants (cattle, goat), monogastrics (pig) and birds (chicken), using three target samples related to metabolism (liver) and immunity (CD4+ and CD8+ T cells).<br><br>RESULTS: RNA-seq assays considerably extended the available catalog of annotated transcripts and identified differentially expressed genes with unknown function, including new syntenic lncRNAs. ATAC-seq highlighted an enrichment for transcription factor binding sites in differentially accessible regions of the chromatin. Comparative analyses revealed a core set of conserved regulatory regions across species. Topologically associating domains (TADs) and epigenetic A/B compartments annotated from Hi-C data were consistent with RNA-seq and ATAC-seq data. Multi-species comparisons showed that conserved TAD boundaries had stronger insulation properties than species-specific ones and that the genomic distribution of orthologous genes in A/B compartments was significantly conserved across species.<br><br>CONCLUSIONS: We report the first multi-species and multi-assay genome annotation results obtained by a FAANG project. Beyond the generation of reference annotations and the confirmation of previous findings on model animals, the integrative analysis of data from multiple assays and species sheds a new light on the multi-scale selective pressure shaping genome organization from birds to mammals. Overall, these results emphasize the value of FAANG for research on domesticated animals and reinforces the importance of future meta-analyses of the reference datasets being generated by this community on different species.},
}
@article {pmid31881832,
year = {2019},
author = {Gan, W and Luo, J and Li, YZ and Guo, JL and Zhu, M and Li, ML},
title = {A computational method to predict topologically associating domain boundaries combining histone Marks and sequence information.},
journal = {BMC genomics},
volume = {20},
number = {Suppl 13},
pages = {980},
pmid = {31881832},
issn = {1471-2164},
mesh = {Algorithms ; Area Under Curve ; Chromatin/metabolism ; Histone Code ; Histones/*chemistry/metabolism ; *Neural Networks, Computer ; Protein Binding ; ROC Curve ; },
abstract = {BACKGROUND: The three-dimensional (3D) structure of chromatins plays significant roles during cell differentiation and development. Hi-C and other 3C-based technologies allow us to look deep into the chromatin architectures. Many studies have suggested that topologically associating domains (TAD), as the structure and functional unit, are conserved across different organs. However, our understanding about the underlying mechanism of the TAD boundary formation is still limited.<br><br>RESULTS: We developed a computational method, TAD-Lactuca, to infer this structure by taking the contextual information of the epigenetic modification signals and the primary DNA sequence information on the genome. TAD-Lactuca is found stable in the case of multi-resolutions and different datasets. It could achieve high accuracy and even outperforms the state-of-art methods when the sequence patterns were incorporated. Moreover, several transcript factor binding motifs, besides the well-known CCCTC-binding factor (CTCF) motif, were found significantly enriched on the boundaries.<br><br>CONCLUSIONS: We provided a low cost, effective method to predict TAD boundaries. Above results suggested the incorporation of sequence features could significantly improve the performance. The sequence motif enrichment analysis indicates several gene regulation motifs around the boundaries, which is consistent with TADs may serve as the functional units of gene regulation and implies the sequence patterns would be important in chromatin folding.},
}
@article {pmid31879954,
year = {2020},
author = {Daban, JR},
title = {Supramolecular multilayer organization of chromosomes: possible functional roles of planar chromatin in gene expression and DNA replication and repair.},
journal = {FEBS letters},
volume = {594},
number = {3},
pages = {395-411},
doi = {10.1002/1873-3468.13724},
pmid = {31879954},
issn = {1873-3468},
mesh = {Animals ; Biomechanical Phenomena ; Chromatin/genetics/*metabolism ; *DNA Repair ; *DNA Replication ; *Gene Expression Regulation ; Humans ; Mitosis ; },
abstract = {Experimental evidence indicates that the chromatin filament is self-organized into a multilayer planar structure that is densely stacked in metaphase and unstacked in interphase. This chromatin organization is unexpected, but it is shown that diverse supramolecular assemblies, including dinoflagellate chromosomes, are multilayered. The mechanical strength of planar chromatin protects the genome integrity, even when double-strand breaks are produced. Here, it is hypothesized that the chromatin filament in the loops and topologically associating domains is folded within the thin layers of the multilaminar chromosomes. It is also proposed that multilayer chromatin has two states: inactive when layers are stacked and active when layers are unstacked. Importantly, the well-defined topology of planar chromatin may facilitate DNA replication without entanglements and DNA repair by homologous recombination.},
}
@article {pmid31866047,
year = {2020},
author = {Schilit, SLP and Menon, S and Friedrich, C and Kammin, T and Wilch, E and Hanscom, C and Jiang, S and Kliesch, S and Talkowski, ME and Tüttelmann, F and MacQueen, AJ and Morton, CC},
title = {SYCP2 Translocation-Mediated Dysregulation and Frameshift Variants Cause Human Male Infertility.},
journal = {American journal of human genetics},
volume = {106},
number = {1},
pages = {41-57},
pmid = {31866047},
issn = {1537-6605},
support = {P01 GM061354/GM/NIGMS NIH HHS/United States ; R15 GM116109/GM/NIGMS NIH HHS/United States ; P30 CA006516/CA/NCI NIH HHS/United States ; R15 GM104827/GM/NIGMS NIH HHS/United States ; F31 HD090780/HD/NICHD NIH HHS/United States ; },
mesh = {Adult ; Cell Cycle Proteins/*genetics ; *Chromosome Aberrations ; DNA-Binding Proteins/*genetics ; Female ; *Frameshift Mutation ; Humans ; Infertility, Male/*etiology/pathology ; Karyotyping ; Male ; Oligospermia/*etiology/pathology ; Pedigree ; Phenotype ; Translocation, Genetic ; },
abstract = {Unexplained infertility affects 2%-3% of reproductive-aged couples. One approach to identifying genes involved in infertility is to study subjects with this clinical phenotype and a de novo balanced chromosomal aberration (BCA). While BCAs may reduce fertility by production of unbalanced gametes, a chromosomal rearrangement may also disrupt or dysregulate genes important in fertility. One such subject, DGAP230, has severe oligozoospermia and 46,XY,t(20;22)(q13.3;q11.2). We identified exclusive overexpression of SYCP2 from the der(20) allele that is hypothesized to result from enhancer adoption. Modeling the dysregulation in budding yeast resulted in disrupted structural integrity of the synaptonemal complex, a common cause of defective spermatogenesis in mammals. Exome sequencing of infertile males revealed three heterozygous SYCP2 frameshift variants in additional subjects with cryptozoospermia and azoospermia. In sum, this investigation illustrates the power of precision cytogenetics for annotation of the infertile genome, suggests that these mechanisms should be considered as an alternative etiology to that of segregation of unbalanced gametes in infertile men harboring a BCA, and provides evidence of SYCP2-mediated male infertility in humans.},
}
@article {pmid31861077,
year = {2019},
author = {Lesne, A and Baudement, MO and Rebouissou, C and Forné, T},
title = {Exploring Mammalian Genome within Phase-Separated Nuclear Bodies: Experimental Methods and Implications for Gene Expression.},
journal = {Genes},
volume = {10},
number = {12},
pages = {},
pmid = {31861077},
issn = {2073-4425},
mesh = {Animals ; Chromatin/metabolism ; DNA/metabolism ; Gene Expression ; *Genome ; High-Throughput Nucleotide Sequencing/methods ; Intranuclear Inclusion Bodies/*metabolism ; Ribonucleoproteins/genetics/metabolism ; },
abstract = {The importance of genome organization at the supranucleosomal scale in the control of gene expression is increasingly recognized today. In mammals, Topologically Associating Domains (TADs) and the active/inactive chromosomal compartments are two of the main nuclear structures that contribute to this organization level. However, recent works reviewed here indicate that, at specific loci, chromatin interactions with nuclear bodies could also be crucial to regulate genome functions, in particular transcription. They moreover suggest that these nuclear bodies are membrane-less organelles dynamically self-assembled and disassembled through mechanisms of phase separation. We have recently developed a novel genome-wide experimental method, High-salt Recovered Sequences sequencing (HRS-seq), which allows the identification of chromatin regions associated with large ribonucleoprotein (RNP) complexes and nuclear bodies. We argue that the physical nature of such RNP complexes and nuclear bodies appears to be central in their ability to promote efficient interactions between distant genomic regions. The development of novel experimental approaches, including our HRS-seq method, is opening new avenues to understand how self-assembly of phase-separated nuclear bodies possibly contributes to mammalian genome organization and gene expression.},
}
@article {pmid31851943,
year = {2019},
author = {Chen, C and Yu, W and Tober, J and Gao, P and He, B and Lee, K and Trieu, T and Blobel, GA and Speck, NA and Tan, K},
title = {Spatial Genome Re-organization between Fetal and Adult Hematopoietic Stem Cells.},
journal = {Cell reports},
volume = {29},
number = {12},
pages = {4200-4211.e7},
pmid = {31851943},
issn = {2211-1247},
support = {R01 GM104369/GM/NIGMS NIH HHS/United States ; R01 HD089245/HD/NICHD NIH HHS/United States ; U01 CA226187/CA/NCI NIH HHS/United States ; R01 HG006130/HG/NHGRI NIH HHS/United States ; U01 HL129998/HL/NHLBI NIH HHS/United States ; R01 GM108716/GM/NIGMS NIH HHS/United States ; },
mesh = {Adult Stem Cells/*cytology/*metabolism ; Animals ; Enhancer Elements, Genetic/genetics ; Female ; GATA3 Transcription Factor/genetics/metabolism ; Hematopoietic Stem Cells/*cytology/*metabolism ; Male ; Mice ; Nuclear Receptor Subfamily 4, Group A, Member 1/genetics/metabolism ; Promoter Regions, Genetic/genetics ; },
abstract = {Fetal hematopoietic stem cells (HSCs) undergo a developmental switch to become adult HSCs with distinct functional properties. To better understand the molecular mechanisms underlying the developmental switch, we have conducted deep sequencing of the 3D genome, epigenome, and transcriptome of fetal and adult HSCs in mouse. We find that chromosomal compartments and topologically associating domains (TADs) are largely conserved between fetal and adult HSCs. However, there is a global trend of increased compartmentalization and TAD boundary strength in adult HSCs. In contrast, intra-TAD chromatin interactions are much more dynamic and widespread, involving over a thousand gene promoters and distal enhancers. These developmental-stage-specific enhancer-promoter interactions are mediated by different sets of transcription factors, such as TCF3 and MAFB in fetal HSCs, versus NR4A1 and GATA3 in adult HSCs. Loss-of-function studies of TCF3 confirm the role of TCF3 in mediating condition-specific enhancer-promoter interactions and gene regulation in fetal HSCs.},
}
@article {pmid31848476,
year = {2020},
author = {Kempfer, R and Pombo, A},
title = {Methods for mapping 3D chromosome architecture.},
journal = {Nature reviews. Genetics},
volume = {21},
number = {4},
pages = {207-226},
pmid = {31848476},
issn = {1471-0064},
mesh = {Cell Nucleus/genetics ; Chromatin/chemistry ; Chromatin Immunoprecipitation ; Chromosomes/*chemistry ; Genomics/methods ; Humans ; In Situ Hybridization, Fluorescence ; },
abstract = {Determining how chromosomes are positioned and folded within the nucleus is critical to understanding the role of chromatin topology in gene regulation. Several methods are available for studying chromosome architecture, each with different strengths and limitations. Established imaging approaches and proximity ligation-based chromosome conformation capture (3C) techniques (such as DNA-FISH and Hi-C, respectively) have revealed the existence of chromosome territories, functional nuclear landmarks (such as splicing speckles and the nuclear lamina) and topologically associating domains. Improvements to these methods and the recent development of ligation-free approaches, including GAM, SPRITE and ChIA-Drop, are now helping to uncover new aspects of 3D genome topology that confirm the nucleus to be a complex, highly organized organelle.},
}
@article {pmid31847870,
year = {2019},
author = {An, L and Yang, T and Yang, J and Nuebler, J and Xiang, G and Hardison, RC and Li, Q and Zhang, Y},
title = {OnTAD: hierarchical domain structure reveals the divergence of activity among TADs and boundaries.},
journal = {Genome biology},
volume = {20},
number = {1},
pages = {282},
pmid = {31847870},
issn = {1474-760X},
support = {T32 GM102057/NH/NIH HHS/United States ; R01 GM121613/GM/NIGMS NIH HHS/United States ; U54 DK107980/DK/NIDDK NIH HHS/United States ; R24 DK106766/NH/NIH HHS/United States ; R01 GM109453/GM/NIGMS NIH HHS/United States ; R01 GM109453/NH/NIH HHS/United States ; R24 DK106766/DK/NIDDK NIH HHS/United States ; R01 GM121613/NH/NIH HHS/United States ; },
mesh = {Algorithms ; Chromatin/*metabolism ; *Chromatin Assembly and Disassembly ; Epigenesis, Genetic ; Genomics ; Software ; },
abstract = {The spatial organization of chromatin in the nucleus has been implicated in regulating gene expression. Maps of high-frequency interactions between different segments of chromatin have revealed topologically associating domains (TADs), within which most of the regulatory interactions are thought to occur. TADs are not homogeneous structural units but appear to be organized into a hierarchy. We present OnTAD, an optimized nested TAD caller from Hi-C data, to identify hierarchical TADs. OnTAD reveals new biological insights into the role of different TAD levels, boundary usage in gene regulation, the loop extrusion model, and compartmental domains. OnTAD is available at https://github.com/anlin00007/OnTAD.},
}
@article {pmid31831055,
year = {2019},
author = {Llères, D and Moindrot, B and Pathak, R and Piras, V and Matelot, M and Pignard, B and Marchand, A and Poncelet, M and Perrin, A and Tellier, V and Feil, R and Noordermeer, D},
title = {CTCF modulates allele-specific sub-TAD organization and imprinted gene activity at the mouse Dlk1-Dio3 and Igf2-H19 domains.},
journal = {Genome biology},
volume = {20},
number = {1},
pages = {272},
pmid = {31831055},
issn = {1474-760X},
mesh = {Animals ; CCCTC-Binding Factor/*metabolism ; Calcium-Binding Proteins/genetics ; *Genomic Imprinting ; Insulin-Like Growth Factor II/genetics ; Iodide Peroxidase/genetics ; Mice ; RNA, Long Noncoding/genetics ; },
abstract = {BACKGROUND: Genomic imprinting is essential for mammalian development and provides a unique paradigm to explore intra-cellular differences in chromatin configuration. So far, the detailed allele-specific chromatin organization of imprinted gene domains has mostly been lacking. Here, we explored the chromatin structure of the two conserved imprinted domains controlled by paternal DNA methylation imprints-the Igf2-H19 and Dlk1-Dio3 domains-and assessed the involvement of the insulator protein CTCF in mouse cells.<br><br>RESULTS: Both imprinted domains are located within overarching topologically associating domains (TADs) that are similar on both parental chromosomes. At each domain, a single differentially methylated region is bound by CTCF on the maternal chromosome only, in addition to multiple instances of bi-allelic CTCF binding. Combinations of allelic 4C-seq and DNA-FISH revealed that bi-allelic CTCF binding alone, on the paternal chromosome, correlates with a first level of sub-TAD structure. On the maternal chromosome, additional CTCF binding at the differentially methylated region adds a further layer of sub-TAD organization, which essentially hijacks the existing paternal-specific sub-TAD organization. Perturbation of maternal-specific CTCF binding site at the Dlk1-Dio3 locus, using genome editing, results in perturbed sub-TAD organization and bi-allelic Dlk1 activation during differentiation.<br><br>CONCLUSIONS: Maternal allele-specific CTCF binding at the imprinted Igf2-H19 and the Dlk1-Dio3 domains adds an additional layer of sub-TAD organization, on top of an existing three-dimensional configuration and prior to imprinted activation of protein-coding genes. We speculate that this allele-specific sub-TAD organization provides an instructive or permissive context for imprinted gene activation during development.},
}
@article {pmid31829768,
year = {2020},
author = {Barajas-Mora, EM and Feeney, AJ},
title = {Enhancers as regulators of antigen receptor loci three-dimensional chromatin structure.},
journal = {Transcription},
volume = {11},
number = {1},
pages = {37-51},
pmid = {31829768},
issn = {2154-1272},
support = {R56 AI119092/AI/NIAID NIH HHS/United States ; },
mesh = {Animals ; Chromatin/*chemistry/genetics/metabolism ; Humans ; Protein Conformation ; Receptors, Antigen/*chemistry/genetics/metabolism ; },
abstract = {Enhancers are defined as regulatory elements that control transcription in a cell-type and developmental stage-specific manner. They achieve this by physically interacting with their cognate gene promoters. Significantly, these interactions can occur through long genomic distances since enhancers may not be near their cognate promoters. The optimal coordination of enhancer-regulated transcription is essential for the function and identity of the cell. Although great efforts to fully understand the principles of this type of regulation are ongoing, other potential functions of the long-range chromatin interactions (LRCIs) involving enhancers are largely unexplored. We recently uncovered a new role for enhancer elements in determining the three-dimensional (3D) structure of the immunoglobulin kappa (Igκ) light chain receptor locus suggesting a structural function for these DNA elements. This enhancer-mediated locus configuration shapes the resulting Igκ repertoire. We also propose a role for enhancers as critical components of sub-topologically associating domain (subTAD) formation and nuclear spatial localization.},
}
@article {pmid31819944,
year = {2020},
author = {van Schoonhoven, A and Huylebroeck, D and Hendriks, RW and Stadhouders, R},
title = {3D genome organization during lymphocyte development and activation.},
journal = {Briefings in functional genomics},
volume = {19},
number = {2},
pages = {71-82},
pmid = {31819944},
issn = {2041-2657},
mesh = {Animals ; Cell Differentiation/genetics/physiology ; Chromatin/metabolism ; Chromatin Assembly and Disassembly/genetics/physiology ; Humans ; Lymphocytes/metabolism ; Promoter Regions, Genetic/*genetics ; },
abstract = {Chromosomes have a complex three-dimensional (3D) architecture comprising A/B compartments, topologically associating domains and promoter-enhancer interactions. At all these levels, the 3D genome has functional consequences for gene transcription and therefore for cellular identity. The development and activation of lymphocytes involves strict control of gene expression by transcription factors (TFs) operating in a three-dimensionally organized chromatin landscape. As lymphocytes are indispensable for tissue homeostasis and pathogen defense, and aberrant lymphocyte activity is involved in a wide range of human morbidities, acquiring an in-depth understanding of the molecular mechanisms that control lymphocyte identity is highly relevant. Here we review current knowledge of the interplay between 3D genome organization and transcriptional control during B and T lymphocyte development and antigen-dependent activation, placing special emphasis on the role of TFs.},
}
@article {pmid31811132,
year = {2019},
author = {Zhang, S and Chasman, D and Knaack, S and Roy, S},
title = {In silico prediction of high-resolution Hi-C interaction matrices.},
journal = {Nature communications},
volume = {10},
number = {1},
pages = {5449},
pmid = {31811132},
issn = {2041-1723},
support = {R01 HG010045/HG/NHGRI NIH HHS/United States ; },
mesh = {CCCTC-Binding Factor/metabolism ; Cell Line ; Chromatin/chemistry ; Chromosomes/*chemistry ; Computational Biology/*methods ; *Computer Simulation ; Gene Expression Regulation ; Gene Regulatory Networks ; *Genome ; Genomics/*methods ; Humans ; Machine Learning ; Models, Genetic ; Promoter Regions, Genetic/genetics ; },
abstract = {The three-dimensional (3D) organization of the genome plays an important role in gene regulation bringing distal sequence elements in 3D proximity to genes hundreds of kilobases away. Hi-C is a powerful genome-wide technique to study 3D genome organization. Owing to experimental costs, high resolution Hi-C datasets are limited to a few cell lines. Computational prediction of Hi-C counts can offer a scalable and inexpensive approach to examine 3D genome organization across multiple cellular contexts. Here we present HiC-Reg, an approach to predict contact counts from one-dimensional regulatory signals. HiC-Reg predictions identify topologically associating domains and significant interactions that are enriched for CCCTC-binding factor (CTCF) bidirectional motifs and interactions identified from complementary sources. CTCF and chromatin marks, especially repressive and elongation marks, are most important for HiC-Reg's predictive performance. Taken together, HiC-Reg provides a powerful framework to generate high-resolution profiles of contact counts that can be used to study individual locus level interactions and higher-order organizational units of the genome.},
}
@article {pmid31805995,
year = {2019},
author = {Muro, EM and Ibn-Salem, J and Andrade-Navarro, MA},
title = {The distributions of protein coding genes within chromatin domains in relation to human disease.},
journal = {Epigenetics &amp; chromatin},
volume = {12},
number = {1},
pages = {72},
pmid = {31805995},
issn = {1756-8935},
mesh = {Cell Line ; Chromatin/chemistry/*genetics/metabolism ; Databases, Genetic ; Disease/*genetics ; Enhancer Elements, Genetic ; Humans ; Open Reading Frames/*genetics ; Transcription Initiation Site ; },
abstract = {BACKGROUND: Our understanding of the nuclear chromatin structure has increased hugely during the last years mainly as a consequence of the advances in chromatin conformation capture methods like Hi-C. The unprecedented resolution of genome-wide interaction maps shows functional consequences that extend the initial thought of an efficient DNA packaging mechanism: gene regulation, DNA repair, chromosomal translocations and evolutionary rearrangements seem to be only the peak of the iceberg. One key concept emerging from this research is the topologically associating domains (TADs) whose functional role in gene regulation and their association with disease is not fully untangled.<br><br>RESULTS: We report that the lower the number of protein coding genes inside TADs, the higher the tendency of those genes to be associated with disease (p-value&#x2009;=&#x2009;4&#x2009;&#xd7;&#x2009;[Formula: see text]). Moreover, housekeeping genes are less associated with disease than other genes. Accordingly, they are depleted in TADs containing less than three protein coding genes (p-value&#x2009;=&#x2009;3.9&#x2009;&#xd7;&#x2009;[Formula: see text]). We observed that TADs with higher ratios of enhancers versus genes contained higher numbers of disease-associated genes. We interpret these results as an indication that sharing enhancers among genes reduces their involvement in disease. Larger TADs would have more chances to accommodate many genes and select for enhancer sharing along evolution.<br><br>CONCLUSIONS: Genes associated with human disease do not distribute randomly over the TADs. Our observations suggest general rules that confer functional stability to TADs, adding more evidence to the role of TADs as regulatory units.},
}
@article {pmid31801998,
year = {2019},
author = {Chen, X and Ke, Y and Wu, K and Zhao, H and Sun, Y and Gao, L and Liu, Z and Zhang, J and Tao, W and Hou, Z and Liu, H and Liu, J and Chen, ZJ},
title = {Key role for CTCF in establishing chromatin structure in human embryos.},
journal = {Nature},
volume = {576},
number = {7786},
pages = {306-310},
pmid = {31801998},
issn = {1476-4687},
mesh = {CCCTC-Binding Factor/genetics/*metabolism ; *Chromatin ; Embryo, Mammalian ; Embryonic Development ; Gene Expression Regulation ; Humans ; Male ; Spermatozoa/metabolism ; },
abstract = {In the interphase of the cell cycle, chromatin is arranged in a hierarchical structure within the nucleus[1,2], which has an important role in regulating gene expression[3-6]. However, the dynamics of 3D chromatin structure during human embryogenesis remains unknown. Here we report that, unlike mouse sperm, human sperm cells do not express the chromatin regulator CTCF and their chromatin does not contain topologically associating domains (TADs). Following human fertilization, TAD structure is gradually established during embryonic development. In addition, A/B compartmentalization is lost in human embryos at the 2-cell stage and is re-established during embryogenesis. Notably, blocking zygotic genome activation (ZGA) can inhibit TAD establishment in human embryos but not in mouse or Drosophila. Of note, CTCF is expressed at very low levels before ZGA, and is then highly expressed at the ZGA stage when TADs are observed. TAD organization is significantly reduced in CTCF knockdown embryos, suggesting that TAD establishment during ZGA in human embryos requires CTCF expression. Our results indicate that CTCF has a key role in the establishment of 3D chromatin structure during human embryogenesis.},
}
@article {pmid31801603,
year = {2019},
author = {Middelkamp, S and Vlaar, JM and Giltay, J and Korzelius, J and Besselink, N and Boymans, S and Janssen, R and de la Fonteijne, L and van Binsbergen, E and van Roosmalen, MJ and Hochstenbach, R and Giachino, D and Talkowski, ME and Kloosterman, WP and Cuppen, E},
title = {Prioritization of genes driving congenital phenotypes of patients with de novo genomic structural variants.},
journal = {Genome medicine},
volume = {11},
number = {1},
pages = {79},
pmid = {31801603},
issn = {1756-994X},
mesh = {Computational Biology/methods ; DNA Copy Number Variations ; *Genetic Association Studies ; Genetic Diseases, Inborn/*diagnosis/*genetics ; *Genetic Predisposition to Disease ; *Genetic Variation ; Genome, Human ; Genomic Structural Variation ; Humans ; Molecular Sequence Annotation ; *Phenotype ; Whole Genome Sequencing ; },
abstract = {BACKGROUND: Genomic structural variants (SVs) can affect many genes and regulatory elements. Therefore, the molecular mechanisms driving the phenotypes of patients carrying de novo SVs are frequently unknown.<br><br>METHODS: We applied a combination of systematic experimental and bioinformatic methods to improve the molecular diagnosis of 39 patients with multiple congenital abnormalities and/or intellectual disability harboring apparent de novo SVs, most with an inconclusive diagnosis after regular genetic testing.<br><br>RESULTS: In 7 of these cases (18%), whole-genome sequencing analysis revealed disease-relevant complexities of the SVs missed in routine microarray-based analyses. We developed a computational tool to predict the effects on genes directly affected by SVs and on genes indirectly affected likely due to the changes in chromatin organization and impact on regulatory mechanisms. By combining these functional predictions with extensive phenotype information, candidate driver genes were identified in 16/39 (41%) patients. In 8 cases, evidence was found for the involvement of multiple candidate drivers contributing to different parts of the phenotypes. Subsequently, we applied this computational method to two cohorts containing a total of 379 patients with previously detected and classified de novo SVs and identified candidate driver genes in 189 cases (50%), including 40 cases whose SVs were previously not classified as pathogenic. Pathogenic position effects were predicted in 28% of all studied cases with balanced SVs and in 11% of the cases with copy number variants.<br><br>CONCLUSIONS: These results demonstrate an integrated computational and experimental approach to predict driver genes based on analyses of WGS data with phenotype association and chromatin organization datasets. These analyses nominate new pathogenic loci and have strong potential to improve the molecular diagnosis of patients with de novo SVs.},
}
@article {pmid31796947,
year = {2020},
author = {Moretti, C and Stévant, I and Ghavi-Helm, Y},
title = {3D genome organisation in Drosophila.},
journal = {Briefings in functional genomics},
volume = {19},
number = {2},
pages = {92-100},
doi = {10.1093/bfgp/elz029},
pmid = {31796947},
issn = {2041-2657},
mesh = {Animals ; Drosophila/*genetics ; Drosophila Proteins/*genetics ; Genome, Insect/*genetics ; },
abstract = {Ever since Thomas Hunt Morgan's discovery of the chromosomal basis of inheritance by using Drosophila melanogaster as a model organism, the fruit fly has remained an essential model system in studies of genome biology, including chromatin organisation. Very much as in vertebrates, in Drosophila, the genome is organised in territories, compartments and topologically associating domains (TADs). However, these domains might be formed through a slightly different mechanism than in vertebrates due to the presence of a large and potentially redundant set of insulator proteins and the minor role of dCTCF in TAD boundary formation. Here, we review the different levels of chromatin organisation in Drosophila and discuss mechanisms and factors that might be involved in TAD formation. The dynamics of TADs and enhancer-promoter interactions in the context of transcription are covered in the light of currently conflicting results. Finally, we illustrate the value of polymer modelling approaches to infer the principles governing the three-dimensional organisation of the Drosophila genome.},
}
@article {pmid31787081,
year = {2019},
author = {Liu, T and Wang, Z},
title = {Exploring the 2D and 3D structural properties of topologically associating domains.},
journal = {BMC bioinformatics},
volume = {20},
number = {Suppl 16},
pages = {592},
pmid = {31787081},
issn = {1471-2105},
support = {R15 GM120650/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Chromatin/chemistry ; Chromatin Assembly and Disassembly ; DNA/genetics ; Epigenesis, Genetic ; *Genome ; Models, Molecular ; RNA Transport ; RNA, Long Noncoding/genetics ; Reproducibility of Results ; },
abstract = {BACKGROUND: Topologically associating domains (TADs) are genomic regions with varying lengths. The interactions within TADs are more frequent than those between different TADs. TADs or sub-TADs are considered the structural and functional units of the mammalian genomes. Although TADs are important for understanding how genomes function, we have limited knowledge about their 3D structural properties.<br><br>RESULTS: In this study, we designed and benchmarked three metrics for capturing the three-dimensional and two-dimensional structural signatures of TADs,&#xa0;which can help better understand TADs' structural properties and the relationships between structural properties and genetic and epigenetic features. The first metric for capturing 3D structural properties is radius of gyration, which in this study&#xa0;is used to measure the spatial compactness of TADs. The mass value of each DNA bead in a 3D structure is novelly defined as one or more genetic or epigenetic feature(s). The second metric is folding degree. The last metric is exponent parameter, which is used to capture the 2D structural properties based on TADs' Hi-C contact&#xa0;matrices. In general, we observed significant correlations between the three metrics and the genetic and epigenetic features. We made the same observations when using H3K4me3, transcription start sites, and RNA polymerase II to represent the mass value in the modified radius-of-gyration metric. Moreover, we have found that the TADs in the clusters of depleted chromatin states apparently correspond to smaller exponent parameters and larger radius of gyrations. In addition, a new objective function of multidimensional scaling for modelling chromatin or TADs 3D structures was designed and benchmarked, which can handle the DNA&#xa0;bead-pairs with zero&#xa0;Hi-C contact&#xa0;values.<br><br>CONCLUSIONS: The web server for reconstructing chromatin 3D structures using multiple different objective functions and the related source code are publicly available at http://dna.cs.miami.edu/3DChrom/.},
}
@article {pmid31784360,
year = {2020},
author = {Clemens, AW and Wu, DY and Moore, JR and Christian, DL and Zhao, G and Gabel, HW},
title = {MeCP2 Represses Enhancers through Chromosome Topology-Associated DNA Methylation.},
journal = {Molecular cell},
volume = {77},
number = {2},
pages = {279-293.e8},
pmid = {31784360},
issn = {1097-4164},
support = {F31 NS108574/NS/NINDS NIH HHS/United States ; R01 MH117405/MH/NIMH NIH HHS/United States ; T32 GM007067/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Brain/physiology ; Chromosomes/*genetics ; DNA Methylation/*genetics ; Enhancer Elements, Genetic/*genetics ; Female ; Gene Expression Regulation/genetics ; Genome/genetics ; Humans ; Methyl-CpG-Binding Protein 2/*genetics ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Rats ; Repressor Proteins/*genetics ; },
abstract = {The genomes of mammalian neurons contain uniquely high levels of non-CG DNA methylation that can be bound by the Rett syndrome protein, MeCP2, to regulate gene expression. How patterns of non-CG methylation are established in neurons and the mechanism by which this methylation works with MeCP2 to control gene expression is unclear. Here, we find that genes repressed by MeCP2 are often located within megabase-scale regions of high non-CG methylation that correspond with topologically associating domains of chromatin folding. MeCP2 represses enhancers found in these domains that are enriched for non-CG and CG methylation, with the strongest repression occurring for enhancers located within MeCP2-repressed genes. These alterations in enhancer activity provide a mechanism for how MeCP2 disruption in disease can lead to widespread changes in gene expression. Hence, we find that DNA topology can shape non-CG DNA methylation across the genome to dictate MeCP2-mediated enhancer regulation in the brain.},
}
@article {pmid31783642,
year = {2019},
author = {Li, L and Barth, NKH and Pilarsky, C and Taher, L},
title = {Cancer Is Associated with Alterations in the Three-Dimensional Organization of the Genome.},
journal = {Cancers},
volume = {11},
number = {12},
pages = {},
pmid = {31783642},
issn = {2072-6694},
abstract = {The human genome is organized into topologically associating domains (TADs), which represent contiguous regions with a higher frequency of intra-interactions as opposed to inter-interactions. TADs contribute to gene expression regulation by restricting the interactions between their regulatory elements, and TAD disruption has been associated with cancer. Here, we provide a proof of principle that mutations within TADs can be used to predict the survival of cancer patients. Specifically, we constructed a set of 1467 consensus TADs representing the three-dimensional organization of the human genome and used Cox regression analysis to identify a total of 35 prognostic TADs in different cancer types. Interestingly, only 46% of the 35 prognostic TADs comprised genes with known clinical relevance. Moreover, in the vast majority of such cases, the prognostic value of the TAD was not directly related to the presence/absence of mutations in the gene(s), emphasizing the importance of regulatory mutations. In addition, we found that 34% of the prognostic TADs show strong structural perturbations in the cancer genome, consistent with the widespread, global epigenetic dysregulation often observed in cancer patients. In summary, this study elucidates the mechanisms through which non-coding variants may influence cancer progression and opens new avenues for personalized medicine.},
}
@article {pmid31776509,
year = {2019},
author = {Zhang, H and Emerson, DJ and Gilgenast, TG and Titus, KR and Lan, Y and Huang, P and Zhang, D and Wang, H and Keller, CA and Giardine, B and Hardison, RC and Phillips-Cremins, JE and Blobel, GA},
title = {Chromatin structure dynamics during the mitosis-to-G1 phase transition.},
journal = {Nature},
volume = {576},
number = {7785},
pages = {158-162},
pmid = {31776509},
issn = {1476-4687},
support = {R01 DK058044/DK/NIDDK NIH HHS/United States ; DP2 MH110247/MH/NIMH NIH HHS/United States ; R37 DK058044/DK/NIDDK NIH HHS/United States ; R24 DK106766/DK/NIDDK NIH HHS/United States ; U01 HL129998/HL/NHLBI NIH HHS/United States ; U01HL129998A/NH/NIH HHS/United States ; },
mesh = {Animals ; Cell Cycle Proteins/metabolism ; *Chromatin/metabolism ; Chromosomal Proteins, Non-Histone/metabolism ; *G1 Phase ; Mice ; *Mitosis ; },
abstract = {Features of higher-order chromatin organization-such as A/B compartments, topologically associating domains and chromatin loops-are temporarily disrupted during mitosis[1,2]. Because these structures are thought to influence gene regulation, it is important to understand how they are re-established after mitosis. Here we examine the dynamics of chromosome reorganization by Hi-C after mitosis in highly purified, synchronous mouse erythroid cell populations. We observed rapid establishment of A/B compartments, followed by their gradual intensification and expansion. Contact domains form from the 'bottom up'-smaller subTADs are formed initially, followed by convergence into multi-domain TAD structures. CTCF is partially retained on mitotic chromosomes and immediately resumes full binding in ana/telophase. By contrast, cohesin is completely evicted from mitotic chromosomes and regains focal binding at a slower rate. The formation of CTCF/cohesin co-anchored structural loops follows the kinetics of cohesin positioning. Stripe-shaped contact patterns-anchored by CTCF-grow in length, which is consistent with a loop-extrusion process after mitosis. Interactions between cis-regulatory elements can form rapidly, with rates exceeding those of CTCF/cohesin-anchored contacts. Notably, we identified a group of rapidly emerging transient contacts between cis-regulatory elements in ana/telophase that are dissolved upon G1 entry, co-incident with the establishment of inner boundaries or nearby interfering chromatin loops. We also describe the relationship between transcription reactivation and architectural features. Our findings indicate that distinct but mutually influential forces drive post-mitotic chromatin reconfiguration.},
}
@article {pmid31759823,
year = {2020},
author = {Galupa, R and Nora, EP and Worsley-Hunt, R and Picard, C and Gard, C and van Bemmel, JG and Servant, N and Zhan, Y and El Marjou, F and Johanneau, C and Diabangouaya, P and Le Saux, A and Lameiras, S and Pipoli da Fonseca, J and Loos, F and Gribnau, J and Baulande, S and Ohler, U and Giorgetti, L and Heard, E},
title = {A Conserved Noncoding Locus Regulates Random Monoallelic Xist Expression across a Topological Boundary.},
journal = {Molecular cell},
volume = {77},
number = {2},
pages = {352-367.e8},
pmid = {31759823},
issn = {1097-4164},
mesh = {Animals ; Cell Line ; Conserved Sequence/*genetics ; Enhancer Elements, Genetic/genetics ; Mice ; Promoter Regions, Genetic/genetics ; RNA, Antisense/genetics ; RNA, Long Noncoding/*genetics ; Silencer Elements, Transcriptional/genetics ; Transcription, Genetic/genetics ; X Chromosome/*genetics ; },
abstract = {cis-Regulatory communication is crucial in mammalian development and is thought to be restricted by the spatial partitioning of the genome in topologically associating domains (TADs). Here, we discovered that the Xist locus is regulated by sequences in the neighboring TAD. In particular, the promoter of the noncoding RNA Linx (LinxP) acts as a long-range silencer and influences the choice of X chromosome to be inactivated. This is independent of Linx transcription and independent of any effect on Tsix, the antisense regulator of Xist that shares the same TAD as Linx. Unlike Tsix, LinxP is well conserved across mammals, suggesting an ancestral mechanism for random monoallelic Xist regulation. When introduced in the same TAD as Xist, LinxP switches from a silencer to an enhancer. Our study uncovers an unsuspected regulatory axis for X chromosome inactivation and a class of cis-regulatory effects that may exploit TAD partitioning to modulate developmental decisions.},
}
@article {pmid31753851,
year = {2019},
author = {Davidson, IF and Bauer, B and Goetz, D and Tang, W and Wutz, G and Peters, JM},
title = {DNA loop extrusion by human cohesin.},
journal = {Science (New York, N.Y.)},
volume = {366},
number = {6471},
pages = {1338-1345},
doi = {10.1126/science.aaz3418},
pmid = {31753851},
issn = {1095-9203},
mesh = {Cell Cycle Proteins/*chemistry ; Chromosomal Proteins, Non-Histone/*chemistry ; DNA/*chemistry ; DNA-Binding Proteins/*chemistry ; HeLa Cells ; Holoenzymes/chemistry ; Humans ; *Nucleic Acid Conformation ; Proton-Translocating ATPases/*chemistry ; },
abstract = {Eukaryotic genomes are folded into loops and topologically associating domains, which contribute to chromatin structure, gene regulation, and gene recombination. These structures depend on cohesin, a ring-shaped DNA-entrapping adenosine triphosphatase (ATPase) complex that has been proposed to form loops by extrusion. Such an activity has been observed for condensin, which forms loops in mitosis, but not for cohesin. Using biochemical reconstitution, we found that single human cohesin complexes form DNA loops symmetrically at rates up to 2.1 kilo-base pairs per second. Loop formation and maintenance depend on cohesin's ATPase activity and on NIPBL-MAU2, but not on topological entrapment of DNA by cohesin. During loop formation, cohesin and NIPBL-MAU2 reside at the base of loops, which indicates that they generate loops by extrusion. Our results show that cohesin and NIPBL-MAU2 form an active holoenzyme that interacts with DNA either pseudo-topologically or non-topologically to extrude genomic interphase DNA into loops.},
}
@article {pmid31749839,
year = {2019},
author = {Di Filippo, L and Righelli, D and Gagliardi, M and Matarazzo, MR and Angelini, C},
title = {HiCeekR: A Novel Shiny App for Hi-C Data Analysis.},
journal = {Frontiers in genetics},
volume = {10},
number = {},
pages = {1079},
pmid = {31749839},
issn = {1664-8021},
abstract = {The High-throughput Chromosome Conformation Capture (Hi-C) technique combines the power of the Next Generation Sequencing technologies with chromosome conformation capture approach to study the 3D chromatin organization at the genome-wide scale. Although such a technique is quite recent, many tools are already available for pre-processing and analyzing Hi-C data, allowing to identify chromatin loops, topological associating domains and A/B compartments. However, only a few of them provide an exhaustive analysis pipeline or allow to easily integrate and visualize other omic layers. Moreover, most of the available tools are designed for expert users, who have great confidence with command-line applications. In this paper, we present HiCeekR (https://github.com/lucidif/HiCeekR), a novel R Graphical User Interface (GUI) that allows researchers to easily perform a complete Hi-C data analysis. With the aid of the Shiny libraries, it integrates several R/Bioconductor packages for Hi-C data analysis and visualization, guiding the user during the entire process. Here, we describe its architecture and functionalities, then illustrate its capabilities using a publicly available dataset.},
}
@article {pmid31735627,
year = {2019},
author = {Huang, Y and Mouttet, B and Warnatz, HJ and Risch, T and Rietmann, F and Frommelt, F and Ngo, QA and Dobay, MP and Marovca, B and Jenni, S and Tsai, YC and Matzk, S and Amstislavskiy, V and Schrappe, M and Stanulla, M and Gstaiger, M and Bornhauser, B and Yaspo, ML and Bourquin, JP},
title = {The Leukemogenic TCF3-HLF Complex Rewires Enhancers Driving Cellular Identity and Self-Renewal Conferring EP300 Vulnerability.},
journal = {Cancer cell},
volume = {36},
number = {6},
pages = {630-644.e9},
doi = {10.1016/j.ccell.2019.10.004},
pmid = {31735627},
issn = {1878-3686},
mesh = {Basic-Leucine Zipper Transcription Factors/genetics ; DNA-Binding Proteins/genetics ; E1A-Associated p300 Protein/*genetics ; Humans ; Oncogene Proteins, Fusion/*genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*genetics ; Translocation, Genetic ; },
abstract = {The chimeric transcription factor TCF3-HLF defines an incurable acute lymphoblastic leukemia subtype. Here we decipher the regulome of endogenous TCF3-HLF and dissect its essential transcriptional components and targets by functional genomics. We demonstrate that TCF3-HLF recruits HLF binding sites at hematopoietic stem cell/myeloid lineage associated (super-) enhancers to drive lineage identity and self-renewal. Among direct targets, hijacking an HLF binding site in a MYC enhancer cluster by TCF3-HLF activates a conserved MYC-driven transformation program crucial for leukemia propagation in vivo. TCF3-HLF pioneers the cooperation with ERG and recruits histone acetyltransferase p300 (EP300), conferring susceptibility to EP300 inhibition. Our study provides a framework for targeting driving transcriptional dependencies in this fatal leukemia.},
}
@article {pmid31701567,
year = {2019},
author = {Bernardi, G},
title = {The Genomic Code: A Pervasive Encoding/Molding of Chromatin Structures and a Solution of the "Non-Coding DNA" Mystery.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {41},
number = {12},
pages = {e1900106},
doi = {10.1002/bies.201900106},
pmid = {31701567},
issn = {1521-1878},
mesh = {Animals ; Cell Cycle Proteins/metabolism ; Chromatin/*metabolism ; Chromosomal Proteins, Non-Histone/metabolism ; DNA/genetics/*metabolism ; Genome, Human/genetics ; Genomics/methods ; Humans ; Isochores/metabolism ; },
abstract = {Recent investigations have revealed 1) that the isochores of the human genome group into two super-families characterized by two different long-range 3D structures, and 2) that these structures, essentially based on the distribution and topology of short sequences, mold primary chromatin domains (and define nucleosome binding). More specifically, GC-poor, gene-poor isochores are low-heterogeneity sequences with oligo-A spikes that mold the lamina-associated domains (LADs), whereas GC-rich, gene-rich isochores are characterized by single or multiple GC peaks that mold the topologically associating domains (TADs). The formation of these "primary TADs" may be followed by extrusion under the action of cohesin and CTCF. Finally, the genomic code, which is responsible for the pervasive encoding and molding of primary chromatin domains (LADs and primary TADs, namely the "gene spaces"/"spatial compartments") resolves the longstanding problems of "non-coding DNA," "junk DNA," and "selfish DNA" leading to a new vision of the genome as shaped by DNA sequences.},
}
@article {pmid31689436,
year = {2020},
author = {Jerković, I and Szabo, Q and Bantignies, F and Cavalli, G},
title = {Higher-Order Chromosomal Structures Mediate Genome Function.},
journal = {Journal of molecular biology},
volume = {432},
number = {3},
pages = {676-681},
doi = {10.1016/j.jmb.2019.10.014},
pmid = {31689436},
issn = {1089-8638},
mesh = {Animals ; Biomedical Research/methods/trends ; Chromatin/*chemistry/*metabolism ; *Gene Expression Regulation ; *Genome ; Macromolecular Substances/*chemistry/*metabolism ; Molecular Biology/methods/trends ; *Molecular Conformation ; },
abstract = {How chromosomes are organized within the tridimensional space of the nucleus and how can this organization affect genome function have been long-standing questions on the path to understanding genome activity and its link to disease. In the last decade, high-throughput chromosome conformation capture techniques, such as Hi-C, have facilitated the discovery of new principles of genome folding. Chromosomes are folded in multiple high-order structures, with local contacts between enhancers and promoters, intermediate-level contacts forming Topologically Associating Domains (TADs) and higher-order chromatin structures sequestering chromatin into active and repressive compartments. However, despite the increasing evidence that genome organization can influence its function, we are still far from understanding the underlying mechanisms. Deciphering these mechanisms represents a major challenge for the future, which large, international initiatives, such as 4DN, HCA and LifeTime, aim to collaboratively tackle by using a conjunction of state-of-the-art population-based and single-cell approaches.},
}
@article {pmid31689434,
year = {2020},
author = {Mozziconacci, J and Merle, M and Lesne, A},
title = {The 3D Genome Shapes the Regulatory Code of Developmental Genes.},
journal = {Journal of molecular biology},
volume = {432},
number = {3},
pages = {712-723},
doi = {10.1016/j.jmb.2019.10.017},
pmid = {31689434},
issn = {1089-8638},
mesh = {Animals ; Chromatin/*metabolism/*ultrastructure ; *Gene Expression Regulation, Developmental ; *Genes, Developmental ; Macromolecular Substances/*metabolism/*ultrastructure ; *Molecular Conformation ; },
abstract = {We revisit the notion of gene regulatory code in embryonic development in the light of recent findings about genome spatial organization. By analogy with the genetic code, we posit that the concept of code can only be used if the corresponding adaptor can clearly be identified. An adaptor is here defined as an intermediary physical entity mediating the correspondence between codewords and objects in a gratuitous and evolvable way. In the context of the gene regulatory code, the encoded objects are the gene expression levels, while the concentrations of specific transcription factors in the cell nucleus provide the codewords. The notion of code is meaningful in the absence of direct physicochemical relationships between the objects and the codewords, when the mediation by an adaptor is required. We propose that a plausible adaptor for this code is the gene domain, that is, the genome segment delimited by topological insulators and comprising the gene and its enhancer regulatory sequences. We review recent evidences, based on genome-wide chromosome conformation capture experiments, showing that preferential contact domains found in metazoan genomes are the physical traces of gene domains. Accordingly, genome 3D folding plays a direct role in shaping the developmental gene regulatory code.},
}
@article {pmid31685986,
year = {2019},
author = {Abramo, K and Valton, AL and Venev, SV and Ozadam, H and Fox, AN and Dekker, J},
title = {A chromosome folding intermediate at the condensin-to-cohesin transition during telophase.},
journal = {Nature cell biology},
volume = {21},
number = {11},
pages = {1393-1402},
pmid = {31685986},
issn = {1476-4679},
support = {R01 HG003143/HG/NHGRI NIH HHS/United States ; U54 DK107980/DK/NIDDK NIH HHS/United States ; },
mesh = {Adenosine Triphosphatases/*genetics/metabolism ; Cell Compartmentation/genetics ; Cell Cycle Proteins/*genetics/metabolism ; Cell Line, Transformed ; Chromatin/*metabolism/ultrastructure ; Chromosomal Proteins, Non-Histone/*genetics/metabolism ; Chromosome Mapping ; Cytokinesis/genetics ; DNA-Binding Proteins/*genetics/metabolism ; Gene Expression ; HeLa Cells ; Humans ; Interphase ; Multiprotein Complexes/*genetics/metabolism ; S Phase ; *Telophase ; },
abstract = {Chromosome folding is modulated as cells progress through the cell cycle. During mitosis, condensins fold chromosomes into helical loop arrays. In interphase, the cohesin complex generates loops and topologically associating domains (TADs), while a separate process of compartmentalization drives segregation of active and inactive chromatin. We used synchronized cell cultures to determine how the mitotic chromosome conformation transforms into the interphase state. Using high-throughput chromosome conformation capture (Hi-C) analysis, chromatin binding assays and immunofluorescence, we show that, by telophase, condensin-mediated loops are lost and a transient folding intermediate is formed that is devoid of most loops. By cytokinesis, cohesin-mediated CTCF-CTCF loops and the positions of TADs emerge. Compartment boundaries are also established early, but long-range compartmentalization is a slow process and proceeds for hours after cells enter G1. Our results reveal the kinetics and order of events by which the interphase chromosome state is formed and identify telophase as a critical transition between condensin- and cohesin-driven chromosome folding.},
}
@article {pmid31680170,
year = {2020},
author = {Grob, S},
title = {Three-dimensional chromosome organization in flowering plants.},
journal = {Briefings in functional genomics},
volume = {19},
number = {2},
pages = {83-91},
doi = {10.1093/bfgp/elz024},
pmid = {31680170},
issn = {2041-2657},
mesh = {Animals ; Chromosomes, Plant/*genetics ; Magnoliopsida/*genetics ; Oryza/*genetics ; },
abstract = {Research on plant three-dimensional (3D) genome architecture made rapid progress over the past 5 years. Numerous Hi-C interaction data sets were generated in a wide range of plant species, allowing for a comprehensive overview on 3D chromosome folding principles in the plant kingdom. Plants lack important genes reported to be vital for chromosome folding in animals. However, similar 3D structures such as topologically associating domains and chromatin loops were identified. Recent studies in Arabidopsis thaliana revealed how chromosomal regions are positioned within the nucleus by determining their association with both, the nuclear periphery and the nucleolus. Additionally, many plant species exhibit high-frequency interactions among KNOT entangled elements, which are associated with safeguarding the genome from invasive DNA elements. Many of the recently published Hi-C data sets were generated to aid de novo genome assembly and remain to date little explored. These data sets represent a valuable resource for future comparative studies, which may lead to a more profound understanding of the evolution of 3D chromosome organization in plants.},
}
@article {pmid31679987,
year = {2020},
author = {Kantidze, OL and Gurova, KV and Studitsky, VM and Razin, SV},
title = {The 3D Genome as a Target for Anticancer Therapy.},
journal = {Trends in molecular medicine},
volume = {26},
number = {2},
pages = {141-149},
pmid = {31679987},
issn = {1471-499X},
mesh = {Animals ; Antineoplastic Agents/*pharmacology/*therapeutic use ; Chromatin/genetics ; DNA/genetics ; Epigenomics/methods ; Genome/*genetics ; Humans ; Neoplasms/*drug therapy/*genetics ; Small Molecule Libraries/pharmacology/therapeutic use ; Transcription, Genetic/drug effects/genetics ; },
abstract = {The role of 3D genome organization in the precise regulation of gene expression is well established. Accordingly, the mechanistic connections between 3D genome alterations and disease development are becoming increasingly apparent. This opinion article provides a snapshot of our current understanding of the 3D genome alterations associated with cancers. We discuss potential connections of the 3D genome and cancer transcriptional addiction phenomenon as well as molecular mechanisms of action of 3D genome-disrupting drugs. Finally, we highlight issues and perspectives raised by the discovery of the first pharmaceutical strongly affecting 3D genome organization.},
}
@article {pmid31654669,
year = {2020},
author = {de Wit, E},
title = {TADs as the Caller Calls Them.},
journal = {Journal of molecular biology},
volume = {432},
number = {3},
pages = {638-642},
doi = {10.1016/j.jmb.2019.09.026},
pmid = {31654669},
issn = {1089-8638},
support = {637587/ERC_/European Research Council/International ; },
mesh = {Chromatin/*chemistry/*metabolism ; Gene Expression Regulation ; History, 21st Century ; Macromolecular Substances/*chemistry/*metabolism ; Molecular Biology/*history/trends ; *Molecular Conformation ; },
abstract = {Developments in proximity ligation methods and sequencing technologies have provided high-resolution views of the organization of the genome inside the nucleus. A prominent feature of Hi-C maps is regions of increased self-interaction called topologically associating domains (TADs). Despite the strong evolutionary conservation and clear link with gene expression, the exact role of TADs and even their definition remains debatable. Here, I review the discovery of TADs, how they are commonly identified, and the mechanisms that lead to their formation. Furthermore, I discuss recent results that have created a more nuanced view of the role of TADs in the regulation of genes. In light of this, I propose that when we define TADs, we also consider the mechanisms that shape them.},
}
@article {pmid31649247,
year = {2019},
author = {Lhoumaud, P and Badri, S and Rodriguez-Hernaez, J and Sakellaropoulos, T and Sethia, G and Kloetgen, A and Cornwell, M and Bhattacharyya, S and Ay, F and Bonneau, R and Tsirigos, A and Skok, JA},
title = {NSD2 overexpression drives clustered chromatin and transcriptional changes in a subset of insulated domains.},
journal = {Nature communications},
volume = {10},
number = {1},
pages = {4843},
pmid = {31649247},
issn = {2041-1723},
support = {R35 GM122515/GM/NIGMS NIH HHS/United States ; R35 GM128938/GM/NIGMS NIH HHS/United States ; },
mesh = {Binding Sites ; CCCTC-Binding Factor/metabolism ; Cell Cycle Proteins/metabolism ; Cell Line, Tumor ; Chromatin Assembly and Disassembly/*genetics ; Chromosomal Proteins, Non-Histone/metabolism ; Gene Expression/genetics ; Gene Expression Regulation, Neoplastic/*genetics ; Histone-Lysine N-Methyltransferase/*genetics ; Humans ; Logistic Models ; Multiple Myeloma/*genetics ; Repressor Proteins/*genetics ; },
abstract = {CTCF and cohesin play a key role in organizing chromatin into topologically associating domain (TAD) structures. Disruption of a single CTCF binding site is sufficient to change chromosomal interactions leading to alterations in chromatin modifications and gene regulation. However, the extent to which alterations in chromatin modifications can disrupt 3D chromosome organization leading to transcriptional changes is unknown. In multiple myeloma, a 4;14 translocation induces overexpression of the histone methyltransferase, NSD2, resulting in expansion of H3K36me2 and shrinkage of antagonistic H3K27me3 domains. Using isogenic cell lines producing high and low levels of NSD2, here we find oncogene activation is linked to alterations in H3K27ac and CTCF within H3K36me2 enriched chromatin. A logistic regression model reveals that differentially expressed genes are significantly enriched within the same insulated domain as altered H3K27ac and CTCF peaks. These results identify a bidirectional relationship between 2D chromatin and 3D genome organization in gene regulation.},
}
@article {pmid31645724,
year = {2019},
author = {Ochs, F and Karemore, G and Miron, E and Brown, J and Sedlackova, H and Rask, MB and Lampe, M and Buckle, V and Schermelleh, L and Lukas, J and Lukas, C},
title = {Stabilization of chromatin topology safeguards genome integrity.},
journal = {Nature},
volume = {574},
number = {7779},
pages = {571-574},
pmid = {31645724},
issn = {1476-4687},
support = {MC_UU_00016/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Cell Cycle Proteins/deficiency/metabolism ; Cell Line, Tumor ; Chromatin/chemistry/*genetics/*metabolism ; DNA Breaks, Double-Stranded ; DNA Repair ; DNA-Binding Proteins/deficiency/metabolism ; *Genomic Instability ; Humans ; *Nucleic Acid Conformation ; Telomere-Binding Proteins/deficiency/metabolism ; Tumor Suppressor p53-Binding Protein 1/deficiency/metabolism ; },
abstract = {To safeguard genome integrity in response to DNA double-strand breaks (DSBs), mammalian cells mobilize the neighbouring chromatin to shield DNA ends against excessive resection that could undermine repair fidelity and cause damage to healthy chromosomes[1]. This form of genome surveillance is orchestrated by 53BP1, whose accumulation at DSBs triggers sequential recruitment of RIF1 and the shieldin-CST-POLα complex[2]. How this pathway reflects and influences the three-dimensional nuclear architecture is not known. Here we use super-resolution microscopy to show that 53BP1 and RIF1 form an autonomous functional module that stabilizes three-dimensional chromatin topology at sites of DNA breakage. This process is initiated by accumulation of 53BP1 at regions of compact chromatin that colocalize with topologically associating domain (TAD) sequences, followed by recruitment of RIF1 to the boundaries between such domains. The alternating distribution of 53BP1 and RIF1 stabilizes several neighbouring TAD-sized structures at a single DBS site into an ordered, circular arrangement. Depletion of 53BP1 or RIF1 (but not shieldin) disrupts this arrangement and leads to decompaction of DSB-flanking chromatin, reduction in interchromatin space, aberrant spreading of DNA repair proteins, and hyper-resection of DNA ends. Similar topological distortions are triggered by depletion of cohesin, which suggests that the maintenance of chromatin structure after DNA breakage involves basic mechanisms that shape three-dimensional nuclear organization. As topological stabilization of DSB-flanking chromatin is independent of DNA repair, we propose that, besides providing a structural scaffold to protect DNA ends against aberrant processing, 53BP1 and RIF1 safeguard epigenetic integrity at loci that are disrupted by DNA breakage.},
}
@article {pmid31642979,
year = {2020},
author = {Zou, D and Zhang, H and Ke, J and Li, J and Zhu, Y and Gong, Y and Yang, Y and Tian, J and Zhang, Y and Peng, X and Cai, K and Zhong, R and Chang, J and Miao, X},
title = {Three functional variants were identified to affect RPS24 expression and significantly associated with risk of colorectal cancer.},
journal = {Archives of toxicology},
volume = {94},
number = {1},
pages = {295-303},
doi = {10.1007/s00204-019-02600-9},
pmid = {31642979},
issn = {1432-0738},
support = {81502875//National Natural Science Foundation of China/International ; 81222038//National Natural Science Foundation of China/International ; 2016YFC1302702//the National Key Research and Development Plan Program/International ; 2016YFC1302703//the National Key Research and Development Plan Program/International ; 81171878//National Program for Support of Top-notch Young Professionals/International ; 131038//the Fok Ying Tung Foundation for Young Teachers in the Higher Education Institutions of China/International ; },
mesh = {Asian People/genetics ; Case-Control Studies ; Colorectal Neoplasms/*genetics ; Enhancer Elements, Genetic ; Gene Expression Regulation, Neoplastic ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; *Polymorphism, Single Nucleotide ; Promoter Regions, Genetic ; Ribosomal Proteins/*genetics ; },
abstract = {GWAS-identified 10q22.3 loci with lead SNP rs704017 are significantly associated with CRC risk in both Asian and European populations. However, the functional mechanism of this region is unclear. In this study, we performed a fine-mapping analysis to identify the causal SNPs. To identify potential functional SNPs in linkage disequilibrium with the lead SNP, we searched for the potential target genes using a Hi-C database and an RNA interfering-based on-chip approach. The results indicated that rs12263636 (r[2] = 0.41) showed the highest potential to be functional. It resided in a region with enhancer markers and a topologically associating domain. We found that RPS24 was the only gene that significantly promoted the proliferation rate of CRC cells and might have promoter-enhancer interaction with rs12263636. Dual-luciferase reporter assays confirmed that the risk alleles of two variants (rs3740253 and rs7071351) in RPS24 promoter could increase the expression of luciferase. Case control study consisting of 1134 cases and 2039 health controls confirmed that both the two variants were associated with risk of CRC (rs3740253: P = 0.0079, OR = 1.15, 95% CI 1.04-1.28; rs7071351: P = 0.0085, OR = 1.15, 95% CI 1.04-1.28). And plasmid containing mutant haplotypes containing all the three mutations (rs12263636 or rs3740253 and rs7071351) could most significantly increase luciferase expression, compared with any haplotype of the three mutations. The study explained the functional mechanism for the 10q22.3 loci and provided new insights into the prevention and treatment of CRC.},
}
@article {pmid31626801,
year = {2020},
author = {Ghavi-Helm, Y},
title = {Functional Consequences of Chromosomal Rearrangements on Gene Expression: Not So Deleterious After All?.},
journal = {Journal of molecular biology},
volume = {432},
number = {3},
pages = {665-675},
doi = {10.1016/j.jmb.2019.09.010},
pmid = {31626801},
issn = {1089-8638},
mesh = {Animals ; Chromatin/*metabolism ; DNA-Binding Proteins/metabolism ; Enhancer Elements, Genetic ; *Gene Expression ; *Gene Expression Regulation ; *Gene Rearrangement ; Genetic Association Studies ; Promoter Regions, Genetic ; Transcription, Genetic ; },
abstract = {Chromosomes are folded and organized into topologically associating domains (TADs) which provide a framework for the interaction of enhancers with the promoter of their target gene(s). Structural rearrangements observed during evolution or in disease contexts suggest that changes in genome organization strongly affect gene expression and can have drastic phenotypic effects. In this review, I will discuss how recent genomic engineering experiments reveal a more contrasted picture, suggesting that TADs are important but not always essential for gene expression regulation.},
}
@article {pmid31607649,
year = {2019},
author = {Viets, K and Sauria, MEG and Chernoff, C and Rodriguez Viales, R and Echterling, M and Anderson, C and Tran, S and Dove, A and Goyal, R and Voortman, L and Gordus, A and Furlong, EEM and Taylor, J and Johnston, RJ},
title = {Characterization of Button Loci that Promote Homologous Chromosome Pairing and Cell-Type-Specific Interchromosomal Gene Regulation.},
journal = {Developmental cell},
volume = {51},
number = {3},
pages = {341-356.e7},
pmid = {31607649},
issn = {1878-1551},
support = {F31 EY026786/EY/NEI NIH HHS/United States ; R01 EY025598/EY/NEI NIH HHS/United States ; },
mesh = {Animals ; Chromatin/metabolism ; Chromosome Pairing/*genetics ; Chromosomes/*genetics ; Drosophila melanogaster/*genetics ; *Gene Expression Regulation ; *Genetic Loci ; Insulator Elements/genetics ; Transgenes ; },
abstract = {Homologous chromosomes colocalize to regulate gene expression in processes including genomic imprinting, X-inactivation, and transvection. In Drosophila, homologous chromosomes pair throughout development, promoting transvection. The "button" model of pairing proposes that specific regions along chromosomes pair with high affinity. Here, we identify buttons interspersed across the fly genome that pair with their homologous sequences, even when relocated to multiple positions in the genome. A majority of transgenes that span a full topologically associating domain (TAD) function as buttons, but not all buttons contain TADs. Additionally, buttons are enriched for insulator protein clusters. Fragments of buttons do not pair, suggesting that combinations of elements within a button are required for pairing. Pairing is necessary but not sufficient for transvection. Additionally, pairing and transvection are stronger in some cell types than in others, suggesting that pairing strength regulates transvection efficiency between cell types. Thus, buttons pair homologous chromosomes to facilitate cell-type-specific interchromosomal gene regulation.},
}
@article {pmid31605131,
year = {2020},
author = {Mourad, R},
title = {Studying 3D genome evolution using genomic sequence.},
journal = {Bioinformatics (Oxford, England)},
volume = {36},
number = {5},
pages = {1367-1373},
doi = {10.1093/bioinformatics/btz775},
pmid = {31605131},
issn = {1367-4811},
mesh = {Animals ; *Chromatin ; Evolution, Molecular ; Genome, Human ; *Genomics ; High-Throughput Nucleotide Sequencing ; Humans ; },
abstract = {MOTIVATION: The three dimensions (3D) genome is essential to numerous key processes such as the regulation of gene expression and the replication-timing program. In vertebrates, chromatin looping is often mediated by CTCF, and marked by CTCF motif pairs in convergent orientation. Comparative high-throughput sequencing technique (Hi-C) recently revealed that chromatin looping evolves across species. However, Hi-C experiments are complex and costly, which currently limits their use for evolutionary studies over a large number of species.<br><br>RESULTS: Here, we propose a novel approach to study the 3D genome evolution in vertebrates using the genomic sequence only, e.g. without the need for Hi-C data. The approach is simple and relies on comparing the distances between convergent and divergent CTCF motifs by computing a ratio we named the 3D ratio or '3DR'. We show that 3DR is a powerful statistic to detect CTCF looping encoded in the human genome sequence, thus reflecting strong evolutionary constraints encoded in DNA and associated with the 3D genome. When comparing vertebrate genomes, our results reveal that 3DR which underlies CTCF looping and topologically associating domain organization evolves over time and suggest that ancestral character reconstruction can be used to infer 3DR in ancestral genomes.<br><br>The R code is available at https://github.com/morphos30/PhyloCTCFLooping.<br><br>SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},
}
@article {pmid31601616,
year = {2019},
author = {Renschler, G and Richard, G and Valsecchi, CIK and Toscano, S and Arrigoni, L and Ramírez, F and Akhtar, A},
title = {Hi-C guided assemblies reveal conserved regulatory topologies on X and autosomes despite extensive genome shuffling.},
journal = {Genes &amp; development},
volume = {33},
number = {21-22},
pages = {1591-1612},
pmid = {31601616},
issn = {1549-5477},
mesh = {Algorithms ; Animals ; Chromosomes, Insect/genetics ; Conserved Sequence ; Dosage Compensation, Genetic ; Drosophila/embryology/*genetics ; Embryo, Nonmammalian ; *Evolution, Molecular ; Gene Expression Regulation/*genetics ; Genome, Insect/*genetics ; },
abstract = {Genome rearrangements that occur during evolution impose major challenges on regulatory mechanisms that rely on three-dimensional genome architecture. Here, we developed a scaffolding algorithm and generated chromosome-length assemblies from Hi-C data for studying genome topology in three distantly related Drosophila species. We observe extensive genome shuffling between these species with one synteny breakpoint after approximately every six genes. A/B compartments, a set of large gene-dense topologically associating domains (TADs), and spatial contacts between high-affinity sites (HAS) located on the X chromosome are maintained over 40 million years, indicating architectural conservation at various hierarchies. Evolutionary conserved genes cluster in the vicinity of HAS, while HAS locations appear evolutionarily flexible, thus uncoupling functional requirement of dosage compensation from individual positions on the linear X chromosome. Therefore, 3D architecture is preserved even in scenarios of thousands of rearrangements highlighting its relevance for essential processes such as dosage compensation of the X chromosome.},
}
@article {pmid31591517,
year = {2020},
author = {Le Caignec, C and Pichon, O and Briand, A and de Courtivron, B and Bonnard, C and Lindenbaum, P and Redon, R and Schluth-Bolard, C and Diguet, F and Rollat-Farnier, PA and Sanchez-Castro, M and Vuillaume, ML and Sanlaville, D and Duboule, D and Mégarbané, A and Toutain, A},
title = {Fryns type mesomelic dysplasia of the upper limbs caused by inverted duplications of the HOXD gene cluster.},
journal = {European journal of human genetics : EJHG},
volume = {28},
number = {3},
pages = {324-332},
pmid = {31591517},
issn = {1476-5438},
mesh = {Bone Diseases, Developmental/*genetics/pathology ; Cells, Cultured ; Female ; *Gene Duplication ; Homeodomain Proteins/*genetics ; Humans ; Infant ; Loss of Function Mutation ; Male ; Multigene Family ; Phenotype ; Upper Extremity Deformities, Congenital/*genetics/pathology ; },
abstract = {The HoxD cluster is critical for vertebrate limb development. Enhancers located in both the telomeric and centromeric gene deserts flanking the cluster regulate the transcription of HoxD genes. In rare patients, duplications, balanced translocations or inversions misregulating HOXD genes are responsible for mesomelic dysplasia of the upper and lower limbs. By aCGH, whole-genome mate-pair sequencing, long-range PCR and fiber fluorescent in situ hybridization, we studied patients from two families displaying mesomelic dysplasia limited to the upper limbs. We identified microduplications including the HOXD cluster and showed that microduplications were in an inverted orientation and inserted between the HOXD cluster and the telomeric enhancers. Our results highlight the existence of an autosomal dominant condition consisting of isolated ulnar dysplasia caused by microduplications inserted between the HOXD cluster and the telomeric enhancers. The duplications likely disconnect the HOXD9 to HOXD11 genes from their regulatory sequences. This presumptive loss-of-function may have contributed to the phenotype. In both cases, however, these rearrangements brought HOXD13 closer to telomeric enhancers, suggesting that the alterations derive from the dominant-negative effect of this digit-specific protein when ectopically expressed during the early development of forearms, through the disruption of topologically associating domain structure at the HOXD locus.},
}
@article {pmid31542774,
year = {2020},
author = {Ooi, WF and Nargund, AM and Lim, KJ and Zhang, S and Xing, M and Mandoli, A and Lim, JQ and Ho, SWT and Guo, Y and Yao, X and Lin, SJ and Nandi, T and Xu, C and Ong, X and Lee, M and Tan, AL and Lam, YN and Teo, JX and Kaneda, A and White, KP and Lim, WK and Rozen, SG and Teh, BT and Li, S and Skanderup, AJ and Tan, P},
title = {Integrated paired-end enhancer profiling and whole-genome sequencing reveals recurrent CCNE1 and IGF2 enhancer hijacking in primary gastric adenocarcinoma.},
journal = {Gut},
volume = {69},
number = {6},
pages = {1039-1052},
doi = {10.1136/gutjnl-2018-317612},
pmid = {31542774},
issn = {1468-3288},
mesh = {Adenocarcinoma/genetics/*metabolism ; Cyclin E/*metabolism ; Enhancer Elements, Genetic/*genetics ; Genomic Structural Variation/genetics ; Humans ; Insulin-Like Growth Factor II/*metabolism ; Oncogene Proteins/*metabolism ; Stomach Neoplasms/genetics/*metabolism ; Whole Genome Sequencing ; },
abstract = {OBJECTIVE: Genomic structural variations (SVs) causing rewiring of cis-regulatory elements remain largely unexplored in gastric cancer (GC). To identify SVs affecting enhancer elements in GC (enhancer-based SVs), we integrated epigenomic enhancer profiles revealed by paired-end H3K27ac ChIP-sequencing from primary GCs with tumour whole-genome sequencing (WGS) data (PeNChIP-seq/WGS).<br><br>DESIGN: We applied PeNChIP-seq to 11 primary GCs and matched normal tissues combined with WGS profiles of >200 GCs. Epigenome profiles were analysed alongside matched RNA-seq data to identify tumour-associated enhancer-based SVs with altered cancer transcription. Functional validation of candidate enhancer-based SVs was performed using CRISPR/Cas9 genome editing, chromosome conformation capture assays (4C-seq, Capture-C) and Hi-C analysis of primary GCs.<br><br>RESULTS: PeNChIP-seq/WGS revealed ~150 enhancer-based SVs in GC. The majority (63%) of SVs linked to target gene deregulation were associated with increased tumour expression. Enhancer-based SVs targeting CCNE1, a key driver of therapy resistance, occurred in 8% of patients frequently juxtaposing diverse distal enhancers to CCNE1 proximal regions. CCNE1-rearranged GCs were associated with high CCNE1 expression, disrupted CCNE1 topologically associating domain (TAD) boundaries, and novel TAD interactions in CCNE1-rearranged primary tumours. We also observed IGF2 enhancer-based SVs, previously noted in colorectal cancer, highlighting a common non-coding genetic driver alteration in gastric and colorectal malignancies.<br><br>CONCLUSION: Integrated paired-end NanoChIP-seq and WGS of gastric tumours reveals tumour-associated regulatory SV in regions associated with both simple and complex genomic rearrangements. Genomic rearrangements may thus exploit enhancer-hijacking as a common mechanism to drive oncogene expression in GC.},
}
@article {pmid31522987,
year = {2019},
author = {Hansen, AS and Hsieh, TS and Cattoglio, C and Pustova, I and Saldaña-Meyer, R and Reinberg, D and Darzacq, X and Tjian, R},
title = {Distinct Classes of Chromatin Loops Revealed by Deletion of an RNA-Binding Region in CTCF.},
journal = {Molecular cell},
volume = {76},
number = {3},
pages = {395-411.e13},
pmid = {31522987},
issn = {1097-4164},
support = {R01 CA199652/CA/NCI NIH HHS/United States ; U01 EB021236/EB/NIBIB NIH HHS/United States ; R01 NS100897/NS/NINDS NIH HHS/United States ; U54 DK107980/DK/NIDDK NIH HHS/United States ; U01 DA047729/DA/NIDA NIH HHS/United States ; S10 OD018174/OD/NIH HHS/United States ; K99 GM130896/GM/NIGMS NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; },
mesh = {Animals ; CCCTC-Binding Factor/chemistry/genetics/*metabolism ; Cell Line ; Chromatin/chemistry/genetics/*metabolism ; Gene Expression Regulation, Developmental ; Male ; Mice ; Mice, Transgenic ; Mouse Embryonic Stem Cells/*metabolism ; Mutation ; Nucleic Acid Conformation ; Protein Binding ; Protein Interaction Domains and Motifs ; Structure-Activity Relationship ; },
abstract = {Mammalian genomes are folded into topologically associating domains (TADs), consisting of chromatin loops anchored by CTCF and cohesin. Some loops are cell-type specific. Here we asked whether CTCF loops are established by a universal or locus-specific mechanism. Investigating the molecular determinants of CTCF clustering, we found that CTCF self-association in vitro is RNase sensitive and that an internal RNA-binding region (RBRi) mediates CTCF clustering and RNA interaction in vivo. Strikingly, deleting the RBRi impairs about half of all chromatin loops in mESCs and causes deregulation of gene expression. Disrupted loop formation correlates with diminished clustering and chromatin binding of RBRi mutant CTCF, which in turn results in a failure to halt cohesin-mediated extrusion. Thus, CTCF loops fall into at least two classes: RBRi-independent and RBRi-dependent loops. We speculate that evidence for RBRi-dependent loops may provide a molecular mechanism for establishing cell-specific CTCF loops, potentially regulated by RNA(s) or other RBRi-interacting partners.},
}
@article {pmid31515496,
year = {2019},
author = {Rhie, SK and Perez, AA and Lay, FD and Schreiner, S and Shi, J and Polin, J and Farnham, PJ},
title = {A high-resolution 3D epigenomic map reveals insights into the creation of the prostate cancer transcriptome.},
journal = {Nature communications},
volume = {10},
number = {1},
pages = {4154},
pmid = {31515496},
issn = {2041-1723},
support = {R01 CA136924/CA/NCI NIH HHS/United States ; P30 CA014089/CA/NCI NIH HHS/United States ; K01 CA229995/CA/NCI NIH HHS/United States ; },
mesh = {Cell Line, Tumor ; Chromatin/metabolism ; Enhancer Elements, Genetic ; Epigenesis, Genetic ; *Epigenomics ; Genetic Loci ; Histone Code/genetics ; Humans ; Male ; Promoter Regions, Genetic ; Prostatic Neoplasms/*genetics ; Receptors, Androgen/genetics ; Transcriptome/*genetics ; },
abstract = {To better understand the impact of chromatin structure on regulation of the prostate cancer transcriptome, we develop high-resolution chromatin interaction maps in normal and prostate cancer cells using in situ Hi-C. By combining the in situ Hi-C data with active and repressive histone marks, CTCF binding sites, nucleosome-depleted regions, and transcriptome profiling, we identify topologically associating domains (TADs) that change in size and epigenetic states between normal and prostate cancer cells. Moreover, we identify normal and prostate cancer-specific enhancer-promoter loops and involved transcription factors. For example, we show that FOXA1 is enriched in prostate cancer-specific enhancer-promoter loop anchors. We also find that the chromatin structure surrounding the androgen receptor (AR) locus is altered in the prostate cancer cells with many cancer-specific enhancer-promoter loops. This creation of 3D epigenomic maps enables a better understanding of prostate cancer biology and mechanisms of gene regulation.},
}
@article {pmid31511252,
year = {2019},
author = {Williamson, I and Kane, L and Devenney, PS and Flyamer, IM and Anderson, E and Kilanowski, F and Hill, RE and Bickmore, WA and Lettice, LA},
title = {Developmentally regulated Shh expression is robust to TAD perturbations.},
journal = {Development (Cambridge, England)},
volume = {146},
number = {19},
pages = {},
pmid = {31511252},
issn = {1477-9129},
support = {MC_UU_00007/2/MRC_/Medical Research Council/United Kingdom ; MC_UU_00007/8/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Animals ; Base Pairing/genetics ; CCCTC-Binding Factor ; Chromatin/metabolism ; Embryo, Mammalian/metabolism ; Enhancer Elements, Genetic/*genetics ; Extremities/embryology ; *Gene Expression Regulation, Developmental ; Genome ; Hedgehog Proteins/*genetics/metabolism ; Mice ; Organ Specificity/genetics ; Phenotype ; Sequence Deletion/genetics ; },
abstract = {Topologically associating domains (TADs) have been proposed to both guide and constrain enhancer activity. Shh is located within a TAD known to contain all its enhancers. To investigate the importance of chromatin conformation and TAD integrity on developmental gene regulation, we have manipulated the Shh TAD - creating internal deletions, deleting CTCF sites, and deleting and inverting sequences at TAD boundaries. Chromosome conformation capture and fluorescence in situ hybridisation assays were used to investigate the changes in chromatin conformation that result from these manipulations. Our data suggest that these substantial alterations in TAD structure have no readily detectable effect on Shh expression patterns or levels of Shh expression during development - except where enhancers are deleted - and result in no detectable phenotypes. Only in the case of a larger deletion at one TAD boundary could ectopic influence of the Shh limb enhancer be detected on a gene (Mnx1) in the neighbouring TAD. Our data suggests that, contrary to expectations, the developmental regulation of Shh expression is remarkably robust to TAD perturbations.},
}
@article {pmid31510693,
year = {2019},
author = {Liu, Q and Lv, H and Jiang, R},
title = {hicGAN infers super resolution Hi-C data with generative adversarial networks.},
journal = {Bioinformatics (Oxford, England)},
volume = {35},
number = {14},
pages = {i99-i107},
pmid = {31510693},
issn = {1367-4811},
mesh = {*Chromatin ; *Genome ; Genomics ; Molecular Conformation ; *Software ; },
abstract = {MOTIVATION: Hi-C is a genome-wide technology for investigating 3D chromatin conformation by measuring physical contacts between pairs of genomic regions. The resolution of Hi-C data directly impacts the effectiveness and accuracy of downstream analysis such as identifying topologically associating domains (TADs) and meaningful chromatin loops. High resolution Hi-C data are valuable resources which implicate the relationship between 3D genome conformation and function, especially linking distal regulatory elements to their target genes. However, high resolution Hi-C data across various tissues and cell types are not always available due to the high sequencing cost. It is therefore indispensable to develop computational approaches for enhancing the resolution of Hi-C data.<br><br>RESULTS: We proposed hicGAN, an open-sourced framework, for inferring high resolution Hi-C data from low resolution Hi-C data with generative adversarial networks (GANs). To the best of our knowledge, this is the first study to apply GANs to 3D genome analysis. We demonstrate that hicGAN effectively enhances the resolution of low resolution Hi-C data by generating matrices that are highly consistent with the original high resolution Hi-C matrices. A typical scenario of usage for our approach is to enhance low resolution Hi-C data in new cell types, especially where the high resolution Hi-C data are not available. Our study not only presents a novel approach for enhancing Hi-C data resolution, but also provides fascinating insights into disclosing complex mechanism underlying the formation of chromatin contacts.<br><br>We release hicGAN as an open-sourced software at https://github.com/kimmo1019/hicGAN.<br><br>SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},
}
@article {pmid31506350,
year = {2019},
author = {Ray, J and Munn, PR and Vihervaara, A and Lewis, JJ and Ozer, A and Danko, CG and Lis, JT},
title = {Chromatin conformation remains stable upon extensive transcriptional changes driven by heat shock.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {116},
number = {39},
pages = {19431-19439},
pmid = {31506350},
issn = {1091-6490},
support = {R01 HG009309/HG/NHGRI NIH HHS/United States ; U01 HL129958/HL/NHLBI NIH HHS/United States ; },
mesh = {Animals ; Binding Sites ; Biological Evolution ; Cell Line ; Chromatin/*chemistry/metabolism ; Chromosomes/metabolism ; Drosophila/genetics ; Enhancer Elements, Genetic ; Gene Expression Regulation/*genetics ; Gene Knockdown Techniques ; Heat Shock Transcription Factors/genetics/metabolism ; Heat-Shock Proteins/genetics ; Heat-Shock Response/*genetics ; Humans ; K562 Cells ; Molecular Conformation ; Promoter Regions, Genetic ; },
abstract = {Heat shock (HS) initiates rapid, extensive, and evolutionarily conserved changes in transcription that are accompanied by chromatin decondensation and nucleosome loss at HS loci. Here we have employed in situ Hi-C to determine how heat stress affects long-range chromatin conformation in human and Drosophila cells. We found that compartments and topologically associating domains (TADs) remain unchanged by an acute HS. Knockdown of Heat Shock Factor 1 (HSF1), the master transcriptional regulator of the HS response, identified HSF1-dependent genes and revealed that up-regulation is often mediated by distal HSF1 bound enhancers. HSF1-dependent genes were usually found in the same TAD as the nearest HSF1 binding site. Although most interactions between HSF1 binding sites and target promoters were established in the nonheat shock (NHS) condition, a subset increased contact frequency following HS. Integrating information about HSF1 binding strength, RNA polymerase abundance at the HSF1 bound sites (putative enhancers), and contact frequency with a target promoter accurately predicted which up-regulated genes were direct targets of HSF1 during HS. Our results suggest that the chromatin conformation necessary for a robust HS response is preestablished in NHS cells of diverse metazoan species.},
}
@article {pmid31500627,
year = {2019},
author = {Kikuchi, M and Hara, N and Hasegawa, M and Miyashita, A and Kuwano, R and Ikeuchi, T and Nakaya, A},
title = {Enhancer variants associated with Alzheimer's disease affect gene expression via chromatin looping.},
journal = {BMC medical genomics},
volume = {12},
number = {1},
pages = {128},
pmid = {31500627},
issn = {1755-8794},
support = {16K07222//Japan Science and Technology Agency/International ; 16K07222//Japan Science and Technology Agency/International ; 17K15049//Japan Science and Technology Agency/International ; 22129004//Japan Science and Technology Agency/International ; 24310144//Japan Science and Technology Agency/International ; 24651221//Japan Science and Technology Agency/International ; An Integrated Database of Clinical and Genomic Information//Japan Agency for Medical Research and Development/International ; An Integrated Database of Clinical and Genomic Information//Japan Agency for Medical Research and Development/International ; A Research and Development Grants for Dementia//Japan Agency for Medical Research and Development/International ; A Research and Development Grants for Dementia//Japan Agency for Medical Research and Development/International ; },
mesh = {Alzheimer Disease/*genetics ; Binding Sites ; CCCTC-Binding Factor/metabolism ; Chromatin/chemistry/*metabolism ; Enhancer Elements, Genetic ; *Gene Expression Regulation ; *Genetic Variation ; Humans ; *Nucleic Acid Conformation ; Polymorphism, Single Nucleotide/genetics ; Quantitative Trait Loci/genetics ; },
abstract = {BACKGROUND: Genome-wide association studies (GWASs) have identified single-nucleotide polymorphisms (SNPs) that may be genetic factors underlying Alzheimer's disease (AD). However, how these AD-associated SNPs (AD SNPs) contribute to the pathogenesis of this disease is poorly understood because most of them are located in non-coding regions, such as introns and intergenic regions. Previous studies reported that some disease-associated SNPs affect regulatory elements including enhancers. We hypothesized that non-coding AD SNPs are located in enhancers and affect gene expression levels via chromatin loops.<br><br>METHODS: To characterize AD SNPs within non-coding regions, we extracted 406&#x2009;AD SNPs with GWAS p-values of less than 1.00&#x2009;&#xd7;&#x2009;10[-&#x2009;6] from the GWAS catalog database. Of these, we selected 392 SNPs within non-coding regions. Next, we checked whether those non-coding AD SNPs were located in enhancers that typically regulate gene expression levels using publicly available data for enhancers that were predicted in 127 human tissues or cell types. We sought expression quantitative trait locus (eQTL) genes affected by non-coding AD SNPs within enhancers because enhancers are regulatory elements that influence the gene expression levels. To elucidate how the non-coding AD SNPs within enhancers affect the gene expression levels, we identified chromatin-chromatin interactions by Hi-C experiments.<br><br>RESULTS: We report the following findings: (1) nearly 30% of non-coding AD SNPs are located in enhancers; (2) eQTL genes affected by non-coding AD SNPs within enhancers are associated with amyloid beta clearance, synaptic transmission, and immune responses; (3) 95% of the AD SNPs located in enhancers co-localize with their eQTL genes in topologically associating domains suggesting that regulation may occur through chromatin higher-order structures; (4) rs1476679 spatially contacts the promoters of eQTL genes via CTCF-CTCF interactions; (5) the effect of other AD SNPs such as rs7364180 is likely to be, at least in part, indirect through regulation of transcription factors that in turn regulate AD associated genes.<br><br>CONCLUSION: Our results suggest that non-coding AD SNPs may affect the function of enhancers thereby influencing the expression levels of surrounding or distant genes via chromatin loops. This result may explain how some non-coding AD SNPs contribute to AD pathogenesis.},
}
@article {pmid31495695,
year = {2019},
author = {Anderson, EC and Frankino, PA and Higuchi-Sanabria, R and Yang, Q and Bian, Q and Podshivalova, K and Shin, A and Kenyon, C and Dillin, A and Meyer, BJ},
title = {X Chromosome Domain Architecture Regulates Caenorhabditis elegans Lifespan but Not Dosage Compensation.},
journal = {Developmental cell},
volume = {51},
number = {2},
pages = {192-207.e6},
pmid = {31495695},
issn = {1878-1551},
support = {R01 GM030702/GM/NIGMS NIH HHS/United States ; T32 GM007232/GM/NIGMS NIH HHS/United States ; F32 AG053023/AG/NIA NIH HHS/United States ; R35 GM131845/GM/NIGMS NIH HHS/United States ; S10 OD018174/OD/NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; },
mesh = {Adenosine Triphosphatases/genetics/metabolism ; Animals ; Caenorhabditis elegans/metabolism ; Caenorhabditis elegans Proteins/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Dosage Compensation, Genetic/*genetics ; Gene Expression Regulation/*genetics ; Longevity/*physiology ; Multiprotein Complexes/genetics/metabolism ; X Chromosome/*genetics ; },
abstract = {Mechanisms establishing higher-order chromosome structures and their roles in gene regulation are elusive. We analyzed chromosome architecture during nematode X chromosome dosage compensation, which represses transcription via a dosage-compensation condensin complex (DCC) that binds hermaphrodite Xs and establishes megabase-sized topologically associating domains (TADs). We show that DCC binding at high-occupancy sites (rex sites) defines eight TAD boundaries. Single rex deletions disrupted boundaries, and single insertions created new boundaries, demonstrating that a rex site is necessary and sufficient to define DCC-dependent boundary locations. Deleting eight rex sites (8rexΔ) recapitulated TAD structure of DCC mutants, permitting analysis when chromosome-wide domain architecture was disrupted but most DCC binding remained. 8rexΔ animals exhibited no changes in X expression and lacked dosage-compensation mutant phenotypes. Hence, TAD boundaries are neither the cause nor the consequence of DCC-mediated gene repression. Abrogating TAD structure did, however, reduce thermotolerance, accelerate aging, and shorten lifespan, implicating chromosome architecture in stress responses and aging.},
}
@article {pmid31491387,
year = {2019},
author = {Kaaij, LJT and Mohn, F and van der Weide, RH and de Wit, E and Bühler, M},
title = {The ChAHP Complex Counteracts Chromatin Looping at CTCF Sites that Emerged from SINE Expansions in Mouse.},
journal = {Cell},
volume = {178},
number = {6},
pages = {1437-1451.e14},
doi = {10.1016/j.cell.2019.08.007},
pmid = {31491387},
issn = {1097-4172},
mesh = {Animals ; Binding Sites ; CCCTC-Binding Factor/*metabolism ; Cell Line ; Chromatin/*metabolism ; Chromobox Protein Homolog 5 ; Chromosomal Proteins, Non-Histone/*metabolism ; DNA Helicases/*metabolism ; Embryonic Stem Cells/cytology/*metabolism ; Homeodomain Proteins/*metabolism ; Mice ; Nerve Tissue Proteins/*metabolism ; Protein Binding ; Protein Domains ; *Retroelements ; },
abstract = {CCCTC-binding factor (CTCF) and cohesin are key players in three-dimensional chromatin organization. The topologically associating domains (TADs) demarcated by CTCF are remarkably well conserved between species, although genome-wide CTCF binding has diverged substantially following transposon-mediated motif expansions. Therefore, the CTCF consensus motif poorly predicts TADs, and additional factors must modulate CTCF binding and subsequent TAD formation. Here, we demonstrate that the ChAHP complex (CHD4, ADNP, HP1) competes with CTCF for a common set of binding motifs. In Adnp knockout cells, novel insulated regions are formed at sites normally bound by ChAHP, whereas proximal canonical boundaries are weakened. These data reveal that CTCF-mediated loop formation is modulated by a distinct zinc-finger protein complex. Strikingly, ChAHP-bound loci are mainly situated within less diverged SINE B2 transposable elements. This implicates ChAHP in maintenance of evolutionarily conserved spatial chromatin organization by buffering novel CTCF binding sites that emerged through SINE expansions.},
}
@article {pmid31449516,
year = {2019},
author = {Tan, G and Polychronopoulos, D and Lenhard, B},
title = {CNEr: A toolkit for exploring extreme noncoding conservation.},
journal = {PLoS computational biology},
volume = {15},
number = {8},
pages = {e1006940},
pmid = {31449516},
issn = {1553-7358},
support = {//Wellcome Trust/United Kingdom ; MC_UP_1102/1/MRC_/Medical Research Council/United Kingdom ; 106954/Z/15/Z/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Algorithms ; Animals ; Computational Biology ; *Conserved Sequence ; Databases, Genetic ; Drosophila/genetics ; Genome ; Genomics/statistics &amp; numerical data ; Humans ; Models, Genetic ; RNA, Untranslated/genetics ; Sea Urchins/genetics ; *Software ; Tsetse Flies/genetics ; },
abstract = {Conserved Noncoding Elements (CNEs) are elements exhibiting extreme noncoding conservation in Metazoan genomes. They cluster around developmental genes and act as long-range enhancers, yet nothing that we know about their function explains the observed conservation levels. Clusters of CNEs coincide with topologically associating domains (TADs), indicating ancient origins and stability of TAD locations. This has suggested further hypotheses about the still elusive origin of CNEs, and has provided a comparative genomics-based method of estimating the position of TADs around developmentally regulated genes in genomes where chromatin conformation capture data is missing. To enable researchers in gene regulation and chromatin biology to start deciphering this phenomenon, we developed CNEr, a R/Bioconductor toolkit for large-scale identification of CNEs and for studying their genomic properties. We apply CNEr to two novel genome comparisons-fruit fly vs tsetse fly, and two sea urchin genomes-and report novel insights gained from their analysis. We also show how to reveal interesting characteristics of CNEs by coupling CNEr with existing Bioconductor packages. CNEr is available at Bioconductor (https://bioconductor.org/packages/CNEr/) and maintained at github (https://github.com/ge11232002/CNEr).},
}
@article {pmid31445093,
year = {2020},
author = {Li, X and An, Z and Zhang, Z},
title = {Comparison of computational methods for 3D genome analysis at single-cell Hi-C level.},
journal = {Methods (San Diego, Calif.)},
volume = {181-182},
number = {},
pages = {52-61},
doi = {10.1016/j.ymeth.2019.08.005},
pmid = {31445093},
issn = {1095-9130},
mesh = {Chromatin/genetics ; Chromosomes/genetics/metabolism ; Computational Biology/*methods ; Data Analysis ; Datasets as Topic ; Genome ; High-Throughput Nucleotide Sequencing/*methods ; Molecular Conformation ; Single-Cell Analysis/*methods ; },
abstract = {Hi-C is a high-throughput chromosome conformation capture technology that is becoming routine in the literature. Although the price of sequencing has been dropping dramatically, high-resolution Hi-C data are not always an option for many studies, such as in single cells. However, the performance of current computational methods based on Hi-C at the ultra-sparse data condition has yet to be fully assessed. Therefore, in this paper, after briefly surveying the primary computational methods for Hi-C data analysis, we assess the performance of representative methods on data normalization, identification of compartments, Topologically Associating Domains (TADs) and chromatin loops under the condition of ultra-low resolution. We showed that most state-of-the-art methods do not work properly for that condition. Then, we applied the three best-performing methods on real single-cell Hi-C data, and their performance indicates that compartments may be a statistical feature emerging from the cell population, while TADs and chromatin loops may dynamically exist in single cells.},
}
@article {pmid31439835,
year = {2019},
author = {Abdalla, MOA and Yamamoto, T and Maehara, K and Nogami, J and Ohkawa, Y and Miura, H and Poonperm, R and Hiratani, I and Nakayama, H and Nakao, M and Saitoh, N},
title = {The Eleanor ncRNAs activate the topological domain of the ESR1 locus to balance against apoptosis.},
journal = {Nature communications},
volume = {10},
number = {1},
pages = {3778},
pmid = {31439835},
issn = {2041-1723},
mesh = {Antineoplastic Agents, Hormonal/pharmacology/therapeutic use ; Apoptosis/drug effects/*genetics ; Aromatase Inhibitors/pharmacology/therapeutic use ; Binding Sites/genetics ; Breast Neoplasms/drug therapy/*genetics/pathology ; Chromatin/genetics/metabolism ; Drug Resistance, Neoplasm/genetics ; Epigenesis, Genetic ; Estrogen Receptor alpha/*genetics/metabolism ; Estrogens/metabolism ; Female ; Forkhead Box Protein O3/genetics/metabolism ; *Gene Expression Regulation, Neoplastic ; Genetic Loci/genetics ; High-Throughput Nucleotide Sequencing ; Humans ; MCF-7 Cells ; Promoter Regions, Genetic/genetics ; RNA, Untranslated/*metabolism ; Up-Regulation ; },
abstract = {MCF7 cells acquire estrogen-independent proliferation after long-term estrogen deprivation (LTED), which recapitulates endocrine therapy resistance. LTED cells can become primed for apoptosis, but the underlying mechanism is largely unknown. We previously reported that Eleanor non-coding RNAs (ncRNAs) upregulate the ESR1 gene in LTED cells. Here, we show that Eleanors delineate the topologically associating domain (TAD) of the ESR1 locus in the active nuclear compartment of LTED cells. The TAD interacts with another transcriptionally active TAD, which is 42.9 Mb away from ESR1 and contains a gene encoding the apoptotic transcription factor FOXO3. Inhibition of a promoter-associated Eleanor suppresses all genes inside the Eleanor TAD and the long-range interaction between the two TADs, but keeps FOXO3 active to facilitate apoptosis in LTED cells. These data indicate a role of ncRNAs in chromatin domain regulation, which may underlie the apoptosis-prone nature of therapy-resistant breast cancer cells and could be good therapeutic targets.},
}
@article {pmid31427791,
year = {2019},
author = {Zhang, Y and Li, T and Preissl, S and Amaral, ML and Grinstein, JD and Farah, EN and Destici, E and Qiu, Y and Hu, R and Lee, AY and Chee, S and Ma, K and Ye, Z and Zhu, Q and Huang, H and Fang, R and Yu, L and Izpisua Belmonte, JC and Wu, J and Evans, SM and Chi, NC and Ren, B},
title = {Transcriptionally active HERV-H retrotransposons demarcate topologically associating domains in human pluripotent stem cells.},
journal = {Nature genetics},
volume = {51},
number = {9},
pages = {1380-1388},
pmid = {31427791},
issn = {1546-1718},
support = {T32 GM008806/GM/NIGMS NIH HHS/United States ; UM1 HL128773/HL/NHLBI NIH HHS/United States ; U54 DK107977/DK/NIDDK NIH HHS/United States ; U01 HL131003/HL/NHLBI NIH HHS/United States ; },
mesh = {Animals ; Cell Differentiation ; Chromatin/*genetics ; Endogenous Retroviruses/*genetics ; *Gene Expression Regulation ; Humans ; Pluripotent Stem Cells/*cytology/physiology ; Primates ; *Response Elements ; Retroelements/*genetics ; Transcription Factors/genetics/metabolism ; *Transcription, Genetic ; },
abstract = {Chromatin architecture has been implicated in cell type-specific gene regulatory programs, yet how chromatin remodels during development remains to be fully elucidated. Here, by interrogating chromatin reorganization during human pluripotent stem cell (hPSC) differentiation, we discover a role for the primate-specific endogenous retrotransposon human endogenous retrovirus subfamily H (HERV-H) in creating topologically associating domains (TADs) in hPSCs. Deleting these HERV-H elements eliminates their corresponding TAD boundaries and reduces the transcription of upstream genes, while de novo insertion of HERV-H elements can introduce new TAD boundaries. The ability of HERV-H to create TAD boundaries depends on high transcription, as transcriptional repression of HERV-H elements prevents the formation of boundaries. This ability is not limited to hPSCs, as these actively transcribed HERV-H elements and their corresponding TAD boundaries also appear in pluripotent stem cells from other hominids but not in more distantly related species lacking HERV-H elements. Overall, our results provide direct evidence for retrotransposons in actively shaping cell type- and species-specific chromatin architecture.},
}
@article {pmid31406346,
year = {2019},
author = {Miura, H and Takahashi, S and Poonperm, R and Tanigawa, A and Takebayashi, SI and Hiratani, I},
title = {Single-cell DNA replication profiling identifies spatiotemporal developmental dynamics of chromosome organization.},
journal = {Nature genetics},
volume = {51},
number = {9},
pages = {1356-1368},
pmid = {31406346},
issn = {1546-1718},
mesh = {Animals ; Cell Differentiation ; Cell Nucleus/genetics/*metabolism ; Cells, Cultured ; Cellular Reprogramming ; *Chromatin Assembly and Disassembly ; Chromosomes/*genetics ; *DNA Replication ; Female ; Genome ; Male ; Mice ; Mice, Inbred C57BL ; Mouse Embryonic Stem Cells/cytology/*metabolism ; Neurons/cytology/metabolism ; Single-Cell Analysis/*methods ; *Spatio-Temporal Analysis ; },
abstract = {In mammalian cells, chromosomes are partitioned into megabase-sized topologically associating domains (TADs). TADs can be in either A (active) or B (inactive) subnuclear compartments, which exhibit early and late replication timing (RT), respectively. Here, we show that A/B compartments change coordinately with RT changes genome wide during mouse embryonic stem cell (mESC) differentiation. While A to B compartment changes and early to late RT changes were temporally inseparable, B to A changes clearly preceded late to early RT changes and transcriptional activation. Compartments changed primarily by boundary shifting, altering the compartmentalization of TADs facing the A/B compartment interface, which was conserved during reprogramming and confirmed in individual cells by single-cell Repli-seq. Differentiating mESCs altered single-cell Repli-seq profiles gradually but uniformly, transiently resembling RT profiles of epiblast-derived stem cells (EpiSCs), suggesting that A/B compartments might also change gradually but uniformly toward a primed pluripotent state. These results provide insights into how megabase-scale chromosome organization changes in individual cells during differentiation.},
}
@article {pmid31401119,
year = {2020},
author = {Arnould, C and Legube, G},
title = {The Secret Life of Chromosome Loops upon DNA Double-Strand Break.},
journal = {Journal of molecular biology},
volume = {432},
number = {3},
pages = {724-736},
pmid = {31401119},
issn = {1089-8638},
mesh = {Chromatin/*metabolism/*ultrastructure ; *DNA Breaks, Double-Stranded ; *DNA Repair ; Macromolecular Substances/*metabolism/*ultrastructure ; *Molecular Conformation ; },
abstract = {DNA double-strand breaks (DSBs) are harmful lesions that severely challenge genomic integrity, and recent evidence suggests that DSBs occur more frequently on the genome than previously thought. These lesions activate a complex and multilayered response called the DNA damage response, which allows to coordinate their repair with the cell cycle progression. While the mechanistic details of repair processes have been narrowed, thanks to several decades of intense studies, our knowledge of the impact of DSB on chromatin composition and chromosome architecture is still very sparse. However, the recent development of various tools to induce DSB at annotated loci, compatible with next-generation sequencing-based approaches, is opening a new framework to tackle these questions. Here we discuss the influence of initial and DSB-induced chromatin conformation and the strong potential of 3C-based technologies to decipher the contribution of chromosome architecture during DSB repair.},
}
@article {pmid31385379,
year = {2020},
author = {Yao, S and Dong, SS and Ding, JM and Rong, Y and Zhang, YJ and Chen, H and Chen, JB and Chen, YX and Yan, H and Dai, Z and Guo, Y},
title = {Sex-specific SNP-SNP interaction analyses within topologically associated domains reveals ANGPT1 as a novel tumor suppressor gene for lung cancer.},
journal = {Genes, chromosomes &amp; cancer},
volume = {59},
number = {1},
pages = {13-22},
doi = {10.1002/gcc.22793},
pmid = {31385379},
issn = {1098-2264},
abstract = {Genetic interaction has been recognized to be an important cause of the missing heritability. The topologically associating domain (TAD) is a self-interacting genomic region, and the DNA sequences within a TAD physically interact with each other more frequently. Sex differences influence cancer susceptibility at the genetic level. Here, we performed both regular and sex-specific genetic interaction analyses within TAD to identify susceptibility genes for lung cancer in 5204 lung cancer patients and 7389 controls. We found that one SNP pair, rs4262299-rs1654701, was associated with lung cancer in women after multiple testing corrections (combined P = 8.52 × 10[-9]). Single-SNP analyses did not detect significant association signals for these two SNPs. Both identified SNPs are located in the intron region of ANGPT1. We further found that 5% of nonsmall cell lung cancer patients have an alteration in ANGPT1, indicated the potential role of ANGPT1 in the neoplastic progression in lung cancer. The expression of ANGPT1 was significantly down-regulated in patients in lung squamous cell carcinoma and lung adenocarcinoma. We checked the interaction effect on the ANGPT1 expression and lung cancer and found that the minor allele "G" of rs1654701 increased ANGPT1 gene expression and decreased lung cancer risk with the increased dosage of "A" of rs4262299, which consistent with the tumor suppressor function of ANGPT1. Survival analyses found that the high expression of ANGPT1 was individually associated with a higher survival probability in lung cancer patients. In summary, our results suggest that ANGPT1 may be a novel tumor suppressor gene for lung cancer.},
}
@article {pmid31383969,
year = {2019},
author = {Xie, T and Zhang, FG and Zhang, HY and Wang, XT and Hu, JH and Wu, XM},
title = {Biased gene retention during diploidization in Brassica linked to three-dimensional genome organization.},
journal = {Nature plants},
volume = {5},
number = {8},
pages = {822-832},
doi = {10.1038/s41477-019-0479-8},
pmid = {31383969},
issn = {2055-0278},
mesh = {Brassica/*genetics ; Chromatin/chemistry ; *Diploidy ; Evolution, Molecular ; *Genome, Plant ; Nucleic Acid Conformation ; Protein Conformation ; Protein Interaction Maps ; },
abstract = {The non-random three-dimensional (3D) organization of the genome in the nucleus is critical to gene regulation and genome function. Using high-throughput chromatin conformation capture, we generated chromatin interaction maps for Brassica rapa and Brassica oleracea at a high resolution and characterized the conservation and divergence of chromatin organization in these two species. Large-scale chromatin structures, including A/B compartments and topologically associating domains, are notably conserved between B. rapa and B. oleracea, yet their KNOT structures are highly divergent. We found that genes retained in less fractionated subgenomes exhibited stronger interaction strengths, and diploidization-resistant duplicates retained in pairs or triplets are more likely to be colocalized in both B. rapa and B. oleracea. These observations suggest that spatial constraint in duplicated genes is correlated to their biased retention in the diploidization process. In addition, we found strong similarities in the epigenetic modification and Gene Ontology terms of colocalized paralogues, which were largely conserved across B. rapa and B. oleracea, indicating functional constraints on their 3D positioning in the nucleus. This study presents an investigation of the spatial organization of genomes in Brassica and provides insights on the role of 3D organization in the genome evolution of this genus.},
}
@article {pmid31363138,
year = {2019},
author = {Kim, D and An, H and Shearer, RS and Sharif, M and Fan, C and Choi, JO and Ryu, S and Park, Y},
title = {A principled strategy for mapping enhancers to genes.},
journal = {Scientific reports},
volume = {9},
number = {1},
pages = {11043},
pmid = {31363138},
issn = {2045-2322},
support = {R01 NS094181/NS/NINDS NIH HHS/United States ; R21 NS102558/NS/NINDS NIH HHS/United States ; },
mesh = {Animals ; Cells, Cultured ; Chromatin Assembly and Disassembly ; *Enhancer Elements, Genetic ; Gene Expression Regulation, Developmental ; *Genetic Loci ; Mice ; Oligodendroglia/cytology/metabolism ; Sequence Analysis, DNA/*methods ; Transcription Factors/*genetics ; },
abstract = {Mapping enhancers to genes is a fundamental goal of modern biology. We have developed an innovative strategy that maps enhancers to genes in a principled manner. We illustrate its power by applying it to Myrf. Despite being a master regulator of oligodendrocytes, oligodendrocyte enhancers governing Myrf expression remain elusive. Since chromatin conformation capture studies have shown that a gene and its enhancer tend to be found in the same topologically associating domain (TAD), we started with the delineation of the Myrf TAD. A genome-wide map of putative oligodendrocyte enhancers uncovered 6 putative oligodendrocyte enhancers in the Myrf TAD, narrowing down the search space for Myrf enhancers from the entire genome to 6 loci in a principled manner. Epigenome editing experiments revealed that two of them govern Myrf expression for oligodendrocyte development. Our new method is simple, principled, and powerful, providing a systematic way to find enhancers that regulate the expression of a gene of interest. Since it can be applied to most cell types, it would greatly facilitate our effort to unravel transcriptional regulatory networks of diverse cell types.},
}
@article {pmid31362752,
year = {2019},
author = {Sadowski, M and Kraft, A and Szalaj, P and Wlasnowolski, M and Tang, Z and Ruan, Y and Plewczynski, D},
title = {Spatial chromatin architecture alteration by structural variations in human genomes at the population scale.},
journal = {Genome biology},
volume = {20},
number = {1},
pages = {148},
pmid = {31362752},
issn = {1474-760X},
support = {P30 CA034196/CA/NCI NIH HHS/United States ; 1U54DK107967-01/NH/NIH HHS/United States ; },
mesh = {Algorithms ; Chromatin/*chemistry ; Gene Expression Regulation ; *Genome, Human ; *Genomic Structural Variation ; Humans ; Models, Molecular ; Racial Groups/genetics ; Transcription, Genetic ; },
abstract = {BACKGROUND: The number of reported examples of chromatin architecture alterations involved in the regulation of gene transcription and in disease is increasing. However, no genome-wide testing has been performed to assess the abundance of these events and their importance relative to other factors affecting genome regulation. This is particularly interesting given that a vast majority of genetic variations identified in association studies are located outside coding sequences. This study attempts to address this lack by analyzing the impact on chromatin spatial organization of genetic variants identified in individuals from 26 human populations and in genome-wide association studies.<br><br>RESULTS: We assess the tendency of structural variants to accumulate in spatially interacting genomic segments and design an algorithm to model chromatin conformational changes caused by structural variations. We show that differential gene transcription is closely linked to the variation in chromatin interaction networks mediated by RNA polymerase II. We also demonstrate that CTCF-mediated interactions are well conserved across populations, but enriched with disease-associated SNPs. Moreover, we find boundaries of topological domains as relatively frequent targets of duplications, which suggest that these duplications can be an important evolutionary mechanism of genome spatial organization.<br><br>CONCLUSIONS: This study assesses the critical impact of genetic variants on the higher-order organization of chromatin folding and provides insight into the mechanisms regulating gene transcription at the population scale, of which local arrangement of chromatin loops seems to be the most significant. It provides the first insight into the variability of the human 3D genome at the population scale.},
}
@article {pmid31362571,
year = {2019},
author = {Dumur, T and Duncan, S and Graumann, K and Desset, S and Randall, RS and Scheid, OM and Prodanov, D and Tatout, C and Baroux, C},
title = {Probing the 3D architecture of the plant nucleus with microscopy approaches: challenges and solutions.},
journal = {Nucleus (Austin, Tex.)},
volume = {10},
number = {1},
pages = {181-212},
pmid = {31362571},
issn = {1949-1042},
mesh = {Animals ; Artificial Intelligence ; *Cell Nucleus/chemistry ; Humans ; *Imaging, Three-Dimensional ; In Situ Hybridization, Fluorescence ; Microscopy, Confocal ; Microscopy, Fluorescence ; *Plant Cells ; },
abstract = {The eukaryotic cell nucleus is a central organelle whose architecture determines genome function at multiple levels. Deciphering nuclear organizing principles influencing cellular responses and identity is a timely challenge. Despite many similarities between plant and animal nuclei, plant nuclei present intriguing specificities. Complementary to molecular and biochemical approaches, 3D microscopy is indispensable for resolving nuclear architecture. However, novel solutions are required for capturing cell-specific, sub-nuclear and dynamic processes. We provide a pointer for utilising high-to-super-resolution microscopy and image processing to probe plant nuclear architecture in 3D at the best possible spatial and temporal resolution and at quantitative and cell-specific levels. High-end imaging and image-processing solutions allow the community now to transcend conventional practices and benefit from continuously improving approaches. These promise to deliver a comprehensive, 3D view of plant nuclear architecture and to capture spatial dynamics of the nuclear compartment in relation to cellular states and responses. Abbreviations: 3D and 4D: Three and Four dimensional; AI: Artificial Intelligence; ant: antipodal nuclei (ant); CLSM: Confocal Laser Scanning Microscopy; CTs: Chromosome Territories; DL: Deep Learning; DLIm: Dynamic Live Imaging; ecn: egg nucleus; FACS: Fluorescence-Activated Cell Sorting; FISH: Fluorescent In Situ Hybridization; FP: Fluorescent Proteins (GFP, RFP, CFP, YFP, mCherry); FRAP: Fluorescence Recovery After Photobleaching; GPU: Graphics Processing Unit; KEEs: KNOT Engaged Elements; INTACT: Isolation of Nuclei TAgged in specific Cell Types; LADs: Lamin-Associated Domains; ML: Machine Learning; NA: Numerical Aperture; NADs: Nucleolar Associated Domains; PALM: Photo-Activated Localization Microscopy; Pixel: Picture element; pn: polar nuclei; PSF: Point Spread Function; RHF: Relative Heterochromatin Fraction; SIM: Structured Illumination Microscopy; SLIm: Static Live Imaging; SMC: Spore Mother Cell; SNR: Signal to Noise Ratio; SRM: Super-Resolution Microscopy; STED: STimulated Emission Depletion; STORM: STochastic Optical Reconstruction Microscopy; syn: synergid nuclei; TADs: Topologically Associating Domains; Voxel: Volumetric pixel.},
}
@article {pmid31362468,
year = {2019},
author = {Kim, K and Eom, J and Jung, I},
title = {Characterization of Structural Variations in the Context of 3D Chromatin Structure.},
journal = {Molecules and cells},
volume = {42},
number = {7},
pages = {512-522},
pmid = {31362468},
issn = {0219-1032},
mesh = {Chromatin/*chemistry ; Gene Rearrangement/genetics ; Genome ; *Genomic Structural Variation ; *Imaging, Three-Dimensional ; },
abstract = {Chromosomes located in the nucleus form discrete units of genetic material composed of DNA and protein complexes. The genetic information is encoded in linear DNA sequences, but its interpretation requires an understanding of threedimensional (3D) structure of the chromosome, in which distant DNA sequences can be juxtaposed by highly condensed chromatin packing in the space of nucleus to precisely control gene expression. Recent technological innovations in exploring higher-order chromatin structure have uncovered organizational principles of the 3D genome and its various biological implications. Very recently, it has been reported that large-scale genomic variations may disrupt higher-order chromatin organization and as a consequence, greatly contribute to disease-specific gene regulation for a range of human diseases. Here, we review recent developments in studying the effect of structural variation in gene regulation, and the detection and the interpretation of structural variations in the context of 3D chromatin structure.},
}
@article {pmid31359064,
year = {2019},
author = {Caporale, AL and Gonda, CM and Franchini, LF},
title = {Transcriptional Enhancers in the FOXP2 Locus Underwent Accelerated Evolution in the Human Lineage.},
journal = {Molecular biology and evolution},
volume = {},
number = {},
pages = {},
doi = {10.1093/molbev/msz173},
pmid = {31359064},
issn = {1537-1719},
abstract = {Unique human features such as complex language are the result of molecular evolutionary changes that modified developmental programs of our brain. The human-specific evolution of the forkhead box P2 (FOXP2) gene coding region has been linked to the emergence of speech and language in the human kind. However, little is known about how the expression of FOXP2 is regulated and if its regulatory machinery evolved in a lineage-specific manner in humans. In order to identify FOXP2 regulatory regions containing human-specific changes we used databases of human accelerated non-coding sequences or HARs. We found that the topologically associating domain (TAD) determined using developing human cerebral cortex containing the FOXP2 locus includes two clusters of 12 HARs, placing the locus occupied by FOXP2 among the top regions showing fast acceleration rates in non-coding regions in the human genome. Using in vivo enhancer assays in zebrafish, we found that at least five FOXP2-HARs behave as transcriptional enhancers throughout different developmental stages. In addition, we found that at least two FOXP2-HARs direct the expression of the reporter gene EGFP to foxP2 expressing regions and cells. Moreover, we uncovered two FOXP2-HARs showing reporter expression gain of function in the nervous system when compared with the chimpanzee ortholog sequences. Our results indicate that regulatory sequences in the FOXP2 locus underwent a human-specific evolutionary process suggesting that the transcriptional machinery controlling this gene could have also evolved differentially in the human lineage.},
}
@article {pmid31358994,
year = {2019},
author = {Despang, A and Schöpflin, R and Franke, M and Ali, S and Jerković, I and Paliou, C and Chan, WL and Timmermann, B and Wittler, L and Vingron, M and Mundlos, S and Ibrahim, DM},
title = {Functional dissection of the Sox9-Kcnj2 locus identifies nonessential and instructive roles of TAD architecture.},
journal = {Nature genetics},
volume = {51},
number = {8},
pages = {1263-1271},
doi = {10.1038/s41588-019-0466-z},
pmid = {31358994},
issn = {1546-1718},
mesh = {Animals ; CCCTC-Binding Factor/genetics/*metabolism ; Cell Cycle Proteins/genetics/*metabolism ; *Chromatin Assembly and Disassembly ; Chromosomal Proteins, Non-Histone/genetics/*metabolism ; *Enhancer Elements, Genetic ; Female ; *Gene Expression Regulation, Developmental ; Male ; Mice ; Mice, Inbred C57BL ; Potassium Channels, Inwardly Rectifying/genetics/*metabolism ; Promoter Regions, Genetic ; SOX9 Transcription Factor/genetics/*metabolism ; },
abstract = {The genome is organized in three-dimensional units called topologically associating domains (TADs), through a process dependent on the cooperative action of cohesin and the DNA-binding factor CTCF. Genomic rearrangements of TADs have been shown to cause gene misexpression and disease, but genome-wide depletion of CTCF has no drastic effects on transcription. Here, we investigate TAD function in vivo in mouse limb buds at the Sox9-Kcnj2 locus. We show that the removal of all major CTCF sites at the boundary and within the TAD resulted in a fusion of neighboring TADs, without major effects on gene expression. Gene misexpression and disease phenotypes, however, were achieved by redirecting regulatory activity through inversions and/or the repositioning of boundaries. Thus, TAD structures provide robustness and precision but are not essential for developmental gene regulation. Aberrant disease-related gene activation is not induced by a mere loss of insulation but requires CTCF-dependent redirection of enhancer-promoter contacts.},
}
@article {pmid31323043,
year = {2019},
author = {Eres, IE and Luo, K and Hsiao, CJ and Blake, LE and Gilad, Y},
title = {Reorganization of 3D genome structure may contribute to gene regulatory evolution in primates.},
journal = {PLoS genetics},
volume = {15},
number = {7},
pages = {e1008278},
pmid = {31323043},
issn = {1553-7404},
support = {T32 GM007197/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Chromatin Assembly and Disassembly ; Computational Biology/*methods ; Evolution, Molecular ; Gene Expression Profiling/*methods ; Gene Expression Regulation ; Genome ; Humans ; Pan troglodytes/*genetics ; Sequence Analysis, RNA/methods ; },
abstract = {A growing body of evidence supports the notion that variation in gene regulation plays a crucial role in both speciation and adaptation. However, a comprehensive functional understanding of the mechanisms underlying regulatory evolution remains elusive. In primates, one of the crucial missing pieces of information towards a better understanding of regulatory evolution is a comparative annotation of interactions between distal regulatory elements and promoters. Chromatin conformation capture technologies have enabled genome-wide quantifications of such distal 3D interactions. However, relatively little comparative research in primates has been done using such technologies. To address this gap, we used Hi-C to characterize 3D chromatin interactions in induced pluripotent stem cells (iPSCs) from humans and chimpanzees. We also used RNA-seq to collect gene expression data from the same lines. We generally observed that lower-order, pairwise 3D genomic interactions are conserved in humans and chimpanzees, but higher order genomic structures, such as topologically associating domains (TADs), are not as conserved. Inter-species differences in 3D genomic interactions are often associated with gene expression differences between the species. To provide additional functional context to our observations, we considered previously published chromatin data from human stem cells. We found that inter-species differences in 3D genomic interactions, which are also associated with gene expression differences between the species, are enriched for both active and repressive marks. Overall, our data demonstrate that, as expected, an understanding of 3D genome reorganization is key to explaining regulatory evolution.},
}
@article {pmid31308546,
year = {2019},
author = {Ghavi-Helm, Y and Jankowski, A and Meiers, S and Viales, RR and Korbel, JO and Furlong, EEM},
title = {Highly rearranged chromosomes reveal uncoupling between genome topology and gene expression.},
journal = {Nature genetics},
volume = {51},
number = {8},
pages = {1272-1282},
pmid = {31308546},
issn = {1546-1718},
support = {336045/ERC_/European Research Council/International ; 787611/ERC_/European Research Council/International ; },
mesh = {Animals ; Chromatin/*genetics ; Chromosome Mapping ; Chromosomes, Insect/*genetics ; Drosophila melanogaster/*genetics ; *Enhancer Elements, Genetic ; Female ; *Gene Expression Regulation ; *Gene Rearrangement ; *Genome, Insect ; Male ; Promoter Regions, Genetic ; },
abstract = {Chromatin topology is intricately linked to gene expression, yet its functional requirement remains unclear. Here, we comprehensively assessed the interplay between genome topology and gene expression using highly rearranged chromosomes (balancers) spanning ~75% of the Drosophila genome. Using transheterozyte (balancer/wild-type) embryos, we measured allele-specific changes in topology and gene expression in cis, while minimizing trans effects. Through genome sequencing, we resolved eight large nested inversions, smaller inversions, duplications and thousands of deletions. These extensive rearrangements caused many changes to chromatin topology, disrupting long-range loops, topologically associating domains (TADs) and promoter interactions, yet these are not predictive of changes in expression. Gene expression is generally not altered around inversion breakpoints, indicating that mis-appropriate enhancer-promoter activation is a rare event. Similarly, shuffling or fusing TADs, changing intra-TAD connections and disrupting long-range inter-TAD loops does not alter expression for the majority of genes. Our results suggest that properties other than chromatin topology ensure productive enhancer-promoter interactions.},
}
@article {pmid31299961,
year = {2019},
author = {Rodríguez-Carballo, E and Lopez-Delisle, L and Yakushiji-Kaminatsui, N and Ullate-Agote, A and Duboule, D},
title = {Impact of genome architecture on the functional activation and repression of Hox regulatory landscapes.},
journal = {BMC biology},
volume = {17},
number = {1},
pages = {55},
pmid = {31299961},
issn = {1741-7007},
mesh = {Animals ; Chromatin/*genetics ; Gene Rearrangement/*genetics ; Genes, Homeobox/*genetics ; *Genome ; Mice ; },
abstract = {BACKGROUND: The spatial organization of the mammalian genome relies upon the formation of chromatin domains of various scales. At the level of gene regulation in cis, collections of enhancer sequences define large regulatory landscapes that usually match with the presence of topologically associating domains (TADs). These domains often contain ranges of enhancers displaying similar or related tissue specificity, suggesting that in some cases, such domains may act as coherent regulatory units, with a global on or off state. By using the HoxD gene cluster, which specifies the topology of the developing limbs via highly orchestrated regulation of gene expression, as a paradigm, we investigated how the arrangement of regulatory domains determines their activity and function.<br><br>RESULTS: Proximal and distal cells in the developing limb express different levels of Hoxd genes, regulated by flanking 3' and 5' TADs, respectively. We characterized the effect of large genomic rearrangements affecting these two TADs, including their fusion into a single chromatin domain. We show that, within a single hybrid TAD, the activation of both proximal and distal limb enhancers globally occurred as when both TADs are intact. However, the activity of the 3' TAD in distal cells is generally increased in the fused TAD, when compared to wild type where it is silenced. Also, target gene activity in distal cells depends on whether or not these genes had previously responded to proximal enhancers, which determines the presence or absence of H3K27me3 marks. We also show that the polycomb repressive complex 2 is mainly recruited at the Hox gene cluster and can extend its coverage to far-cis regulatory sequences as long as confined to the neighboring TAD structure.<br><br>CONCLUSIONS: We conclude that antagonistic limb proximal and distal enhancers can exert their specific effects when positioned into the same TAD and in the absence of their genuine target genes. We also conclude that removing these target genes reduced the coverage of a regulatory landscape by chromatin marks associated with silencing, which correlates with its prolonged activity in time.},
}
@article {pmid31283985,
year = {2020},
author = {Mizi, A and Gade Gusmao, E and Papantonis, A},
title = {iHi-C 2.0: A simple approach for mapping native spatial chromatin organisation from low cell numbers.},
journal = {Methods (San Diego, Calif.)},
volume = {170},
number = {},
pages = {33-37},
doi = {10.1016/j.ymeth.2019.07.003},
pmid = {31283985},
issn = {1095-9130},
mesh = {Cell Count ; Cell Fractionation/methods ; Cell Line ; Cell Nucleus/genetics ; Chromatin/*genetics ; Chromosome Mapping/*methods ; Genomics/*methods ; High-Throughput Nucleotide Sequencing/*methods ; Humans ; Nucleic Acid Conformation ; Pluripotent Stem Cells ; Whole Genome Sequencing/methods ; },
abstract = {Genome organization is now understood to be tightly linked to all genomic functions. Thus, the high-resolution mapping of higher-order chromosomal structures via 3C-based approaches has become an integral tool for studying transcriptional and cell cycle regulation, signaling effects or disease onset. Nonetheless, 3C-based protocols are not without caveats, like dependencies on fixation conditions, restriction enzyme pervasiveness in crosslinked chromatin and ligation efficiency. To address some of these caveats, we describe here the streamlined iHi-C 2.0 protocol that allows for the genome-wide interrogation of native spatial chromatin contacts without a need for chemical fixation. This approach improves ligation efficiency and presents minimal material losses, and is thus suitable for analysing samples with limiting cell numbers. Following high throughput sequencing, iHi-C 2.0 generates high signal-to-noise and focal maps of the interactions within and between mammalian chromosomes under native conditions.},
}
@article {pmid31266973,
year = {2019},
author = {Huang, H and Chen, ST and Titus, KR and Emerson, DJ and Bassett, DS and Phillips-Cremins, JE},
title = {A subset of topologically associating domains fold into mesoscale core-periphery networks.},
journal = {Scientific reports},
volume = {9},
number = {1},
pages = {9526},
pmid = {31266973},
issn = {2045-2322},
support = {DP2 MH110247/MH/NIMH NIH HHS/United States ; U01 HL129998/HL/NHLBI NIH HHS/United States ; },
mesh = {CCCTC-Binding Factor/antagonists &amp; inhibitors/genetics/metabolism ; Chromatin Assembly and Disassembly ; Chromosomes/*chemistry/genetics/metabolism ; Embryonic Stem Cells/cytology/metabolism ; Genome ; Humans ; Mental Disorders/genetics/pathology ; *Models, Biological ; Neural Stem Cells/cytology/metabolism ; Neurons/chemistry/metabolism ; Polymorphism, Single Nucleotide ; RNA Interference ; },
abstract = {Mammalian genomes are folded into a hierarchy of compartments, topologically associating domains (TADs), subTADs, and long-range looping interactions. The higher-order folding patterns of chromatin contacts within TADs and how they localize to disease-associated single nucleotide variants (daSNVs) remains an open area of investigation. Here, we analyze high-resolution Hi-C data with graph theory to understand possible mesoscale network architecture within chromatin domains. We identify a subset of TADs exhibiting strong core-periphery mesoscale structure in embryonic stem cells, neural progenitor cells, and cortical neurons. Hyper-connected core nodes co-localize with genomic segments engaged in multiple looping interactions and enriched for occupancy of the architectural protein CCCTC binding protein (CTCF). CTCF knockdown and in silico deletion of CTCF-bound core nodes disrupts core-periphery structure, whereas in silico mutation of cell type-specific enhancer or gene nodes has a negligible effect. Importantly, neuropsychiatric daSNVs are significantly more likely to localize with TADs folded into core-periphery networks compared to domains devoid of such structure. Together, our results reveal that a subset of TADs encompasses looping interactions connected into a core-periphery mesoscale network. We hypothesize that daSNVs in the periphery of genome folding networks might preserve global nuclear architecture but cause local topological and functional disruptions contributing to human disease. By contrast, daSNVs co-localized with hyper-connected core nodes might cause severe topological and functional disruptions. Overall, these findings shed new light into the mesoscale network structure of fine scale genome folding within chromatin domains and its link to common genetic variants in human disease.},
}
@article {pmid31260328,
year = {2019},
author = {Li, Y and Wu, A and Liu, G and Liu, L},
title = {A Review of Methods to Quantify the Genomic Similarity of Topological Associating Domains.},
journal = {Journal of computational biology : a journal of computational molecular cell biology},
volume = {26},
number = {11},
pages = {1326-1338},
doi = {10.1089/cmb.2019.0129},
pmid = {31260328},
issn = {1557-8666},
mesh = {Algorithms ; Animals ; Chromatin/genetics/*ultrastructure ; Eukaryota/genetics/*ultrastructure ; Genome/*genetics ; *Genomics ; Mice ; Molecular Conformation ; },
abstract = {Topologically associating domains (TADs) are the most fundamental elements and significant structures of the eukaryotic genome. Currently, algorithms have been developed to find the TADs. But few algorithms are reported to compare the similarity of TADs between genomes. In this study, mice Hi-C sequencing data of four contrasts were enrolled. Seventeen algorithms, including BPscore, Jaccard index (JI) distance, VI distance, image hash, image subtraction, image variance, and so on, were used to quantify the genomic similarity of TADs. Image subtraction, Euclidean distance, and Manhattan distance were significantly better for TAD difference detection than the others. Deferent Hash (dHash) with the best zoom size ranked the second, followed by improved Hamming distance algorithm and JI distance. Advantages and disadvantages of various algorithms for quantifying the similarity of TADs were compared. Our work could provide the fundament for TADs comparison.},
}
@article {pmid31235599,
year = {2019},
author = {Zhou, J and Ma, J and Chen, Y and Cheng, C and Bao, B and Peng, J and Sejnowski, TJ and Dixon, JR and Ecker, JR},
title = {Robust single-cell Hi-C clustering by convolution- and random-walk-based imputation.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {116},
number = {28},
pages = {14011-14018},
pmid = {31235599},
issn = {1091-6490},
support = {P30 CA014195/CA/NCI NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; R21 HG009274/HG/NHGRI NIH HHS/United States ; },
mesh = {Algorithms ; Chromatin/*ultrastructure ; Chromosome Structures/*ultrastructure ; Cluster Analysis ; *Computational Biology ; Genome/genetics ; Humans ; Molecular Conformation ; *Single-Cell Analysis ; },
abstract = {Three-dimensional genome structure plays a pivotal role in gene regulation and cellular function. Single-cell analysis of genome architecture has been achieved using imaging and chromatin conformation capture methods such as Hi-C. To study variation in chromosome structure between different cell types, computational approaches are needed that can utilize sparse and heterogeneous single-cell Hi-C data. However, few methods exist that are able to accurately and efficiently cluster such data into constituent cell types. Here, we describe scHiCluster, a single-cell clustering algorithm for Hi-C contact matrices that is based on imputations using linear convolution and random walk. Using both simulated and real single-cell Hi-C data as benchmarks, scHiCluster significantly improves clustering accuracy when applied to low coverage datasets compared with existing methods. After imputation by scHiCluster, topologically associating domain (TAD)-like structures (TLSs) can be identified within single cells, and their consensus boundaries were enriched at the TAD boundaries observed in bulk cell Hi-C samples. In summary, scHiCluster facilitates visualization and comparison of single-cell 3D genomes.},
}
@article {pmid31216471,
year = {2019},
author = {Cuadrado, A and Giménez-Llorente, D and Kojic, A and Rodríguez-Corsino, M and Cuartero, Y and Martín-Serrano, G and Gómez-López, G and Marti-Renom, MA and Losada, A},
title = {Specific Contributions of Cohesin-SA1 and Cohesin-SA2 to TADs and Polycomb Domains in Embryonic Stem Cells.},
journal = {Cell reports},
volume = {27},
number = {12},
pages = {3500-3510.e4},
pmid = {31216471},
issn = {2211-1247},
mesh = {Animals ; Binding Sites ; CCCTC-Binding Factor/genetics/metabolism ; Cell Cycle Proteins/genetics/*metabolism ; Chromatin/genetics/*metabolism ; Chromosomal Proteins, Non-Histone/genetics/*metabolism ; Enhancer Elements, Genetic ; *Gene Expression Regulation ; Male ; Mice ; Mouse Embryonic Stem Cells/cytology/*metabolism ; Polycomb-Group Proteins/genetics/*metabolism ; Promoter Regions, Genetic ; Protein Binding ; Protein Isoforms ; },
abstract = {Cohesin exists in two variants carrying either STAG/SA1 or SA2. Here we have addressed their specific contributions to the unique spatial organization of the mouse embryonic stem cell genome, which ensures super-enhancer-dependent transcription of pluripotency factors and repression of lineage-specification genes within Polycomb domains. We find that cohesin-SA2 facilitates Polycomb domain compaction through Polycomb repressing complex 1 (PRC1) recruitment and promotes the establishment of long-range interaction networks between distant Polycomb-bound promoters that are important for gene repression. Cohesin-SA1, in contrast, disrupts these networks, while preserving topologically associating domain (TAD) borders. The diverse effects of both complexes on genome topology may reflect two modes of action of cohesin. One, likely involving loop extrusion, establishes overall genome arrangement in TADs together with CTCF and prevents excessive segregation of same-class compartment regions. The other is required for organization of local transcriptional hubs such as Polycomb domains and super-enhancers, which define cell identity.},
}
@article {pmid31205001,
year = {2019},
author = {Cattoglio, C and Pustova, I and Walther, N and Ho, JJ and Hantsche-Grininger, M and Inouye, CJ and Hossain, MJ and Dailey, GM and Ellenberg, J and Darzacq, X and Tjian, R and Hansen, AS},
title = {Determining cellular CTCF and cohesin abundances to constrain 3D genome models.},
journal = {eLife},
volume = {8},
number = {},
pages = {},
pmid = {31205001},
issn = {2050-084X},
support = {UO1-EB021236/NH/NIH HHS/United States ; U01 DA047728/DA/NIDA NIH HHS/United States ; U01 EB021236/EB/NIBIB NIH HHS/United States ; U01 EB021223/NH/NIH HHS/United States ; U01 DA047729/DA/NIDA NIH HHS/United States ; U54-DK107980/NH/NIH HHS/United States ; LA1-08013//California Institute of Regenerative Medicine/International ; K99 GM130896/GM/NIGMS NIH HHS/United States ; U01 DA047728/NH/NIH HHS/United States ; iNEXT 653706//Horizon 2020 Framework Programme/International ; 003061/HHMI/Howard Hughes Medical Institute/United States ; K99GM130896/NH/NIH HHS/United States ; U54 DK107980/DK/NIDDK NIH HHS/United States ; },
mesh = {Animals ; CCCTC-Binding Factor ; Cell Cycle Proteins ; *Chromatin ; *Chromosomal Proteins, Non-Histone ; Humans ; },
abstract = {Achieving a quantitative and predictive understanding of 3D genome architecture remains a major challenge, as it requires quantitative measurements of the key proteins involved. Here, we report the quantification of CTCF and cohesin, two causal regulators of topologically associating domains (TADs) in mammalian cells. Extending our previous imaging studies (Hansen et al., 2017), we estimate bounds on the density of putatively DNA loop-extruding cohesin complexes and CTCF binding site occupancy. Furthermore, co-immunoprecipitation studies of an endogenously tagged subunit (Rad21) suggest the presence of cohesin dimers and/or oligomers. Finally, based on our cell lines with accurately measured protein abundances, we report a method to conveniently determine the number of molecules of any Halo-tagged protein in the cell. We anticipate that our results and the established tool for measuring cellular protein abundances will advance a more quantitative understanding of 3D genome organization, and facilitate protein quantification, key to comprehend diverse biological processes.},
}
@article {pmid31204999,
year = {2019},
author = {Holzmann, J and Politi, AZ and Nagasaka, K and Hantsche-Grininger, M and Walther, N and Koch, B and Fuchs, J and Dürnberger, G and Tang, W and Ladurner, R and Stocsits, RR and Busslinger, GA and Novák, B and Mechtler, K and Davidson, IF and Ellenberg, J and Peters, JM},
title = {Absolute quantification of cohesin, CTCF and their regulators in human cells.},
journal = {eLife},
volume = {8},
number = {},
pages = {},
pmid = {31204999},
issn = {2050-084X},
support = {WWTF LS09-13//Vienna Science and Technology Fund/International ; International PhD Programme//European Molecular Biology Laboratory/International ; U01 DA047728/DA/NIDA NIH HHS/United States ; Laura Bassi Centre for Optimized Structural Studies grant FFG-840283//Austrian Research Promotion Agency/International ; Common Fund 4D Nucleome Program (U01 DA047728)/NH/NIH HHS/United States ; Allen Distinguished Investigator Program//Paul G. Allen Frontiers Group/International ; Common Fund 4D Nucleome Program (U01 EB021223)/NH/NIH HHS/United States ; ALTF 1335-2016//European Molecular Biology Organization/International ; Common Fund 4D Nucleome Program (U01 EB021223 / U01 DA047728)/NH/NIH HHS/United States ; 693949//Horizon 2020 Framework Programme/International ; LT001527/2017//Human Frontier Science Program/International ; I 3686-B25 MEIOREC - ERA-CAPS//Austrian Science Fund/International ; 823839//Horizon 2020 Framework Programme/International ; 503464 (MitoCheck)//Sixth Framework Programme/International ; 653706//Horizon 2020 Framework Programme/International ; U01 EB021223/EB/NIBIB NIH HHS/United States ; Wittgenstein award Z196-B20//Austrian Science Fund/International ; 241548 (MitoSys)//Seventh Framework Programme/International ; FFG-834223//Austrian Research Promotion Agency/International ; FWF special research program SFB F34//Austrian Science Fund/International ; FFG-852936//Austrian Research Promotion Agency/International ; },
mesh = {CCCTC-Binding Factor/*genetics/metabolism ; Carrier Proteins/*genetics/metabolism ; Cell Cycle Proteins/*genetics/metabolism ; Cell Line ; Chromatids/genetics ; Chromatin/genetics/metabolism ; Chromosomal Proteins, Non-Histone/*genetics/metabolism ; Chromosome Segregation/genetics ; Fluorescence Recovery After Photobleaching/methods ; G1 Phase/genetics ; *Gene Dosage ; *Gene Expression ; Genome, Human/genetics ; HeLa Cells ; Humans ; Mass Spectrometry/methods ; Nuclear Proteins/*genetics/metabolism ; Proto-Oncogene Proteins/*genetics/metabolism ; },
abstract = {The organisation of mammalian genomes into loops and topologically associating domains (TADs) contributes to chromatin structure, gene expression and recombination. TADs and many loops are formed by cohesin and positioned by CTCF. In proliferating cells, cohesin also mediates sister chromatid cohesion, which is essential for chromosome segregation. Current models of chromatin folding and cohesion are based on assumptions of how many cohesin and CTCF molecules organise the genome. Here we have measured absolute copy numbers and dynamics of cohesin, CTCF, NIPBL, WAPL and sororin by mass spectrometry, fluorescence-correlation spectroscopy and fluorescence recovery after photobleaching in HeLa cells. In G1-phase, there are ~250,000 nuclear cohesin complexes, of which ~ 160,000 are chromatin-bound. Comparison with chromatin immunoprecipitation-sequencing data implies that some genomic cohesin and CTCF enrichment sites are unoccupied in single cells at any one time. We discuss the implications of these findings for how cohesin can contribute to genome organisation and cohesion.},
}
@article {pmid31201308,
year = {2019},
author = {Shukron, O and Piras, V and Noordermeer, D and Holcman, D},
title = {Statistics of chromatin organization during cell differentiation revealed by heterogeneous cross-linked polymers.},
journal = {Nature communications},
volume = {10},
number = {1},
pages = {2626},
pmid = {31201308},
issn = {2041-1723},
mesh = {Animals ; Cell Differentiation/*genetics ; Chromatin/*metabolism ; *Chromatin Assembly and Disassembly ; Cross-Linking Reagents/chemistry ; High-Throughput Nucleotide Sequencing ; Models, Molecular ; Nucleic Acid Conformation ; Polymers/*chemistry ; X Chromosome/*metabolism ; },
abstract = {Chromatin of mammalian nucleus folds into discrete contact enriched regions such as Topologically Associating Domains (TADs). Folding hierarchy and internal organization of TADs is highly dynamic throughout cellular differentiation, and are correlated with gene activation and silencing. To account for multiple interacting TADs, we developed a parsimonious randomly cross-linked (RCL) polymer model that maps high frequency Hi-C encounters within and between TADs into direct loci interactions using cross-links at a given base-pair resolution. We reconstruct three TADs of the mammalian X chromosome for three stages of differentiation. We compute the radius of gyration of TADs and the encounter probability between genomic segments. We found 1) a synchronous compaction and decompaction of TADs throughout differentiation and 2) high order organization into meta-TADs resulting from weak inter-TAD interactions. Finally, the present framework allows to infer transient properties of the chromatin from steady-state statistics embedded in the Hi-C/5C data.},
}
@article {pmid31197269,
year = {2019},
author = {Zheng, H and Xie, W},
title = {The role of 3D genome organization in development and cell differentiation.},
journal = {Nature reviews. Molecular cell biology},
volume = {20},
number = {9},
pages = {535-550},
doi = {10.1038/s41580-019-0132-4},
pmid = {31197269},
issn = {1471-0080},
mesh = {Animals ; *Cell Differentiation ; Chromatin/genetics/*metabolism ; *Gene Expression Regulation ; *Genome, Human ; Humans ; Stem Cells/*metabolism ; *Transcription, Genetic ; },
abstract = {In eukaryotes, the genome does not exist as a linear molecule but instead is hierarchically packaged inside the nucleus. This complex genome organization includes multiscale structural units of chromosome territories, compartments, topologically associating domains, which are often demarcated by architectural proteins such as CTCF and cohesin, and chromatin loops. The 3D organization of chromatin modulates biological processes such as transcription, DNA replication, cell division and meiosis, which are crucial for cell differentiation and animal development. In this Review, we discuss recent progress in our understanding of the general principles of chromatin folding, its regulation and its functions in mammalian development. Specifically, we discuss the dynamics of 3D chromatin and genome organization during gametogenesis, embryonic development, lineage commitment and stem cell differentiation, and focus on the functions of chromatin architecture in transcription regulation. Finally, we discuss the role of 3D genome alterations in the aetiology of developmental disorders and human diseases.},
}
@article {pmid31181064,
year = {2019},
author = {Qi, Y and Zhang, B},
title = {Predicting three-dimensional genome organization with chromatin states.},
journal = {PLoS computational biology},
volume = {15},
number = {6},
pages = {e1007024},
pmid = {31181064},
issn = {1553-7358},
mesh = {*Chromatin/chemistry/genetics ; Computational Biology/*methods ; Genome, Human/*genetics ; Humans ; *Models, Molecular ; },
abstract = {We introduce a computational model to simulate chromatin structure and dynamics. Starting from one-dimensional genomics and epigenomics data that are available for hundreds of cell types, this model enables de novo prediction of chromatin structures at five-kilo-base resolution. Simulated chromatin structures recapitulate known features of genome organization, including the formation of chromatin loops, topologically associating domains (TADs) and compartments, and are in quantitative agreement with chromosome conformation capture experiments and super-resolution microscopy measurements. Detailed characterization of the predicted structural ensemble reveals the dynamical flexibility of chromatin loops and the presence of cross-talk among neighboring TADs. Analysis of the model's energy function uncovers distinct mechanisms for chromatin folding at various length scales and suggests a need to go beyond simple A/B compartment types to predict specific contacts between regulatory elements using polymer simulations.},
}
@article {pmid31158401,
year = {2019},
author = {Elias, MS and Wright, SC and Remenyi, J and Abbott, JC and Bray, SE and Cole, C and Edwards, S and Gierlinski, M and Glok, M and McGrath, JA and Nicholson, WV and Paternoster, L and Prescott, AR and Have, ST and Whitfield, PD and Lamond, AI and Brown, SJ},
title = {EMSY expression affects multiple components of the skin barrier with relevance to atopic dermatitis.},
journal = {The Journal of allergy and clinical immunology},
volume = {144},
number = {2},
pages = {470-481},
pmid = {31158401},
issn = {1097-6825},
support = {MC_UU_00011/1/MRC_/Medical Research Council/United Kingdom ; 106865/Z/15/Z/WT_/Wellcome Trust/United Kingdom ; 097945/B/11/Z/WT_/Wellcome Trust/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; 105024/Z/14/Z/WT_/Wellcome Trust/United Kingdom ; 108058/Z/15/Z/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Chromosomes, Human, Pair 11/genetics/immunology ; Dermatitis, Atopic/genetics/*immunology/pathology ; Female ; Filaggrin Proteins ; Gene Expression Regulation/*immunology ; Genome-Wide Association Study ; Humans ; Male ; Membrane Proteins/genetics/immunology ; Neoplasm Proteins/genetics/*immunology ; Nuclear Proteins/genetics/*immunology ; Repressor Proteins/genetics/*immunology ; Skin/*immunology/pathology ; Transcription, Genetic/*immunology ; },
abstract = {BACKGROUND: Atopic dermatitis (AD) is a common, complex, and highly heritable inflammatory skin disease. Genome-wide association studies offer opportunities to identify molecular targets for drug development. A risk locus on chromosome 11q13.5 lies between 2 candidate genes, EMSY and LRRC32 (leucine-rich repeat-containing 32) but the functional mechanisms affecting risk of AD remain unclear.<br><br>OBJECTIVES: We sought to apply a combination of genomic and molecular analytic techniques to investigate which genes are responsible for genetic risk at this locus and to define mechanisms contributing to atopic skin disease.<br><br>METHODS: We used interrogation of available genomic and chromosome conformation data in keratinocytes, small interfering RNA (siRNA)-mediated knockdown in skin organotypic culture and functional assessment of barrier parameters, mass spectrometric global proteomic analysis and quantitative lipid analysis, electron microscopy of organotypic skin, and immunohistochemistry of human skin samples.<br><br>RESULTS: Genomic data indicate active promoters in the genome-wide association study locus and upstream of EMSY; EMSY, LRRC32, and intergenic variants all appear to be within a single topologically associating domain. siRNA-knockdown of EMSY in organotypic culture leads to enhanced development of barrier function, reflecting increased expression of structural and functional proteins, including filaggrin and filaggrin-2, as well as long-chain ceramides. Conversely, overexpression of EMSY in keratinocytes leads to a reduction in markers of barrier formation. Skin biopsy samples from patients with AD show greater EMSY staining in the nucleus, which is consistent with an increased functional effect of this transcriptional control protein.<br><br>CONCLUSION: Our findings demonstrate an important role for EMSY in transcriptional regulation and skin barrier formation, supporting EMSY inhibition as a therapeutic approach.},
}
@article {pmid31133748,
year = {2019},
author = {van Bemmel, JG and Galupa, R and Gard, C and Servant, N and Picard, C and Davies, J and Szempruch, AJ and Zhan, Y and Żylicz, JJ and Nora, EP and Lameiras, S and de Wit, E and Gentien, D and Baulande, S and Giorgetti, L and Guttman, M and Hughes, JR and Higgs, DR and Gribnau, J and Heard, E},
title = {The bipartite TAD organization of the X-inactivation center ensures opposing developmental regulation of Tsix and Xist.},
journal = {Nature genetics},
volume = {51},
number = {6},
pages = {1024-1034},
pmid = {31133748},
issn = {1546-1718},
support = {MC_UU_12009/15/MRC_/Medical Research Council/United Kingdom ; MC_U137961145/MRC_/Medical Research Council/United Kingdom ; MC_PC_15065/MRC_/Medical Research Council/United Kingdom ; 201369/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; MR/R008108/1/MRC_/Medical Research Council/United Kingdom ; MC_U137961144/MRC_/Medical Research Council/United Kingdom ; MC_UU_00016/14/MRC_/Medical Research Council/United Kingdom ; MC_UU_00016/4/MRC_/Medical Research Council/United Kingdom ; G1000801/MRC_/Medical Research Council/United Kingdom ; MR/N00969X/1/MRC_/Medical Research Council/United Kingdom ; 759366/ERC_/European Research Council/International ; MC_UU_12009/4/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; },
mesh = {Animals ; Cell Differentiation/genetics ; Ectopic Gene Expression ; Embryonic Stem Cells/cytology/metabolism ; Female ; *Gene Expression Regulation, Developmental ; Gene Silencing ; Genetic Loci ; Male ; Mice ; Models, Biological ; Promoter Regions, Genetic ; RNA, Long Noncoding/*genetics ; Sequence Inversion ; Transcription, Genetic ; *X Chromosome Inactivation ; },
abstract = {The mouse X-inactivation center (Xic) locus represents a powerful model for understanding the links between genome architecture and gene regulation, with the non-coding genes Xist and Tsix showing opposite developmental expression patterns while being organized as an overlapping sense/antisense unit. The Xic is organized into two topologically associating domains (TADs) but the role of this architecture in orchestrating cis-regulatory information remains elusive. To explore this, we generated genomic inversions that swap the Xist/Tsix transcriptional unit and place their promoters in each other's TAD. We found that this led to a switch in their expression dynamics: Xist became precociously and ectopically upregulated, both in male and female pluripotent cells, while Tsix expression aberrantly persisted during differentiation. The topological partitioning of the Xic is thus critical to ensure proper developmental timing of X inactivation. Our study illustrates how the genomic architecture of cis-regulatory landscapes can affect the regulation of mammalian developmental processes.},
}
@article {pmid31133702,
year = {2019},
author = {Redolfi, J and Zhan, Y and Valdes-Quezada, C and Kryzhanovska, M and Guerreiro, I and Iesmantavicius, V and Pollex, T and Grand, RS and Mulugeta, E and Kind, J and Tiana, G and Smallwood, SA and de Laat, W and Giorgetti, L},
title = {DamC reveals principles of chromatin folding in vivo without crosslinking and ligation.},
journal = {Nature structural &amp; molecular biology},
volume = {26},
number = {6},
pages = {471-480},
pmid = {31133702},
issn = {1545-9985},
support = {678423/ERC_/European Research Council/International ; },
mesh = {Animals ; Bacterial Proteins/metabolism ; CCCTC-Binding Factor/*metabolism ; Cell Line ; Chromatin/chemistry/*metabolism ; Chromosomes/chemistry/metabolism ; *DNA Methylation ; Mice ; Mouse Embryonic Stem Cells/chemistry/metabolism ; Nucleic Acid Conformation ; Recombinant Fusion Proteins/metabolism ; Site-Specific DNA-Methyltransferase (Adenine-Specific)/*metabolism ; },
abstract = {Current understanding of chromosome folding is largely reliant on chromosome conformation capture (3C)-based experiments, where chromosomal interactions are detected as ligation products after chromatin crosslinking. To measure chromosome structure in vivo, quantitatively and without crosslinking and ligation, we implemented a modified version of DNA adenine methyltransferase identification (DamID) named DamC, which combines DNA methylation-based detection of chromosomal interactions with next-generation sequencing and biophysical modeling of methylation kinetics. DamC performed in mouse embryonic stem cells provides the first in vivo validation of the existence of topologically associating domains (TADs), CTCF loops and confirms 3C-based measurements of the scaling of contact probabilities. Combining DamC with transposon-mediated genomic engineering shows that new loops can be formed between ectopic and endogenous CTCF sites, which redistributes physical interactions within TADs. DamC provides the first crosslinking- and ligation-free demonstration of the existence of key structural features of chromosomes and provides novel insights into how chromosome structure within TADs can be manipulated.},
}
@article {pmid31125724,
year = {2019},
author = {Bompadre, O and Andrey, G},
title = {Chromatin topology in development and disease.},
journal = {Current opinion in genetics &amp; development},
volume = {55},
number = {},
pages = {32-38},
doi = {10.1016/j.gde.2019.04.007},
pmid = {31125724},
issn = {1879-0380},
mesh = {Animals ; Chromatin Assembly and Disassembly/*genetics ; Chromosomes/*genetics ; Enhancer Elements, Genetic ; *Gene Expression Regulation ; *Genetic Predisposition to Disease ; Humans ; Promoter Regions, Genetic ; },
abstract = {The discovery of domains of preferential interaction or Topologically Associating Domains (TADs) has provided a framework to understand the relation between enhancers and promoters within intricate regulatory landscapes. It has also enabled the conceptualization of the effect of non-coding structural variants on TADs structure and insulation and reveal new patho-mechanisms leading to disease. Here, we will review current knowledge on enhancer-promoter communication in relation to TAD structure. In particular, we will discuss how enhancer-promoter interaction dynamics is established within or outside of TADs. We will further provide an overview of how mutations affect the normal organization of the genome and how it impacts the normal ability of enhancers to induce transcription at their cognate promoters in disease. Finally, we will discuss the future directions to be explored to understand the mutual influences between 3D chromatin topology and gene regulation.},
}
@article {pmid31118510,
year = {2019},
author = {Borsos, M and Perricone, SM and Schauer, T and Pontabry, J and de Luca, KL and de Vries, SS and Ruiz-Morales, ER and Torres-Padilla, ME and Kind, J},
title = {Genome-lamina interactions are established de novo in the early mouse embryo.},
journal = {Nature},
volume = {569},
number = {7758},
pages = {729-733},
pmid = {31118510},
issn = {1476-4687},
support = {678423/ERC_/European Research Council/International ; },
mesh = {Animals ; *Chromosome Positioning ; DNA-Binding Proteins/metabolism ; Embryo, Mammalian/*cytology/embryology/*metabolism ; Embryonic Development ; Female ; Fertilization ; Genome/*physiology ; Jumonji Domain-Containing Histone Demethylases/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Nuclear Lamina/*metabolism ; Oocytes/cytology/metabolism ; Zygote/cytology/metabolism ; },
abstract = {In mammals, the emergence of totipotency after fertilization involves extensive rearrangements of the spatial positioning of the genome[1,2]. However, the contribution of spatial genome organization to the regulation of developmental programs is unclear[3]. Here we generate high-resolution maps of genomic interactions with the nuclear lamina (a filamentous meshwork that lines the inner nuclear membrane) in mouse pre-implantation embryos. We reveal that nuclear organization is not inherited from the maternal germline but is instead established de novo shortly after fertilization. The two parental genomes establish lamina-associated domains (LADs)[4] with different features that converge after the 8-cell stage. We find that the mechanism of LAD establishment is unrelated to DNA replication. Instead, we show that paternal LAD formation in zygotes is prevented by ectopic expression of Kdm5b, which suggests that LAD establishment may be dependent on remodelling of H3K4 methylation. Our data suggest a step-wise assembly model whereby early LAD formation precedes consolidation of topologically associating domains.},
}
@article {pmid31110352,
year = {2019},
author = {Dellino, GI and Palluzzi, F and Chiariello, AM and Piccioni, R and Bianco, S and Furia, L and De Conti, G and Bouwman, BAM and Melloni, G and Guido, D and Giacò, L and Luzi, L and Cittaro, D and Faretta, M and Nicodemi, M and Crosetto, N and Pelicci, PG},
title = {Release of paused RNA polymerase II at specific loci favors DNA double-strand-break formation and promotes cancer translocations.},
journal = {Nature genetics},
volume = {51},
number = {6},
pages = {1011-1023},
doi = {10.1038/s41588-019-0421-z},
pmid = {31110352},
issn = {1546-1718},
mesh = {Animals ; Cell Line, Tumor ; Cells, Cultured ; *DNA Breaks, Double-Stranded ; DNA Repair ; Enhancer Elements, Genetic ; Etoposide/pharmacology ; Flow Cytometry ; Fluorescent Antibody Technique ; Gene Expression Regulation, Neoplastic/drug effects ; *Genetic Loci ; Genomics/methods ; Introns ; Neoplasms/*genetics/*metabolism/pathology ; Promoter Regions, Genetic ; RNA Polymerase II/*metabolism ; RNA Splice Sites ; Topoisomerase Inhibitors/pharmacology ; Transcription Initiation Site ; },
abstract = {It is not clear how spontaneous DNA double-strand breaks (DSBs) form and are processed in normal cells, and whether they predispose to cancer-associated translocations. We show that DSBs in normal mammary cells form upon release of paused RNA polymerase II (Pol II) at promoters, 5' splice sites and active enhancers, and are processed by end-joining in the absence of a canonical DNA-damage response. Logistic and causal-association models showed that Pol II pausing at long genes is the main predictor and determinant of DSBs. Damaged introns with paused Pol II-pS5, TOP2B and XRCC4 are enriched in translocation breakpoints, and map at topologically associating domain boundary-flanking regions showing high interaction frequencies with distal loci. Thus, in unperturbed growth conditions, release of paused Pol II at specific loci and chromatin territories favors DSB formation, leading to chromosomal translocations.},
}
@article {pmid31084607,
year = {2019},
author = {Lesage, A and Dahirel, V and Victor, JM and Barbi, M},
title = {Polymer coil-globule phase transition is a universal folding principle of Drosophila epigenetic domains.},
journal = {Epigenetics &amp; chromatin},
volume = {12},
number = {1},
pages = {28},
pmid = {31084607},
issn = {1756-8935},
mesh = {Animals ; Chromatin/metabolism/physiology ; Chromatin Assembly and Disassembly/genetics/physiology ; Drosophila Proteins/genetics ; Drosophila melanogaster/genetics ; Epigenesis, Genetic/genetics ; Epigenomics/*methods ; Models, Statistical ; Models, Theoretical ; Physical Chromosome Mapping/*methods ; Polymers ; },
abstract = {BACKGROUND: Localized functional domains within chromosomes, known as topologically associating domains (TADs), have been recently highlighted. In Drosophila, TADs are biochemically defined by epigenetic marks, this suggesting that the 3D arrangement may be the "missing link" between epigenetics and gene activity. Recent observations (Boettiger et al. in Nature 529(7586):418-422, 2016) provide access to structural features of these domains with unprecedented resolution thanks to super-resolution experiments. In particular, they give access to the distribution of the radii of gyration for domains of different linear length and associated with different transcriptional activity states: active, inactive or repressed. Intriguingly, the observed scaling laws lack consistent interpretation in polymer physics.<br><br>RESULTS: We develop a new methodology conceived to extract the best information from such super-resolution data by exploiting the whole distribution of gyration radii, and to place these experimental results on a theoretical framework. We show that the experimental data are compatible with the finite-size behavior of a self-attracting polymer. The same generic polymer model leads to quantitative differences between active, inactive and repressed domains. Active domains behave as pure polymer coils, while inactive and repressed domains both lie at the coil-globule crossover. For the first time, the "color-specificity" of both&#xa0;the persistence length and the mean interaction energy are estimated, leading to important differences between epigenetic states.<br><br>CONCLUSION: These results point toward a crucial role of criticality to enhance the system responsivity, resulting in both energy transitions&#xa0;and structural rearrangements. We get strong indications that epigenetically induced changes in nucleosome-nucleosome interaction can cause chromatin to shift between different activity states.},
}
@article {pmid31056477,
year = {2019},
author = {Battle, SL and Doni Jayavelu, N and Azad, RN and Hesson, J and Ahmed, FN and Overbey, EG and Zoller, JA and Mathieu, J and Ruohola-Baker, H and Ware, CB and Hawkins, RD},
title = {Enhancer Chromatin and 3D Genome Architecture Changes from Naive to Primed Human Embryonic Stem Cell States.},
journal = {Stem cell reports},
volume = {12},
number = {5},
pages = {1129-1144},
pmid = {31056477},
issn = {2213-6711},
support = {T32 GM095421/GM/NIGMS NIH HHS/United States ; T32 LM012419/LM/NLM NIH HHS/United States ; R01 DK103667/DK/NIDDK NIH HHS/United States ; R01 AR065952/AR/NIAMS NIH HHS/United States ; P30 DK017047/DK/NIDDK NIH HHS/United States ; },
mesh = {Animals ; Blastocyst/cytology/*metabolism ; Cell Differentiation/genetics ; Chromatin/*genetics ; Embryo, Mammalian/cytology/embryology/metabolism ; Embryonic Development/genetics ; Enhancer Elements, Genetic/*genetics ; Gene Expression Regulation, Developmental ; Germ Layers/cytology/*metabolism ; Human Embryonic Stem Cells/cytology/*metabolism ; Humans ; },
abstract = {During mammalian embryogenesis, changes in morphology and gene expression are concurrent with epigenomic reprogramming. Using human embryonic stem cells representing the preimplantation blastocyst (naive) and postimplantation epiblast (primed), our data in 2iL/I/F naive cells demonstrate that a substantial portion of known human enhancers are premarked by H3K4me1, providing an enhanced open chromatin state in naive pluripotency. The 2iL/I/F enhancer repertoire occupies 9% of the genome, three times that of primed cells, and can exist in broad chromatin domains over 50 kb. Enhancer chromatin states are largely poised. Seventy-seven percent of 2iL/I/F enhancers are decommissioned in a stepwise manner as cells become primed. While primed topologically associating domains are largely unaltered upon differentiation, naive 2iL/I/F domains expand across primed boundaries, affecting three-dimensional genome architecture. Differential topologically associating domain edges coincide with 2iL/I/F H3K4me1 enrichment. Our results suggest that naive-derived 2iL/I/F cells have a unique chromatin landscape, which may reflect early embryogenesis.},
}
@article {pmid31048460,
year = {2019},
author = {Delaneau, O and Zazhytska, M and Borel, C and Giannuzzi, G and Rey, G and Howald, C and Kumar, S and Ongen, H and Popadin, K and Marbach, D and Ambrosini, G and Bielser, D and Hacker, D and Romano, L and Ribaux, P and Wiederkehr, M and Falconnet, E and Bucher, P and Bergmann, S and Antonarakis, SE and Reymond, A and Dermitzakis, ET},
title = {Chromatin three-dimensional interactions mediate genetic effects on gene expression.},
journal = {Science (New York, N.Y.)},
volume = {364},
number = {6439},
pages = {},
doi = {10.1126/science.aat8266},
pmid = {31048460},
issn = {1095-9203},
support = {//European Research Council/International ; },
mesh = {Chromatin/chemistry/*metabolism ; *Gene Expression Regulation ; Genetic Variation ; Genome, Human ; Humans ; Quantitative Trait Loci ; Regulatory Elements, Transcriptional ; },
abstract = {Studying the genetic basis of gene expression and chromatin organization is key to characterizing the effect of genetic variability on the function and structure of the human genome. Here we unravel how genetic variation perturbs gene regulation using a dataset combining activity of regulatory elements, gene expression, and genetic variants across 317 individuals and two cell types. We show that variability in regulatory activity is structured at the intra- and interchromosomal levels within 12,583 cis-regulatory domains and 30 trans-regulatory hubs that highly reflect the local (that is, topologically associating domains) and global (that is, open and closed chromatin compartments) nuclear chromatin organization. These structures delimit cell type-specific regulatory networks that control gene expression and coexpression and mediate the genetic effects of cis- and trans-acting regulatory variants on genes.},
}
@article {pmid31039743,
year = {2019},
author = {Yu, J and Hu, M and Li, C},
title = {Joint analyses of multi-tissue Hi-C and eQTL data demonstrate close spatial proximity between eQTLs and their target genes.},
journal = {BMC genetics},
volume = {20},
number = {1},
pages = {43},
pmid = {31039743},
issn = {1471-2156},
support = {U54 DK107977/DK/NIDDK NIH HHS/United States ; },
mesh = {Chromatin/*genetics ; *Gene Expression Regulation ; Genome-Wide Association Study ; *High-Throughput Nucleotide Sequencing ; Humans ; Odds Ratio ; Polymorphism, Single Nucleotide ; *Quantitative Trait Loci ; },
abstract = {BACKGROUND: Gene regulation is important for cells and tissues to function. It has been studied from two aspects at the genomic level, the identification of expression quantitative trait loci (eQTLs) and identification of long-range chromatin interactions. It is important to understand their relationship, such as whether eQTLs regulate their target genes through physical chromatin interaction. Although chromatin interactions have been widely believed to be one of the main mechanisms underlying eQTLs, most evidence came from studies of cell lines and yet no direct evidence exists for tissues.<br><br>RESULTS: We performed various joint analyses of eQTL and high-throughput chromatin conformation capture (Hi-C) data from 11 human primary tissue types and 2 human cell lines. We found that chromatin interaction frequency is positively associated with the number of genes that have eQTLs and that eQTLs and their target genes tend to fall into the same topologically associating domain (TAD). These results are consistent across all tissues and cell lines we evaluated. Moreover, in 6 out of 11 tissues (aorta, dorsolateral prefrontal cortex, hippocampus, pancreas, small bowel, and spleen), tissue-specific eQTLs are significantly enriched in tissue-specific frequently interacting regions (FIREs).<br><br>CONCLUSIONS: Our data have demonstrated the close spatial proximity between eQTLs and their target genes among multiple human primary tissues.},
}
@article {pmid31032382,
year = {2019},
author = {Majumder, K and Boftsi, M and Pintel, DJ},
title = {Viral Chromosome Conformation Capture (V3C) Assays for Identifying Trans-interaction Sites between Lytic Viruses and the Cellular Genome.},
journal = {Bio-protocol},
volume = {9},
number = {6},
pages = {},
pmid = {31032382},
issn = {2331-8325},
support = {F32 AI131468/AI/NIAID NIH HHS/United States ; R01 AI046458/AI/NIAID NIH HHS/United States ; R01 AI116595/AI/NIAID NIH HHS/United States ; R56 AI046458/AI/NIAID NIH HHS/United States ; },
abstract = {The folding mechanisms of the mammalian genome package our genetic material into the nucleus, and in doing so, dictate its appropriate replication and expression. Chromosome conformation capture technology has enabled the dissection of the folding principles of the cellular genome. This has led to a better understanding of the role played by architectural proteins in forming and dissolving 3D-chromatin-structure. These assays are based on the principle of crosslinking distant cellular sites that are proximal to each other in 3D space using formaldehyde followed by digestion of formed hybrid DNA junctions. Invading viruses, such as the lytic parvovirus Minute Virus of Mice (MVM), establish distinct replication centers within the nuclear environment at cellular sites that preferentially undergo DNA damage, but do not integrate into the cellular DNA. We have adapted chromosome conformation capture technology to study the trans-interaction between MVM and the cellular genome, which we have dubbed V3C, which can be extended to a whole-genome analysis we term V3C-seq. This protocol describes the procedure for performing, as well as analyzing V3C-seq assays, and can be adapted for mapping the cellular interaction sites of any non-integrating DNA virus.},
}
@article {pmid31022553,
year = {2019},
author = {Liu, G and Dean, A},
title = {Enhancer long-range contacts: The multi-adaptor protein LDB1 is the tie that binds.},
journal = {Biochimica et biophysica acta. Gene regulatory mechanisms},
volume = {1862},
number = {6},
pages = {625-633},
doi = {10.1016/j.bbagrm.2019.04.003},
pmid = {31022553},
issn = {1876-4320},
mesh = {Adaptor Proteins, Signal Transducing/*metabolism ; Animals ; Caenorhabditis elegans ; Cell Differentiation ; Chromatin ; DNA-Binding Proteins/genetics/*metabolism ; *Enhancer Elements, Genetic ; Gene Expression ; Humans ; LIM Domain Proteins/genetics/*metabolism ; Models, Molecular ; Neurogenesis ; Nuclear Proteins/metabolism ; Organogenesis ; Promoter Regions, Genetic ; Protein Domains/physiology ; Protein Interaction Domains and Motifs ; Transcription Factors/genetics/*metabolism ; Transcriptome ; },
abstract = {The eukaryotic genome is organized at varying levels into chromosome territories, transcriptional compartments and topologically associating domains (TADs), which are architectural features largely shared between different cell types and across species. In contrast, within TADs, chromatin loops connect enhancers and their target genes to establish unique transcriptomes that distinguish cells and tissues from each other and underlie development and differentiation. How these tissue-specific and temporal stage-specific long-range contacts are formed and maintained is a fundamental question in biology. The widely expressed Lim domain binding 1 protein, LDB1, plays a critical role in connecting enhancers and genes by forming complexes with cell-type specificity across diverse developmental pathways including neurogenesis, cardiogenesis, retinogenesis and hematopoiesis. Here we review the multiple roles of LDB1 in cell fate determination and in chromatin loop formation, with an emphasis on mammalian systems, to illuminate how LDB1 functions in normal cells and in diseases such as cancer.},
}
@article {pmid31011212,
year = {2019},
author = {Paulsen, J and Liyakat Ali, TM and Nekrasov, M and Delbarre, E and Baudement, MO and Kurscheid, S and Tremethick, D and Collas, P},
title = {Long-range interactions between topologically associating domains shape the four-dimensional genome during differentiation.},
journal = {Nature genetics},
volume = {51},
number = {5},
pages = {835-843},
doi = {10.1038/s41588-019-0392-0},
pmid = {31011212},
issn = {1546-1718},
mesh = {Adipogenesis/genetics ; Animals ; Cell Differentiation/*genetics ; Cell Lineage/genetics ; Chromatin/*genetics/ultrastructure ; Chromatin Assembly and Disassembly ; Gene Expression ; Genome ; Genome, Human ; Humans ; Mice ; Models, Genetic ; Mouse Embryonic Stem Cells/cytology ; Neural Stem Cells/cytology ; Neurogenesis/genetics ; Nuclear Lamina/genetics ; Stem Cells/cytology ; },
abstract = {Genomic information is selectively used to direct spatial and temporal gene expression during differentiation. Interactions between topologically associating domains (TADs) and between chromatin and the nuclear lamina organize and position chromosomes in the nucleus. However, how these genomic organizers together shape genome architecture is unclear. Here, using a dual-lineage differentiation system, we report long-range TAD-TAD interactions that form constitutive and variable TAD cliques. A differentiation-coupled relationship between TAD cliques and lamina-associated domains suggests that TAD cliques stabilize heterochromatin at the nuclear periphery. We also provide evidence of dynamic TAD cliques during mouse embryonic stem-cell differentiation and somatic cell reprogramming and of inter-TAD associations in single-cell high-resolution chromosome conformation capture (Hi-C) data. TAD cliques represent a level of four-dimensional genome conformation that reinforces the silencing of repressed developmental genes.},
}
@article {pmid31001319,
year = {2019},
author = {Ma, CY and Madden, P and Gontarz, P and Wang, T and Zhang, B},
title = {FeatSNP: An Interactive Database for Brain-Specific Epigenetic Annotation of Human SNPs.},
journal = {Frontiers in genetics},
volume = {10},
number = {},
pages = {262},
pmid = {31001319},
issn = {1664-8021},
support = {U01 HG009391/HG/NHGRI NIH HHS/United States ; R01 HG007175/HG/NHGRI NIH HHS/United States ; U01 CA200060/CA/NCI NIH HHS/United States ; R25 DA027995/DA/NIDA NIH HHS/United States ; U24 ES026699/ES/NIEHS NIH HHS/United States ; R01 HG007354/HG/NHGRI NIH HHS/United States ; },
abstract = {FeatSNP is an online tool and a curated database for exploring 81 million common SNPs' potential functional impact on the human brain. FeatSNP uses the brain transcriptomes of the human population to improve functional annotation of human SNPs by integrating transcription factor binding prediction, public eQTL information, and brain specific epigenetic landscape, as well as information of Topologically Associating Domains (TADs). FeatSNP supports both single and batched SNP searching, and its interactive user interface enables users to explore the functional annotations and generate publication-quality visualization results. FeatSNP is freely available on the internet at FeatSNP.org with all major web browsers supported.},
}
@article {pmid30989119,
year = {2019},
author = {Szabo, Q and Bantignies, F and Cavalli, G},
title = {Principles of genome folding into topologically associating domains.},
journal = {Science advances},
volume = {5},
number = {4},
pages = {eaaw1668},
pmid = {30989119},
issn = {2375-2548},
mesh = {Animals ; Chromatin Assembly and Disassembly/*genetics ; Chromosomes/*chemistry/*genetics ; *Epigenomics ; *Genome ; Humans ; },
abstract = {Understanding the mechanisms that underlie chromosome folding within cell nuclei is essential to determine the relationship between genome structure and function. The recent application of "chromosome conformation capture" techniques has revealed that the genome of many species is organized into domains of preferential internal chromatin interactions called "topologically associating domains" (TADs). This chromosome chromosome folding has emerged as a key feature of higher-order genome organization and function through evolution. Although TADs have now been described in a wide range of organisms, they appear to have specific characteristics in terms of size, structure, and proteins involved in their formation. Here, we depict the main features of these domains across species and discuss the relation between chromatin structure, genome activity, and epigenome, highlighting mechanistic principles of TAD formation. We also consider the potential influence of TADs in genome evolution.},
}
@article {pmid30985763,
year = {2019},
author = {Luo, H and Sobh, A and Vulpe, CD and Brewer, E and Dovat, S and Qiu, Y and Huang, S},
title = {HOX Loci Focused CRISPR/sgRNA Library Screening Identifying Critical CTCF Boundaries.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {145},
pages = {},
pmid = {30985763},
issn = {1940-087X},
support = {R01 CA204044/CA/NCI NIH HHS/United States ; R01 DK110108/DK/NIDDK NIH HHS/United States ; R01 HL141950/HL/NHLBI NIH HHS/United States ; },
mesh = {Animals ; Binding Sites ; CCCTC-Binding Factor/*metabolism ; Chromatin ; *Clustered Regularly Interspaced Short Palindromic Repeats ; DNA ; Gene Expression Regulation ; Gene Library ; *Genes, Homeobox ; Humans ; RNA, Guide, Kinetoplastida ; },
abstract = {CCCTC-binding factor (CTCF)-mediated stable topologically associating domains (TADs) play a critical role in constraining interactions of DNA elements that are located in neighboring TADs. CTCF plays an important role in regulating the spatial and temporal expression of HOX genes that control embryonic development, body patterning, hematopoiesis, and leukemogenesis. However, it remains largely unknown whether and how HOX loci associated CTCF boundaries regulate chromatin organization and HOX gene expression. In the current protocol, a specific sgRNA pooled library targeting all CTCF binding sites in the HOXA/B/C/D loci has been generated to examine the effects of disrupting CTCF-associated chromatin boundaries on TAD formation and HOX gene expression. Through CRISPR-Cas9 genetic screening, the CTCF binding site located between HOXA7/HOXA9 genes (CBS7/9) has been identified as a critical regulator of oncogenic chromatin domain, as well as being important for maintaining ectopic HOX gene expression patterns in MLL-rearranged acute myeloid leukemia (AML). Thus, this sgRNA library screening approach provides novel insights into CTCF mediated genome organization in specific gene loci and also provides a basis for the functional characterization of the annotated genetic regulatory elements, both coding and noncoding, during normal biological processes in the post-human genome project era.},
}
@article {pmid30982769,
year = {2019},
author = {Laugsch, M and Bartusel, M and Rehimi, R and Alirzayeva, H and Karaolidou, A and Crispatzu, G and Zentis, P and Nikolic, M and Bleckwehl, T and Kolovos, P and van Ijcken, WFJ and Šarić, T and Koehler, K and Frommolt, P and Lachlan, K and Baptista, J and Rada-Iglesias, A},
title = {Modeling the Pathological Long-Range Regulatory Effects of Human Structural Variation with Patient-Specific hiPSCs.},
journal = {Cell stem cell},
volume = {24},
number = {5},
pages = {736-752.e12},
doi = {10.1016/j.stem.2019.03.004},
pmid = {30982769},
issn = {1875-9777},
mesh = {Adolescent ; Alleles ; Animals ; Branchio-Oto-Renal Syndrome/*genetics ; Cell Differentiation ; Cell Proliferation ; Cells, Cultured ; Enhancer Elements, Genetic/genetics ; Genomic Structural Variation/*genetics ; Haploinsufficiency ; Humans ; Male ; Mice ; Mutation/*genetics ; Neural Crest/*physiology ; Single-Cell Analysis ; Transcription Factor AP-2/genetics/*metabolism ; },
abstract = {The pathological consequences of structural variants disrupting 3D genome organization can be difficult to elucidate in vivo due to differences in gene dosage sensitivity between mice and humans. This is illustrated by branchiooculofacial syndrome (BOFS), a rare congenital disorder caused by heterozygous mutations within TFAP2A, a neural crest regulator for which humans, but not mice, are haploinsufficient. Here, we present a BOFS patient carrying a heterozygous inversion with one breakpoint located within a topologically associating domain (TAD) containing enhancers essential for TFAP2A expression in human neural crest cells (hNCCs). Using patient-specific hiPSCs, we show that, although the inversion shuffles the TFAP2A hNCC enhancers with novel genes within the same TAD, this does not result in enhancer adoption. Instead, the inversion disconnects one TFAP2A allele from its cognate enhancers, leading to monoallelic and haploinsufficient TFAP2A expression in patient hNCCs. Our work illustrates the power of hiPSC differentiation to unveil long-range pathomechanisms.},
}
@article {pmid30944321,
year = {2019},
author = {Yang, M and Vesterlund, M and Siavelis, I and Moura-Castro, LH and Castor, A and Fioretos, T and Jafari, R and Lilljebjörn, H and Odom, DT and Olsson, L and Ravi, N and Woodward, EL and Harewood, L and Lehtiö, J and Paulsson, K},
title = {Proteogenomics and Hi-C reveal transcriptional dysregulation in high hyperdiploid childhood acute lymphoblastic leukemia.},
journal = {Nature communications},
volume = {10},
number = {1},
pages = {1519},
pmid = {30944321},
issn = {2041-1723},
mesh = {Adolescent ; Aneuploidy ; CCCTC-Binding Factor/genetics ; Cell Cycle Proteins/genetics ; Child ; Child, Preschool ; Chromatin/genetics ; Chromosomal Proteins, Non-Histone/genetics ; Chromosome Aberrations ; Core Binding Factor Alpha 2 Subunit/genetics ; Female ; Gene Dosage ; Gene Expression Profiling ; *Gene Expression Regulation, Leukemic ; Genome, Human ; Genome-Wide Association Study ; Humans ; Infant ; Infant, Newborn ; Male ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*genetics ; Proteogenomics/methods ; Proteome/genetics ; Proto-Oncogene Proteins c-ets/genetics ; Repressor Proteins/genetics ; Sequence Analysis, RNA ; *Transcription, Genetic ; },
abstract = {Hyperdiploidy, i.e. gain of whole chromosomes, is one of the most common genetic features of childhood acute lymphoblastic leukemia (ALL), but its pathogenetic impact is poorly understood. Here, we report a proteogenomic analysis on matched datasets from genomic profiling, RNA-sequencing, and mass spectrometry-based analysis of >8,000 genes and proteins as well as Hi-C of primary patient samples from hyperdiploid and ETV6/RUNX1-positive pediatric ALL. We show that CTCF and cohesin, which are master regulators of chromatin architecture, display low expression in hyperdiploid ALL. In line with this, a general genome-wide dysregulation of gene expression in relation to topologically associating domain (TAD) borders were seen in the hyperdiploid group. Furthermore, Hi-C of a limited number of hyperdiploid childhood ALL cases revealed that 2/4 cases displayed a clear loss of TAD boundary strength and 3/4 showed reduced insulation at TAD borders, with putative leukemogenic effects.},
}
@article {pmid30941409,
year = {2019},
author = {Ye, Y and Gao, L and Zhang, S},
title = {MSTD: an efficient method for detecting multi-scale topological domains from symmetric and asymmetric 3D genomic maps.},
journal = {Nucleic acids research},
volume = {47},
number = {11},
pages = {e65},
pmid = {30941409},
issn = {1362-4962},
mesh = {*Algorithms ; Animals ; Binding Sites ; Blood Cells/cytology ; Cells, Cultured ; Chromatin ; Chromosome Mapping/*methods ; Computational Biology/*methods ; Enhancer Elements, Genetic ; Epigenesis, Genetic ; Genomics/*methods ; Humans ; Mice ; Polymorphism, Single Nucleotide ; *Promoter Regions, Genetic ; },
abstract = {The chromosome conformation capture (3C) technique and its variants have been employed to reveal the existence of a hierarchy of structures in three-dimensional (3D) chromosomal architecture, including compartments, topologically associating domains (TADs), sub-TADs and chromatin loops. However, existing methods for domain detection were only designed based on symmetric Hi-C maps, ignoring long-range interaction structures between domains. To this end, we proposed a generic and efficient method to identify multi-scale topological domains (MSTD), including cis- and trans-interacting regions, from a variety of 3D genomic datasets. We first applied MSTD to detect promoter-anchored interaction domains (PADs) from promoter capture Hi-C datasets across 17 primary blood cell types. The boundaries of PADs are significantly enriched with one or the combination of multiple epigenetic factors. Moreover, PADs between functionally similar cell types are significantly conserved in terms of domain regions and expression states. Cell type-specific PADs involve in distinct cell type-specific activities and regulatory events by dynamic interactions within them. We also employed MSTD to define multi-scale domains from typical symmetric Hi-C datasets and illustrated its distinct superiority to the-state-of-art methods in terms of accuracy, flexibility and efficiency.},
}
@article {pmid30909073,
year = {2019},
author = {Braun, R and Ronquist, S and Wangsa, D and Chen, H and Anthuber, L and Gemoll, T and Wangsa, D and Koparde, V and Hunn, C and Habermann, JK and Heselmeyer-Haddad, K and Rajapakse, I and Ried, T},
title = {Single Chromosome Aneuploidy Induces Genome-Wide Perturbation of Nuclear Organization and Gene Expression.},
journal = {Neoplasia (New York, N.Y.)},
volume = {21},
number = {4},
pages = {401-412},
pmid = {30909073},
issn = {1476-5586},
mesh = {*Aneuploidy ; Cell Line, Tumor ; Cell Nucleus/*genetics/metabolism ; Cell Transformation, Neoplastic ; Chromosome Aberrations ; Chromosome Mapping ; *Gene Expression ; Gene Expression Regulation, Neoplastic ; *Genome-Wide Association Study ; Genomics/methods ; Humans ; In Situ Hybridization, Fluorescence ; },
abstract = {Chromosomal aneuploidy is a defining feature of carcinomas and results in tumor-entity specific genomic imbalances. For instance, most sporadic colorectal carcinomas carry extra copies of chromosome 7, an aneuploidy that emerges already in premalignant adenomas, and is maintained throughout tumor progression and in derived cell lines. A comprehensive understanding on how chromosomal aneuploidy affects nuclear organization and gene expression, i.e., the nucleome, remains elusive. We now analyzed a cell line established from healthy colon mucosa with a normal karyotype (46,XY) and its isogenic derived cell line that acquired an extra copy of chromosome 7 as its sole anomaly (47,XY,+7). We studied structure/function relationships consequent to aneuploidization using genome-wide chromosome conformation capture (Hi-C), RNA sequencing and protein profiling. The gain of chromosome 7 resulted in an increase of transcript levels of resident genes as well as genome-wide gene and protein expression changes. The Hi-C analysis showed that the extra copy of chromosome 7 is reflected in more interchromosomal contacts between the triploid chromosomes. Chromatin organization changes are observed genome-wide, as determined by changes in A/B compartmentalization and topologically associating domain (TAD) boundaries. Most notably, chromosome 4 shows a profound loss of chromatin organization, and chromosome 14 contains a large A/B compartment switch region, concurrent with resident gene expression changes. No changes to the nuclear position of the additional chromosome 7 territory were observed when measuring distances of chromosome painting probes by interphase FISH. Genome and protein data showed enrichment in signaling pathways crucial for malignant transformation, such as the HGF/MET-axis. We conclude that a specific chromosomal aneuploidy has profound impact on nuclear structure and function, both locally and genome-wide. Our study provides a benchmark for the analysis of cancer nucleomes with complex karyotypes.},
}
@article {pmid30898144,
year = {2019},
author = {Huynh, L and Hormozdiari, F},
title = {TAD fusion score: discovery and ranking the contribution of deletions to genome structure.},
journal = {Genome biology},
volume = {20},
number = {1},
pages = {60},
pmid = {30898144},
issn = {1474-760X},
mesh = {Algorithms ; *Chromatin ; Computational Biology/*methods ; Developmental Disabilities/*genetics ; *Gene Expression Regulation ; Genome, Human ; Humans ; Neoplasms/*genetics ; *Oncogene Proteins, Fusion ; *Sequence Deletion ; Software ; },
abstract = {Deletions that fuse two adjacent topologically associating domains (TADs) can cause severe developmental disorders. We provide a formal method to quantify deletions based on their potential disruption of the three-dimensional genome structure, denoted as the TAD fusion score. Furthermore, we show that deletions that cause TAD fusion are rare and under negative selection in the general population. Finally, we show that our method correctly gives higher scores to deletions reported to cause various disorders, including developmental disorders and cancer, in comparison to the deletions reported in the 1000 Genomes Project. The TAD fusion score tool is publicly available at https://github.com/HormozdiariLab/TAD-fusion-score .},
}
@article {pmid30894186,
year = {2019},
author = {Nagai, LAE and Park, SJ and Nakai, K},
title = {Analyzing the 3D chromatin organization coordinating with gene expression regulation in B-cell lymphoma.},
journal = {BMC medical genomics},
volume = {11},
number = {Suppl 7},
pages = {127},
pmid = {30894186},
issn = {1755-8794},
mesh = {Animals ; B-Lymphocytes ; *Chromatin ; Chromatin Assembly and Disassembly ; Female ; *Gene Expression Regulation, Neoplastic ; Humans ; Lymphoma, B-Cell/*genetics/ultrastructure ; Male ; Mice ; Mice, Inbred C57BL ; Mouse Embryonic Stem Cells ; Protein Domains ; },
abstract = {BACKGROUND: Eukaryotes compact chromosomes densely and non-randomly, forming three-dimensional structures. Alterations of the chromatin structures are often associated with diseases. In particular, aggressive cancer development from the disruption of the humoral immune system presents abnormal gene regulation which is accompanied by chromatin reorganizations. How the chromatin structures orchestrate the gene expression regulation is still poorly understood. Herein, we focus on chromatin dynamics in normal and abnormal B cell lymphocytes, and investigate its functional impact on the regulation of gene expression.<br><br>METHODS: We conducted an integrative analysis using publicly available multi-omics data that include Hi-C, RNA-seq and ChIP-seq experiments with normal B cells, lymphoma and ES cells. We processed and re-analyzed the data exhaustively and combined different scales of genome structures with transcriptomic and epigenetic features.<br><br>RESULTS: We found that the chromatin organizations are highly preserved among the cells. 5.2% of genes at the specific repressive compartment in normal pro-B cells were switched to the permissive compartment in lymphoma along with increased gene expression. The genes are involved in B-cell related biological processes. Remarkably, the boundaries of topologically associating domains were not enriched by CTCF motif, but significantly enriched with Prdm1 motif that is known to be the key factor of B-cell dysfunction in aggressive lymphoma.<br><br>CONCLUSIONS: This study shows evidence of a complex relationship between chromatin reorganization and gene regulation. However, an unknown mechanism may exist to restrict the structural and functional changes of genomic regions and cognate genes in a specific manner. Our findings suggest the presence of an intricate crosstalk between the higher-order chromatin structure and cancer development.},
}
@article {pmid30875678,
year = {2019},
author = {Chen, D and Lei, EP},
title = {Function and regulation of chromatin insulators in dynamic genome organization.},
journal = {Current opinion in cell biology},
volume = {58},
number = {},
pages = {61-68},
pmid = {30875678},
issn = {1879-0410},
support = {ZIA DK015602-12/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Animals ; CCCTC-Binding Factor/metabolism ; Cell Cycle Proteins/metabolism ; Chromatin/*chemistry/*genetics/metabolism ; Chromosomal Proteins, Non-Histone/metabolism ; Drosophila/genetics ; Gene Expression Regulation ; Humans ; *Insulator Elements ; Nervous System/metabolism ; Repressor Proteins/metabolism ; Transcription Factors/metabolism ; },
abstract = {Chromatin insulators are DNA-protein complexes that play a crucial role in regulating chromatin organization. Within the past two years, a plethora of genome-wide conformation capture studies have helped reveal that insulators are necessary for proper genome-wide organization of topologically associating domains, which are formed in a manner distinct from that of compartments. These studies have also provided novel insights into the mechanics of how CTCF/cohesin-dependent loops form in mammals, strongly supporting the loop extrusion model. In combination with single-cell imaging approaches in both Drosophila and mammals, the dynamics of insulator-mediated chromatin interactions are also coming to light. Insulator-dependent structures vary across individual cells and tissues, highlighting the need to study the regulation of insulators in particular temporal and spatial contexts throughout development.},
}
@article {pmid30871473,
year = {2019},
author = {Liu, T and Porter, J and Zhao, C and Zhu, H and Wang, N and Sun, Z and Mo, YY and Wang, Z},
title = {TADKB: Family classification and a knowledge base of topologically associating domains.},
journal = {BMC genomics},
volume = {20},
number = {1},
pages = {217},
pmid = {30871473},
issn = {1471-2164},
support = {R15 GM120650/GM/NIGMS NIH HHS/United States ; },
mesh = {Algorithms ; Animals ; *Chromatin Assembly and Disassembly ; *Chromosomes, Mammalian ; *Gene Expression Regulation ; *Genome ; Genomics/*methods ; Humans ; *Knowledge Bases ; Mice ; Multigene Family ; RNA, Long Noncoding ; },
abstract = {BACKGROUND: Topologically associating domains (TADs) are considered the structural and functional units of the genome. However, there is a lack of an integrated resource for TADs in the literature where researchers can obtain family classifications and detailed information about TADs.<br><br>RESULTS: We built an online knowledge base TADKB integrating knowledge for TADs in eleven&#xa0;cell types of human and mouse. For each TAD, TADKB provides the predicted three-dimensional (3D) structures of chromosomes and TADs, and detailed annotations about the protein-coding genes and long non-coding RNAs (lncRNAs) existent in each TAD. Besides the 3D chromosomal structures inferred by population Hi-C, the single-cell haplotype-resolved chromosomal 3D structures of 17 GM12878 cells are also integrated in TADKB. A user can submit query gene/lncRNA ID/sequence to search for the TAD(s) that contain(s) the query gene or lncRNA. We also classified TADs into families. To achieve that, we used the TM-scores between reconstructed 3D structures of TADs as structural similarities and the Pearson's correlation coefficients between the fold enrichment of chromatin states as functional similarities. All of the TADs in one cell type were clustered based on structural and functional similarities respectively using the spectral clustering algorithm with various predefined numbers of clusters. We have&#xa0;compared the overlapping TADs from structural and functional clusters and found that most of the TADs in the functional clusters with depleted chromatin states are clustered into one or two structural clusters. This novel finding indicates a connection between the 3D structures of TADs and their DNA functions in terms of chromatin states.<br><br>CONCLUSION: TADKB is available at http://dna.cs.miami.edu/TADKB/ .},
}
@article {pmid30865261,
year = {2019},
author = {Zhu, H and Wang, Z},
title = {SCL: a lattice-based approach to infer 3D chromosome structures from single-cell Hi-C data.},
journal = {Bioinformatics (Oxford, England)},
volume = {35},
number = {20},
pages = {3981-3988},
pmid = {30865261},
issn = {1367-4811},
support = {R15 GM120650/GM/NIGMS NIH HHS/United States ; },
mesh = {Chromatin ; *Chromosome Structures ; *Chromosomes ; DNA ; Software ; },
abstract = {MOTIVATION: In contrast to population-based Hi-C data, single-cell Hi-C data are zero-inflated and do not indicate the frequency of proximate DNA segments. There are a limited number of computational tools that can model the 3D structures of chromosomes based on single-cell Hi-C data.<br><br>RESULTS: We developed single-cell lattice (SCL), a computational method to reconstruct 3D structures of chromosomes based on single-cell Hi-C data. We designed a loss function and a 2&#x2009;D Gaussian function specifically for the characteristics of single-cell Hi-C data. A chromosome is represented as beads-on-a-string and stored in a 3&#x2009;D cubic lattice. Metropolis-Hastings simulation and simulated annealing are used to simulate the structure and minimize the loss function. We evaluated the SCL-inferred 3&#x2009;D structures (at both 500 and 50&#x2009;kb resolutions) using multiple criteria and compared them with the ones generated by another modeling software program. The results indicate that the 3&#x2009;D structures generated by SCL closely fit single-cell Hi-C data. We also found similar patterns of trans-chromosomal contact beads, Lamin-B1 enriched topologically associating domains (TADs), and H3K4me3 enriched TADs by mapping data from previous studies onto the SCL-inferred 3&#x2009;D structures.<br><br>The C++ source code of SCL is freely available at http://dna.cs.miami.edu/SCL/.<br><br>SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},
}
@article {pmid30862957,
year = {2019},
author = {Ulianov, SV and Doronin, SA and Khrameeva, EE and Kos, PI and Luzhin, AV and Starikov, SS and Galitsyna, AA and Nenasheva, VV and Ilyin, AA and Flyamer, IM and Mikhaleva, EA and Logacheva, MD and Gelfand, MS and Chertovich, AV and Gavrilov, AA and Razin, SV and Shevelyov, YY},
title = {Nuclear lamina integrity is required for proper spatial organization of chromatin in Drosophila.},
journal = {Nature communications},
volume = {10},
number = {1},
pages = {1176},
pmid = {30862957},
issn = {2041-1723},
mesh = {Animals ; Cell Line ; Chromatin/*metabolism ; Chromatin Assembly and Disassembly/*genetics ; Chromosomes, Insect/metabolism ; Down-Regulation ; Drosophila melanogaster ; Gene Expression Profiling ; Genes, Insect/genetics ; Histones/*metabolism ; In Situ Hybridization, Fluorescence ; Models, Animal ; Nuclear Lamina/*metabolism ; Up-Regulation ; },
abstract = {How the nuclear lamina (NL) impacts on global chromatin architecture is poorly understood. Here, we show that NL disruption in Drosophila S2 cells leads to chromatin compaction and repositioning from the nuclear envelope. This increases the chromatin density in a fraction of topologically-associating domains (TADs) enriched in active chromatin and enhances interactions between active and inactive chromatin. Importantly, upon NL disruption the NL-associated TADs become more acetylated at histone H3 and less compact, while background transcription is derepressed. Two-colour FISH confirms that a TAD becomes less compact following its release from the NL. Finally, polymer simulations show that chromatin binding to the NL can per se compact attached TADs. Collectively, our findings demonstrate a dual function of the NL in shaping the 3D genome. Attachment of TADs to the NL makes them more condensed but decreases the overall chromatin density in the nucleus by stretching interphase chromosomes.},
}
@article {pmid30853548,
year = {2019},
author = {Al Bkhetan, Z and Kadlof, M and Kraft, A and Plewczynski, D},
title = {Machine learning polymer models of three-dimensional chromatin organization in human lymphoblastoid cells.},
journal = {Methods (San Diego, Calif.)},
volume = {166},
number = {},
pages = {83-90},
pmid = {30853548},
issn = {1095-9130},
support = {U54 DK107967/DK/NIDDK NIH HHS/United States ; },
mesh = {Chromatin/*ultrastructure ; *Computer Simulation ; *Epigenomics ; Gene Expression Regulation/genetics ; Genome, Human ; Humans ; *Machine Learning ; Polymers/chemistry ; Promoter Regions, Genetic/genetics ; Protein Binding/genetics ; },
abstract = {We present machine learning models of human genome three-dimensional structure that combine one dimensional (linear) sequence specificity, epigenomic information, and transcription factor binding profiles, with the polymer-based biophysical simulations in order to explain the extensive long-range chromatin looping observed in ChIA-PET experiments for lymphoblastoid cells. Random Forest, Gradient Boosting Machine (GBM), and Deep Learning models were constructed and evaluated, when predicting high-resolution interactions within Topologically Associating Domains (TADs). The predicted interactions are consistent with the experimental long-read ChIA-PET interactions mediated by CTCF and RNAPOL2 for GM12878 cell line. The contribution of sequence information and chromatin state defined by epigenomic features to the prediction task is analyzed and reported, when using them separately and combined. Furthermore, we design three-dimensional models of chromatin contact domains (CCDs) using real (ChIA-PET) and predicted looping interactions. Initial results show a similarity between both types of 3D computational models (constructed from experimental or predicted interactions). This observation confirms the association between genome sequence, epigenomic and transcription factor profiles, and three-dimensional interactions.},
}
@article {pmid30810370,
year = {2019},
author = {Zaborowski, R and Wilczyński, B},
title = {BPscore: An Effective Metric for Meaningful Comparisons of Structural Chromosome Segmentations.},
journal = {Journal of computational biology : a journal of computational molecular cell biology},
volume = {26},
number = {4},
pages = {305-314},
doi = {10.1089/cmb.2018.0162},
pmid = {30810370},
issn = {1557-8666},
mesh = {Algorithms ; Chromatin/chemistry ; Chromosomes, Human/*chemistry ; Computational Biology/*methods ; Humans ; Molecular Conformation ; },
abstract = {Studying the three-dimensional structure of chromosomes is an emerging field flourishing in recent years because of rapid development of experimental approaches for studying chromosomal contacts. This has led to numerous studies providing results of segmentation of chromosome sequences of different species into so-called topologically associating domains (TADs). As the number of such studies grows steadily and many of them make claims about the perceived differences between TAD structures observed in different conditions, there is a growing need for good measures of similarity (or dissimilarity) between such segmentations. We provide here a bipartite (BP) score, which is a relatively simple distance metric based on the bipartite matching between two segmentations. In this article, we provide the rationale behind choosing specifically this function and show its results on several different data sets, both simulated and experimental. We show that not only the BP score is a proper metric satisfying the triangle inequality, but also that it is providing good granularity of scores for typical situations occurring between different TAD segmentations. We also introduce local variant of the BP metric and show that in actual comparisons between experimental data sets, the local BP score is correlating with the observed changes in gene expression and genome methylation. In summary, we consider the BP score a good foundation for analyzing the dynamics of chromosome structures. The methodology we present in this study could be used by many researchers in their ongoing analyses, making it a popular and useful tool.},
}
@article {pmid30809020,
year = {2019},
author = {Wang, C and Nanni, L and Novakovic, B and Megchelenbrink, W and Kuznetsova, T and Stunnenberg, HG and Ceri, S and Logie, C},
title = {Extensive epigenomic integration of the glucocorticoid response in primary human monocytes and in vitro derived macrophages.},
journal = {Scientific reports},
volume = {9},
number = {1},
pages = {2772},
pmid = {30809020},
issn = {2045-2322},
mesh = {Amino Acid Motifs ; Binding Sites ; Cell Differentiation ; Cells, Cultured ; Chromatin/metabolism ; Chromosomes/genetics ; Epigenesis, Genetic/*drug effects ; Glucocorticoids/*pharmacology ; HeLa Cells ; Histones/genetics/metabolism ; Humans ; Macrophages/cytology/metabolism ; Monocytes/cytology/metabolism ; Receptors, Glucocorticoid/chemistry/metabolism ; Transcription Factors/chemistry/metabolism ; Transcriptome/drug effects ; },
abstract = {Glucocorticoid receptor is a transcription factor that is ubiquitously expressed. Glucocorticoids are circadian steroids that regulate a wide range of bodily functions, including immunity. Here we report that synthetic glucocorticoids affect 1035 mRNAs in isolated healthy human blood monocytes but only 165 in the respective six day-old monocyte-derived macrophages. The majority of the glucocorticoid response in monocytes concerns genes that are dynamic upon monocyte to macrophage differentiation, whereby macrophage-like mRNA levels are often reached in monocytes within four hours of treatment. Concomitantly, over 5000 chromosomal H3K27ac regions undergo remodelling, of which 60% involve increased H3K27ac signal. We find that chromosomal glucocorticoid receptor binding sites correlate with positive but not with negative local epigenomic effects. To investigate further we assigned our data to topologically associating domains (TADs). This shows that about 10% of macrophage TADs harbour at least one GR binding site and that half of all the glucocorticoid-induced H3K27ac regions are confined to these TADs. Our analyses are therefore consistent with the notion that TADs naturally accommodate information from sets of distal glucocorticoid response elements.},
}
@article {pmid30799036,
year = {2019},
author = {Finn, EH and Pegoraro, G and Brandão, HB and Valton, AL and Oomen, ME and Dekker, J and Mirny, L and Misteli, T},
title = {Extensive Heterogeneity and Intrinsic Variation in Spatial Genome Organization.},
journal = {Cell},
volume = {176},
number = {6},
pages = {1502-1515.e10},
pmid = {30799036},
issn = {1097-4172},
support = {U54 DK107980/DK/NIDDK NIH HHS/United States ; ZIA BC010309-20/ImNIH/Intramural NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; },
mesh = {Cell Line ; Cell Nucleus/genetics ; Chromatin/*genetics ; Chromatin Assembly and Disassembly/*physiology ; Chromosomes ; Fibroblasts/physiology ; Genome/genetics ; Genome Components/genetics/*physiology ; High-Throughput Nucleotide Sequencing/methods ; Humans ; Male ; Single-Cell Analysis ; },
abstract = {Several general principles of global 3D genome organization have recently been established, including non-random positioning of chromosomes and genes in the cell nucleus, distinct chromatin compartments, and topologically associating domains (TADs). However, the extent and nature of cell-to-cell and cell-intrinsic variability in genome architecture are still poorly characterized. Here, we systematically probe heterogeneity in genome organization. High-throughput optical mapping of several hundred intra-chromosomal interactions in individual human fibroblasts demonstrates low association frequencies, which are determined by genomic distance, higher-order chromatin architecture, and chromatin environment. The structure of TADs is variable between individual cells, and inter-TAD associations are common. Furthermore, single-cell analysis reveals independent behavior of individual alleles in single nuclei. Our observations reveal extensive variability and heterogeneity in genome organization at the level of individual alleles and demonstrate the coexistence of a broad spectrum of genome configurations in a cell population.},
}
@article {pmid30795893,
year = {2019},
author = {Cardozo Gizzi, AM and Cattoni, DI and Fiche, JB and Espinola, SM and Gurgo, J and Messina, O and Houbron, C and Ogiyama, Y and Papadopoulos, GL and Cavalli, G and Lagha, M and Nollmann, M},
title = {Microscopy-Based Chromosome Conformation Capture Enables Simultaneous Visualization of Genome Organization and Transcription in Intact Organisms.},
journal = {Molecular cell},
volume = {74},
number = {1},
pages = {212-222.e5},
doi = {10.1016/j.molcel.2019.01.011},
pmid = {30795893},
issn = {1097-4164},
mesh = {Animals ; Cell Cycle/genetics ; Chromatin/*genetics/metabolism ; *Chromatin Assembly and Disassembly ; Chromosomes, Insect/*genetics ; Drosophila melanogaster/embryology/*genetics/metabolism ; Gene Expression Regulation, Developmental ; *Genome ; High-Throughput Nucleotide Sequencing/*methods ; In Situ Hybridization, Fluorescence ; Microscopy, Fluorescence/*methods ; RNA/biosynthesis/*genetics ; Single-Cell Analysis/*methods ; *Transcription, Genetic ; *Transcriptional Activation ; },
abstract = {Eukaryotic chromosomes are organized in multiple scales, from nucleosomes to chromosome territories. Recently, genome-wide methods identified an intermediate level of chromosome organization, topologically associating domains (TADs), that play key roles in transcriptional regulation. However, these methods cannot directly examine the interplay between transcriptional activation and chromosome architecture while maintaining spatial information. Here we present a multiplexed, sequential imaging approach (Hi-M) that permits simultaneous detection of chromosome organization and transcription in single nuclei. This allowed us to unveil the changes in 3D chromatin organization occurring upon transcriptional activation and homologous chromosome unpairing during awakening of the zygotic genome in intact Drosophila embryos. Excitingly, the ability of Hi-M to explore the multi-scale chromosome architecture with spatial resolution at different stages of development or during the cell cycle will be key to understanding the mechanisms and consequences of the 4D organization of the genome.},
}
@article {pmid30778237,
year = {2019},
author = {Alavattam, KG and Maezawa, S and Sakashita, A and Khoury, H and Barski, A and Kaplan, N and Namekawa, SH},
title = {Attenuated chromatin compartmentalization in meiosis and its maturation in sperm development.},
journal = {Nature structural &amp; molecular biology},
volume = {26},
number = {3},
pages = {175-184},
pmid = {30778237},
issn = {1545-9985},
support = {DP2 GM119134/GM/NIGMS NIH HHS/United States ; R01 GM098605/GM/NIGMS NIH HHS/United States ; R01 GM122776/GM/NIGMS NIH HHS/United States ; R21 ES027117/ES/NIEHS NIH HHS/United States ; },
mesh = {Animals ; Chromatin/metabolism ; Chromatin Assembly and Disassembly/*physiology ; Chromosomes/metabolism ; Interphase/physiology ; Male ; Meiosis/*physiology ; Meiotic Prophase I/physiology ; Mice ; Mice, Inbred C57BL ; Protein Domains/physiology ; Spermatids/*growth &amp; development ; Spermatocytes/*growth &amp; development ; Spermatogenesis/*physiology ; },
abstract = {Germ cells manifest a unique gene expression program and regain totipotency in the zygote. Here, we perform Hi-C analysis to examine 3D chromatin organization in male germ cells during spermatogenesis. We show that the highly compartmentalized 3D chromatin organization characteristic of interphase nuclei is attenuated in meiotic prophase. Meiotic prophase is predominated by short-range intrachromosomal interactions that represent a condensed form akin to that of mitotic chromosomes. However, unlike mitotic chromosomes, meiotic chromosomes display weak genomic compartmentalization, weak topologically associating domains, and localized point interactions in prophase. In postmeiotic round spermatids, genomic compartmentalization increases and gives rise to the strong compartmentalization seen in mature sperm. The X chromosome lacks domain organization during meiotic sex-chromosome inactivation. We propose that male meiosis occurs amid global reprogramming of 3D chromatin organization and that strengthening of chromatin compartmentalization takes place in spermiogenesis to prepare the next generation of life.},
}
@article {pmid30778236,
year = {2019},
author = {Patel, L and Kang, R and Rosenberg, SC and Qiu, Y and Raviram, R and Chee, S and Hu, R and Ren, B and Cole, F and Corbett, KD},
title = {Dynamic reorganization of the genome shapes the recombination landscape in meiotic prophase.},
journal = {Nature structural &amp; molecular biology},
volume = {26},
number = {3},
pages = {164-174},
pmid = {30778236},
issn = {1545-9985},
support = {P30 CA016672/CA/NCI NIH HHS/United States ; DP2 HD087943/HD/NICHD NIH HHS/United States ; R01 GM104141/GM/NIGMS NIH HHS/United States ; R01 GM065490/GM/NIGMS NIH HHS/United States ; T32 CA009523/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Chromatin/metabolism ; Chromosome Pairing/*genetics ; Chromosomes/metabolism ; DNA Breaks ; Genome/genetics ; Homologous Recombination/*genetics ; Male ; Meiotic Prophase I/*genetics ; Mice ; Mice, Inbred C57BL ; Spermatocytes/cytology ; Spermatogenesis/*genetics ; Synaptonemal Complex/metabolism ; },
abstract = {In meiotic prophase, chromosomes are organized into compacted loop arrays to promote homolog pairing and recombination. Here, we probe the architecture of the mouse spermatocyte genome in early and late meiotic prophase using chromosome conformation capture (Hi-C). Our data support the established loop array model of meiotic chromosomes, and infer loops averaging 0.8-1.0 megabase pairs (Mb) in early prophase and extending to 1.5-2.0 Mb in late prophase as chromosomes compact and homologs undergo synapsis. Topologically associating domains (TADs) are lost in meiotic prophase, suggesting that assembly of the meiotic chromosome axis alters the activity of chromosome-associated cohesin complexes. While TADs are lost, physically separated A and B compartments are maintained in meiotic prophase. Moreover, meiotic DNA breaks and interhomolog crossovers preferentially form in the gene-dense A compartment, revealing a role for chromatin organization in meiotic recombination. Finally, direct detection of interhomolog contacts genome-wide reveals the structural basis for homolog alignment and juxtaposition by the synaptonemal complex.},
}
@article {pmid30778195,
year = {2019},
author = {Zheng, M and Tian, SZ and Capurso, D and Kim, M and Maurya, R and Lee, B and Piecuch, E and Gong, L and Zhu, JJ and Li, Z and Wong, CH and Ngan, CY and Wang, P and Ruan, X and Wei, CL and Ruan, Y},
title = {Multiplex chromatin interactions with single-molecule precision.},
journal = {Nature},
volume = {566},
number = {7745},
pages = {558-562},
pmid = {30778195},
issn = {1476-4687},
support = {U54 DK107967/DK/NIDDK NIH HHS/United States ; UM1 HG009409/HG/NHGRI NIH HHS/United States ; },
mesh = {Animals ; Binding Sites/genetics ; Cell Line ; Chromatin/chemistry/*genetics/*metabolism ; Drosophila melanogaster/cytology/genetics ; Microfluidics/*methods/standards ; Nucleic Acid Conformation ; Promoter Regions, Genetic/genetics ; Protein Binding ; RNA Polymerase II/chemistry/metabolism ; Sequence Analysis, DNA/*methods ; Single Molecule Imaging/*methods/*standards ; Transcription, Genetic ; },
abstract = {The genomes of multicellular organisms are extensively folded into 3D chromosome territories within the nucleus[1]. Advanced 3D genome-mapping methods that combine proximity ligation and high-throughput sequencing (such as chromosome conformation capture, Hi-C)[2], and chromatin immunoprecipitation techniques (such as chromatin interaction analysis by paired-end tag sequencing, ChIA-PET)[3], have revealed topologically associating domains[4] with frequent chromatin contacts, and have identified chromatin loops mediated by specific protein factors for insulation and regulation of transcription[5-7]. However, these methods rely on pairwise proximity ligation and reflect population-level views, and thus cannot reveal the detailed nature of chromatin interactions. Although single-cell Hi-C[8] potentially overcomes this issue, this method may be limited by the sparsity of data that is inherent to current single-cell assays. Recent advances in microfluidics have opened opportunities for droplet-based genomic analysis[9] but this approach has not yet been adapted for chromatin interaction analysis. Here we describe a strategy for multiplex chromatin-interaction analysis via droplet-based and barcode-linked sequencing, which we name ChIA-Drop. We demonstrate the robustness of ChIA-Drop in capturing complex chromatin interactions with single-molecule precision, which has not been possible using methods based on population-level pairwise contacts. By applying ChIA-Drop to Drosophila cells, we show that chromatin topological structures predominantly consist of multiplex chromatin interactions with high heterogeneity; ChIA-Drop also reveals promoter-centred multivalent interactions, which provide topological insights into transcription.},
}
@article {pmid30735655,
year = {2019},
author = {Wang, Y and Wang, H and Zhang, Y and Du, Z and Si, W and Fan, S and Qin, D and Wang, M and Duan, Y and Li, L and Jiao, Y and Li, Y and Wang, Q and Shi, Q and Wu, X and Xie, W},
title = {Reprogramming of Meiotic Chromatin Architecture during Spermatogenesis.},
journal = {Molecular cell},
volume = {73},
number = {3},
pages = {547-561.e6},
doi = {10.1016/j.molcel.2018.11.019},
pmid = {30735655},
issn = {1097-4164},
mesh = {Animals ; *Cellular Reprogramming ; Chromatin/chemistry/genetics/*metabolism ; *Chromatin Assembly and Disassembly ; Gene Expression Regulation, Developmental ; HCT116 Cells ; Humans ; Macaca mulatta ; Male ; *Meiosis ; Mice, Inbred C57BL ; Mice, Knockout ; Nucleic Acid Conformation ; Pachytene Stage ; Protein Conformation ; *Spermatogenesis ; Spermatozoa/*metabolism ; Structure-Activity Relationship ; Time Factors ; Transcription, Genetic ; X Chromosome Inactivation ; },
abstract = {Chromatin organization undergoes drastic reconfiguration during gametogenesis. However, the molecular reprogramming of three-dimensional chromatin structure in this process remains poorly understood for mammals, including primates. Here, we examined three-dimensional chromatin architecture during spermatogenesis in rhesus monkey using low-input Hi-C. Interestingly, we found that topologically associating domains (TADs) undergo dissolution and reestablishment in spermatogenesis. Strikingly, pachytene spermatocytes, where synapsis occurs, are strongly depleted for TADs despite their active transcription state but uniquely show highly refined local compartments that alternate between transcribing and non-transcribing regions (refined-A/B). Importantly, such chromatin organization is conserved in mouse, where it remains largely intact upon transcription inhibition. Instead, it is attenuated in mutant spermatocytes, where the synaptonemal complex failed to be established. Intriguingly, this is accompanied by the restoration of TADs, suggesting that the synaptonemal complex may restrict TADs and promote local compartments. Thus, these data revealed extensive reprogramming of higher-order meiotic chromatin architecture during mammalian gametogenesis.},
}
@article {pmid30733374,
year = {2019},
author = {Skibbens, RV},
title = {Condensins and cohesins - one of these things is not like the other!.},
journal = {Journal of cell science},
volume = {132},
number = {3},
pages = {},
pmid = {30733374},
issn = {1477-9137},
support = {R15 GM110631/GM/NIGMS NIH HHS/United States ; },
mesh = {Adenosine Triphosphatases/genetics/*metabolism/ultrastructure ; Animals ; Cell Cycle Proteins/genetics/*metabolism/ultrastructure ; Chromatin/*metabolism/ultrastructure ; Chromosomal Proteins, Non-Histone/genetics/*metabolism/ultrastructure ; DNA/genetics/*metabolism/ultrastructure ; DNA-Binding Proteins/genetics/*metabolism/ultrastructure ; *Genome ; Interphase ; Mitosis ; Multiprotein Complexes/genetics/*metabolism/ultrastructure ; Protein Binding ; Protein Isoforms/genetics/metabolism/ultrastructure ; Saccharomyces cerevisiae/genetics/metabolism/ultrastructure ; },
abstract = {Condensins and cohesins are highly conserved complexes that tether together DNA loci within a single DNA molecule to produce DNA loops. Condensin and cohesin structures, however, are different, and the DNA loops produced by each underlie distinct cell processes. Condensin rods compact chromosomes during mitosis, with condensin I and II complexes producing spatially defined and nested looping in metazoan cells. Structurally adaptive cohesin rings produce loops, which organize the genome during interphase. Cohesin-mediated loops, termed topologically associating domains or TADs, antagonize the formation of epigenetically defined but untethered DNA volumes, termed compartments. While condensin complexes formed through cis-interactions must maintain chromatin compaction throughout mitosis, cohesins remain highly dynamic during interphase to allow for transcription-mediated responses to external cues and the execution of developmental programs. Here, I review differences in condensin and cohesin structures, and highlight recent advances regarding the intramolecular or cis-based tetherings through which condensins compact DNA during mitosis and cohesins organize the genome during interphase.},
}
@article {pmid30709849,
year = {2019},
author = {Chathoth, KT and Zabet, NR},
title = {Chromatin architecture reorganization during neuronal cell differentiation in Drosophila genome.},
journal = {Genome research},
volume = {29},
number = {4},
pages = {613-625},
pmid = {30709849},
issn = {1549-5469},
support = {//Wellcome Trust/United Kingdom ; 202012/Z/16/Z//Wellcome Trust/United Kingdom ; },
mesh = {Animals ; CCCTC-Binding Factor/metabolism ; Cell Line ; Chromatin/chemistry/*genetics ; *Chromatin Assembly and Disassembly ; DNA-Binding Proteins/metabolism ; Drosophila Proteins/metabolism ; Drosophila melanogaster ; Eye Proteins/metabolism ; *Gene Expression Regulation, Developmental ; Genome, Insect ; *Neurogenesis ; Neurons/cytology/metabolism ; Protein Binding ; RNA Polymerase II/metabolism ; },
abstract = {The organization of the genome into topologically associating domains (TADs) was shown to have a regulatory role in development and cellular function, but the mechanism involved in TAD establishment is still unclear. Here, we present the first high-resolution contact map of Drosophila neuronal cells (BG3) and identify different classes of TADs by comparing this to genome organization in embryonic cells (Kc167). We find that only some TADs are conserved in both cell lines, whereas the rest are cell-type-specific. This is supported by a change in the enrichment of architectural proteins at TAD borders, with BEAF-32 present in embryonic cells and CTCF in neuronal cells. Furthermore, we observe strong divergent transcription, together with RNA Polymerase II occupancy and an increase in DNA accessibility at the TAD borders. TAD borders that are specific to neuronal cells are enriched in enhancers controlled by neuronal-specific transcription factors. Our results suggest that TADs are dynamic across developmental stages and reflect the interplay between insulators, transcriptional states, and enhancer activities.},
}
@article {pmid30702424,
year = {2019},
author = {Zheng, Y and Ay, F and Keles, S},
title = {Generative modeling of multi-mapping reads with mHi-C advances analysis of Hi-C studies.},
journal = {eLife},
volume = {8},
number = {},
pages = {},
pmid = {30702424},
issn = {2050-084X},
support = {Institute Leadership Funds//La Jolla Institute for Allergy and Immunology/International ; R01 HG003747/HG/NHGRI NIH HHS/United States ; R21 HG009744/HG/NHGRI NIH HHS/United States ; HG009744/HG/NHGRI NIH HHS/United States ; U01 HG007019/HG/NHGRI NIH HHS/United States ; HG007019/HG/NHGRI NIH HHS/United States ; },
mesh = {Cell Line ; Chromatin/*genetics ; Computer Simulation ; Enhancer Elements, Genetic/genetics ; Genomics/*methods ; Humans ; Probability ; Promoter Regions, Genetic ; Reproducibility of Results ; },
abstract = {Current Hi-C analysis approaches are unable to account for reads that align to multiple locations, and hence underestimate biological signal from repetitive regions of genomes. We developed and validated mHi-C, a multi-read mapping strategy to probabilistically allocate Hi-C multi-reads. mHi-C exhibited superior performance over utilizing only uni-reads and heuristic approaches aimed at rescuing multi-reads on benchmarks. Specifically, mHi-C increased the sequencing depth by an average of 20% resulting in higher reproducibility of contact matrices and detected interactions across biological replicates. The impact of the multi-reads on the detection of significant interactions is influenced marginally by the relative contribution of multi-reads to the sequencing depth compared to uni-reads, cis-to-trans ratio of contacts, and the broad data quality as reflected by the proportion of mappable reads of datasets. Computational experiments highlighted that in Hi-C studies with short read lengths, mHi-C rescued multi-reads can emulate the effect of longer reads. mHi-C also revealed biologically supported bona fide promoter-enhancer interactions and topologically associating domains involving repetitive genomic regions, thereby unlocking a previously masked portion of the genome for conformation capture studies.},
}
@article {pmid30697540,
year = {2018},
author = {Chapski, DJ and Rosa-Garrido, M and Hua, N and Alber, F and Vondriska, TM},
title = {Spatial Principles of Chromatin Architecture Associated With Organ-Specific Gene Regulation.},
journal = {Frontiers in cardiovascular medicine},
volume = {5},
number = {},
pages = {186},
pmid = {30697540},
issn = {2297-055X},
support = {U54 DK107981/DK/NIDDK NIH HHS/United States ; R01 HL115238/HL/NHLBI NIH HHS/United States ; R01 HL143058/HL/NHLBI NIH HHS/United States ; R01 HL105699/HL/NHLBI NIH HHS/United States ; R01 HL129639/HL/NHLBI NIH HHS/United States ; },
abstract = {Packaging of the genome in the nucleus is a non-random process that is thought to directly contribute to cell type-specific transcriptomes, although this hypothesis remains untested. Epigenome architecture, as assayed by chromatin conformation capture techniques, such as Hi-C, has recently been described in the mammalian cardiac myocyte and found to be remodeled in the setting of heart failure. In the present study, we sought to determine whether the structural features of the epigenome are conserved between different cell types by investigating Hi-C and RNA-seq data from heart and liver. Investigation of genes with enriched expression in heart or liver revealed nuanced interaction paradigms between organs: first, the log2 ratios of heart:liver (or liver:heart) intrachromosomal interactions are higher in organ-specific gene sets (p = 0.009), suggesting that organ-specific genes have specialized chromatin structural features. Despite similar number of total interactions between cell types, intrachromosomal interaction profiles in heart but not liver demonstrate that genes forming promoter-to-transcription-end-site loops in the cardiac nucleus tend to be involved in cardiac-related pathways. The same analysis revealed an analogous organ-specific interaction profile for liver-specific loop genes. Investigation of A/B compartmentalization (marker of chromatin accessibility) revealed that in the heart, 66.7% of cardiac-specific genes are in compartment A, while 66.1% of liver-specific genes are found in compartment B, suggesting that there exists a cardiac chromatin topology that allows for expression of cardiac genes. Analyses of interchromosomal interactions revealed a relationship between interchromosomal interaction count and organ-specific gene localization (p = 2.2 × 10[-16]) and that, for both organs, regions of active or inactive chromatin tend to segregate in 3D space (i.e., active with active, inactive with inactive). 3D models of topologically associating domains (TADs) suggest that TADs tend to interact with regions of similar compartmentalization across chromosomes, revealing trans structural interactions contributing to genomic compartmentalization at distinct structural scales. These models reveal discordant nuclear compaction strategies, with heart packaging compartment A genes preferentially toward the center of the nucleus and liver exhibiting preferential arrangement toward the periphery. Taken together, our data suggest that intra- and interchromosomal chromatin architecture plays a role in orchestrating tissue-specific gene expression.},
}
@article {pmid30692681,
year = {2019},
author = {Donaldson-Collier, MC and Sungalee, S and Zufferey, M and Tavernari, D and Katanayeva, N and Battistello, E and Mina, M and Douglass, KM and Rey, T and Raynaud, F and Manley, S and Ciriello, G and Oricchio, E},
title = {EZH2 oncogenic mutations drive epigenetic, transcriptional, and structural changes within chromatin domains.},
journal = {Nature genetics},
volume = {51},
number = {3},
pages = {517-528},
pmid = {30692681},
issn = {1546-1718},
mesh = {Animals ; Cell Line, Tumor ; Chromatin/*genetics ; DNA Methylation/genetics ; Enhancer of Zeste Homolog 2 Protein/*genetics ; Epigenesis, Genetic/*genetics ; Epigenomics/methods ; Gene Expression Regulation, Neoplastic/genetics ; Gene Silencing/physiology ; Histones/genetics ; Humans ; Mice ; Mutation/*genetics ; Promoter Regions, Genetic/genetics ; Transcription, Genetic/*genetics ; },
abstract = {Chromatin is organized into topologically associating domains (TADs) enriched in distinct histone marks. In cancer, gain-of-function mutations in the gene encoding the enhancer of zeste homolog 2 protein (EZH2) lead to a genome-wide increase in histone-3 Lys27 trimethylation (H3K27me3) associated with transcriptional repression. However, the effects of these epigenetic changes on the structure and function of chromatin domains have not been explored. Here, we found a functional interplay between TADs and epigenetic and transcriptional changes mediated by mutated EZH2. Altered EZH2 (p.Tyr646* (EZH2[Y646X])) led to silencing of entire domains, synergistically inactivating multiple tumor suppressors. Intra-TAD gene silencing was coupled with changes of interactions between gene promoter regions. Notably, gene expression and chromatin interactions were restored by pharmacological inhibition of EZH2[Y646X]. Our results indicate that EZH2[Y646X] alters the topology and function of chromatin domains to promote synergistic oncogenic programs.},
}
@article {pmid30682683,
year = {2019},
author = {Yamamoto, T and Saitoh, N},
title = {Non-coding RNAs and chromatin domains.},
journal = {Current opinion in cell biology},
volume = {58},
number = {},
pages = {26-33},
doi = {10.1016/j.ceb.2018.12.005},
pmid = {30682683},
issn = {1879-0410},
mesh = {Animals ; Cell Cycle Proteins/metabolism ; Cell Nucleus/metabolism ; Chromatin/*chemistry/metabolism ; Chromatin Assembly and Disassembly ; Chromosomal Proteins, Non-Histone/metabolism ; Chromosomes/metabolism ; Humans ; RNA, Untranslated/chemistry/*metabolism ; Transcription Factors/metabolism ; },
abstract = {Large-scale transcriptome analyses have identified a variety of non-coding RNAs (ncRNAs) that are not translated into proteins. Many of them are in the nucleus, where they associate with chromatin and regulate its structure and function. Interphase chromosomes are intricately folded into multiple layers and composed of domains. Recent studies using Hi-C technologies have identified a mega-base self-associating chromatin domain: the topologically associating domain (TAD). The domain boundaries are demarcated with the chromatin regulatory proteins CTCF and cohesin, which are often bound to or recruited by ncRNAs. Some ncRNAs form RNA clouds in the nucleus and coordinate the transcription of multiple genes in a chromatin domain. In this review, we describe the emerging link between long ncRNAs and chromatin domains in the nucleus.},
}
@article {pmid30664301,
year = {2019},
author = {Fritz, AJ and Sehgal, N and Pliss, A and Xu, J and Berezney, R},
title = {Chromosome territories and the global regulation of the genome.},
journal = {Genes, chromosomes &amp; cancer},
volume = {58},
number = {7},
pages = {407-426},
pmid = {30664301},
issn = {1098-2264},
support = {F32 CA220935/CA/NCI NIH HHS/United States ; R01 GM072131/GM/NIGMS NIH HHS/United States ; GM-23922//NIH Clinical Center/International ; F32-CA220935/CA/NCI NIH HHS/United States ; GM-072131//NIH Clinical Center/International ; },
mesh = {Animals ; *Cell Nucleus/genetics/ultrastructure ; *Chromatin/genetics/ultrastructure ; *Chromosomes/genetics/ultrastructure ; *Gene Expression Regulation/genetics/physiology ; *Genome ; Humans ; },
abstract = {Spatial positioning is a fundamental principle governing nuclear processes. Chromatin is organized as a hierarchy from nucleosomes to Mbp chromatin domains (CD) or topologically associating domains (TADs) to higher level compartments culminating in chromosome territories (CT). Microscopic and sequencing techniques have substantiated chromatin organization as a critical factor regulating gene expression. For example, enhancers loop back to interact with their target genes almost exclusively within TADs, distally located coregulated genes reposition into common transcription factories upon activation, and Mbp CDs exhibit dynamic motion and configurational changes in vivo. A longstanding question in the nucleus field is whether an interactive nuclear matrix provides a direct link between structure and function. The findings of nonrandom radial positioning of CT within the nucleus suggest the possibility of preferential interaction patterns among populations of CT. Sequential labeling up to 10 CT followed by application of computer imaging and geometric graph mining algorithms revealed cell-type specific interchromosomal networks (ICN) of CT that are altered during the cell cycle, differentiation, and cancer progression. It is proposed that the ICN correlate with the global level of genome regulation. These approaches also demonstrated that the large scale 3-D topology of CT is specific for each CT. The cell-type specific proximity of certain chromosomal regions in normal cells may explain the propensity of distinct translocations in cancer subtypes. Understanding how genes are dysregulated upon disruption of the normal "wiring" of the nucleus by translocations, deletions, and amplifications that are hallmarks of cancer, should enable more targeted therapeutic strategies.},
}
@article {pmid30661750,
year = {2019},
author = {Ohno, M and Ando, T and Priest, DG and Kumar, V and Yoshida, Y and Taniguchi, Y},
title = {Sub-nucleosomal Genome Structure Reveals Distinct Nucleosome Folding Motifs.},
journal = {Cell},
volume = {176},
number = {3},
pages = {520-534.e25},
doi = {10.1016/j.cell.2018.12.014},
pmid = {30661750},
issn = {1097-4172},
mesh = {Chromatin/genetics/metabolism/*ultrastructure ; Chromatin Assembly and Disassembly/physiology ; Chromosomes/metabolism/ultrastructure ; Nucleosomes/genetics/metabolism/*ultrastructure ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/genetics ; Transcription Initiation Site ; },
abstract = {Elucidating the global and local rules that govern genome-wide, hierarchical chromatin architecture remains a critical challenge. Current high-throughput chromosome conformation capture (Hi-C) technologies have identified large-scale chromatin structural motifs, such as topologically associating domains and looping. However, structural rules at the smallest or nucleosome scale remain poorly understood. Here, we coupled nucleosome-resolved Hi-C technology with simulated annealing-molecular dynamics (SA-MD) simulation to reveal 3D spatial distributions of nucleosomes and their genome-wide orientation in chromatin. Our method, called Hi-CO, revealed distinct nucleosome folding motifs across the yeast genome. Our results uncovered two types of basic secondary structural motifs in nucleosome folding: α-tetrahedron and β-rhombus analogous to α helix and β sheet motifs in protein folding. Using mutants and cell-cycle-synchronized cells, we further uncovered motifs with specific nucleosome positioning and orientation coupled to epigenetic features at individual loci. By illuminating molecular-level structure-function relationships in eukaryotic chromatin, our findings establish organizational principles of nucleosome folding.},
}
@article {pmid30655336,
year = {2019},
author = {Oomen, ME and Hansen, AS and Liu, Y and Darzacq, X and Dekker, J},
title = {CTCF sites display cell cycle-dependent dynamics in factor binding and nucleosome positioning.},
journal = {Genome research},
volume = {29},
number = {2},
pages = {236-249},
pmid = {30655336},
issn = {1549-5469},
support = {U01 EB021236/EB/NIBIB NIH HHS/United States ; R01 HG003143/HG/NHGRI NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; U54 DK107980/DK/NIDDK NIH HHS/United States ; U01 DA047729/DA/NIDA NIH HHS/United States ; K99 GM130896/GM/NIGMS NIH HHS/United States ; },
mesh = {Binding Sites ; CCCTC-Binding Factor/*metabolism ; Cell Cycle/*genetics ; Cells, Cultured ; Chromatin/chemistry ; HeLa Cells ; Histone Code ; Humans ; Interphase/genetics ; Mitosis/genetics ; Nucleosomes/*physiology ; Nucleotide Motifs ; Prometaphase/genetics ; Transcription Initiation Site ; },
abstract = {CCCTC-binding factor (CTCF) plays a key role in the formation of topologically associating domains (TADs) and loops in interphase. During mitosis TADs are absent, but how TAD formation is dynamically controlled during the cell cycle is not known. Several contradicting observations have been made regarding CTCF binding to mitotic chromatin using both genomics- and microscopy-based techniques. Here, we have used four different assays to address this debate. First, using 5C, we confirmed that TADs and CTCF loops are readily detected in interphase, but absent during prometaphase. Second, ATAC-seq analysis showed that CTCF sites display greatly reduced accessibility and lose the CTCF footprint in prometaphase, suggesting loss of CTCF binding and rearrangement of the nucleosomal array around the binding motif. In contrast, transcription start sites remain accessible in prometaphase, although adjacent nucleosomes can also become repositioned and occupy at least a subset of start sites during mitosis. Third, loss of site-specific CTCF binding was directly demonstrated using CUT&amp;RUN. Histone modifications and histone variants are maintained in mitosis, suggesting a role in bookmarking of active CTCF sites. Finally, live-cell imaging, fluorescence recovery after photobleaching, and single molecule tracking showed that almost all CTCF chromatin binding is lost in prometaphase. Combined, our results demonstrate loss of CTCF binding to CTCF sites during prometaphase and rearrangement of the chromatin landscape around CTCF motifs. This, combined with loss of cohesin, would contribute to the observed loss of TADs and CTCF loops during mitosis and reveals that CTCF sites, key architectural cis-elements, display cell cycle stage-dependent dynamics in factor binding and nucleosome positioning.},
}
@article {pmid30596637,
year = {2018},
author = {Tan, ZW and Guarnera, E and Berezovsky, IN},
title = {Exploring chromatin hierarchical organization via Markov State Modelling.},
journal = {PLoS computational biology},
volume = {14},
number = {12},
pages = {e1006686},
pmid = {30596637},
issn = {1553-7358},
mesh = {Algorithms ; CCCTC-Binding Factor/metabolism ; Cell Cycle Proteins/metabolism ; Cell Line ; Chromatin/*genetics/metabolism ; Chromatin Assembly and Disassembly ; Chromosomal Proteins, Non-Histone/metabolism ; Chromosomes, Human, Pair 17/genetics/metabolism ; Computational Biology ; DNA/genetics/metabolism ; DNA-Directed RNA Polymerases/metabolism ; Epigenesis, Genetic ; Gene Expression Regulation ; Gene Regulatory Networks ; Genome, Human ; Histone Code/genetics ; Humans ; Markov Chains ; *Models, Genetic ; },
abstract = {We propose a new computational method for exploring chromatin structural organization based on Markov State Modelling of Hi-C data represented as an interaction network between genomic loci. A Markov process describes the random walk of a traveling probe in the corresponding energy landscape, mimicking the motion of a biomolecule involved in chromatin function. By studying the metastability of the associated Markov State Model upon annealing, the hierarchical structure of individual chromosomes is observed, and corresponding set of structural partitions is identified at each level of hierarchy. Then, the notion of effective interaction between partitions is derived, delineating the overall topology and architecture of chromosomes. Mapping epigenetic data on the graphs of intra-chromosomal effective interactions helps in understanding how chromosome organization facilitates its function. A sketch of whole-genome interactions obtained from the analysis of 539 partitions from all 23 chromosomes, complemented by distributions of gene expression regulators and epigenetic factors, sheds light on the structure-function relationships in chromatin, delineating chromosomal territories, as well as structural partitions analogous to topologically associating domains and active / passive epigenomic compartments. In addition to the overall genome architecture shown by effective interactions, the affinity between partitions of different chromosomes was analyzed as an indicator of the degree of association between partitions in functionally relevant genomic interactions. The overall static picture of whole-genome interactions obtained with the method presented in this work provides a foundation for chromatin structural reconstruction, for the modelling of chromatin dynamics, and for exploring the regulation of genome function. The algorithms used in this study are implemented in a freely available Python package ChromaWalker (https://bitbucket.org/ZhenWahTan/chromawalker).},
}
@article {pmid30595451,
year = {2019},
author = {Sima, J and Chakraborty, A and Dileep, V and Michalski, M and Klein, KN and Holcomb, NP and Turner, JL and Paulsen, MT and Rivera-Mulia, JC and Trevilla-Garcia, C and Bartlett, DA and Zhao, PA and Washburn, BK and Nora, EP and Kraft, K and Mundlos, S and Bruneau, BG and Ljungman, M and Fraser, P and Ay, F and Gilbert, DM},
title = {Identifying cis Elements for Spatiotemporal Control of Mammalian DNA Replication.},
journal = {Cell},
volume = {176},
number = {4},
pages = {816-830.e18},
pmid = {30595451},
issn = {1097-4172},
support = {R01 GM083337/GM/NIGMS NIH HHS/United States ; U54 DK107965/DK/NIDDK NIH HHS/United States ; },
mesh = {Animals ; CCCTC-Binding Factor/genetics/metabolism ; Chromatin ; DNA/genetics ; DNA Replication/*genetics/*physiology ; DNA Replication Timing/genetics/*physiology ; Embryonic Stem Cells ; Enhancer Elements, Genetic/genetics ; Mammals/genetics/metabolism ; Mice ; Repressor Proteins/metabolism ; Spatio-Temporal Analysis ; },
abstract = {The temporal order of DNA replication (replication timing [RT]) is highly coupled with genome architecture, but cis-elements regulating either remain elusive. We created a series of CRISPR-mediated deletions and inversions of a pluripotency-associated topologically associating domain (TAD) in mouse ESCs. CTCF-associated domain boundaries were dispensable for RT. CTCF protein depletion weakened most TAD boundaries but had no effect on RT or A/B compartmentalization genome-wide. By contrast, deletion of three intra-TAD CTCF-independent 3D contact sites caused a domain-wide early-to-late RT shift, an A-to-B compartment switch, weakening of TAD architecture, and loss of transcription. The dispensability of TAD boundaries and the necessity of these "early replication control elements" (ERCEs) was validated by deletions and inversions at additional domains. Our results demonstrate that discrete cis-regulatory elements orchestrate domain-wide RT, A/B compartmentalization, TAD architecture, and transcription, revealing fundamental principles linking genome structure and function.},
}
@article {pmid30594504,
year = {2019},
author = {Negi, S and Bolt, CC and Zhang, H and Stubbs, L},
title = {An extended regulatory landscape drives Tbx18 activity in a variety of prostate-associated cell lineages.},
journal = {Developmental biology},
volume = {446},
number = {2},
pages = {180-192},
pmid = {30594504},
issn = {1095-564X},
support = {F32 HD093555/HD/NICHD NIH HHS/United States ; R01 DK095685/DK/NIDDK NIH HHS/United States ; },
mesh = {Animals ; Binding Sites/genetics ; Cell Differentiation/genetics ; Cell Lineage/genetics ; Chromatin/genetics ; *Gene Expression Regulation, Developmental ; High-Throughput Nucleotide Sequencing/methods ; Male ; Mice, Inbred C3H ; Mice, Inbred C57BL ; Mice, Transgenic ; Promoter Regions, Genetic/genetics ; Prostate/cytology/embryology/*metabolism ; Regulatory Elements, Transcriptional/*genetics ; T-Box Domain Proteins/*genetics/metabolism ; Urogenital System/cytology/embryology/metabolism ; },
abstract = {The evolutionarily conserved transcription factor, Tbx18, is expressed in a dynamic pattern throughout embryonic and early postnatal life and plays crucial roles in the development of multiple organ systems. Previous studies have indicated that this dynamic function is controlled by an expansive regulatory structure, extending far upstream and downstream of the gene. With the goal of identifying elements that interact with the Tbx18 promoter in developing prostate, we coupled chromatin conformation capture (4C) and ATAC-seq from embryonic day 18.5 (E18.5) mouse urogenital sinus (UGS), where Tbx18 is highly expressed. The data revealed dozens of active chromatin elements distributed throughout a 1.5 million base pair topologically associating domain (TAD). To identify cell types contributing to this chromatin signal, we used lineage tracing methods with a Tbx18 Cre "knock-in" allele; these data show clearly that Tbx18-expressing precursors differentiate into wide array of cell types in multiple tissue compartments, most of which have not been previously reported. We also used a 209 kb Cre-expressing Tbx18 transgene, to partition enhancers for specific precursor types into two rough spatial domains. Within this central 209 kb compartment, we identified ECR1, previously described to regulate Tbx18 expression in ureter, as an active regulator of UGS expression. Together these data define the diverse fates of Tbx18+ precursors in prostate-associated tissues for the first time, and identify a highly active TAD controlling the gene's essential function in this tissue.},
}
@article {pmid30591009,
year = {2018},
author = {Liu, T and Wang, Z},
title = {Reconstructing high-resolution chromosome three-dimensional structures by Hi-C complex networks.},
journal = {BMC bioinformatics},
volume = {19},
number = {Suppl 17},
pages = {496},
pmid = {30591009},
issn = {1471-2105},
support = {R15 GM120650/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Chromatin Immunoprecipitation ; Chromosomes, Mammalian/*chemistry/*genetics ; Cluster Analysis ; In Situ Hybridization, Fluorescence ; Mice ; Mouse Embryonic Stem Cells/metabolism ; RNA, Antisense/metabolism ; RNA, Long Noncoding/metabolism ; },
abstract = {BACKGROUND: Hi-C data have been widely used to reconstruct chromosomal three-dimensional (3D) structures. One of the key limitations of Hi-C is the unclear relationship between spatial distance and the number of Hi-C contacts. Many methods used a fixed parameter when converting the number of Hi-C contacts to wish distances. However, a single parameter cannot properly explain the relationship between wish distances and genomic distances or the locations of topologically associating domains (TADs).<br><br>RESULTS: We have&#xa0;addressed one of the key issues of using Hi-C data, that is, the unclear relationship between spatial distances and the number of Hi-C contacts, which is&#xa0;crucial to understand significant biological functions, such as the enhancer-promoter interactions. Specifically, we developed a new method to infer this converting parameter and pairwise Euclidean distances based on the topology of the&#xa0;Hi-C complex network (HiCNet). The inferred distances were modeled by clustering coefficient and multiple other types of constraints. We found that our inferred distances between bead-pairs within the same TAD were apparently smaller than those distances between bead-pairs from different TADs. Our inferred distances had a higher correlation with fluorescence in situ hybridization (FISH) data, fitted the localization patterns of Xist transcripts on DNA, and better matched 156 pairs of protein-enabled long-range chromatin interactions detected by ChIA-PET. Using the inferred distances and another round of optimization, we further reconstructed 40&#x2009;kb high-resolution 3D chromosomal structures of mouse male ES cells. The high-resolution structures successfully&#xa0;illustrate TADs and DNA loops (peaks in Hi-C contact heatmaps) that usually indicate enhancer-promoter interactions.<br><br>CONCLUSIONS: We developed a novel method to infer the wish distances between DNA bead-pairs from Hi-C contacts. High-resolution 3D structures of chromosomes were built based on the newly-inferred wish distances. This whole process has been implemented as a tool named HiCNet, which is publicly available at http://dna.cs.miami.edu/HiCNet/ .},
}
@article {pmid30555922,
year = {2018},
author = {Rhie, SK and Schreiner, S and Witt, H and Armoskus, C and Lay, FD and Camarena, A and Spitsyna, VN and Guo, Y and Berman, BP and Evgrafov, OV and Knowles, JA and Farnham, PJ},
title = {Using 3D epigenomic maps of primary olfactory neuronal cells from living individuals to understand gene regulation.},
journal = {Science advances},
volume = {4},
number = {12},
pages = {eaav8550},
pmid = {30555922},
issn = {2375-2548},
support = {R01 MH110928/MH/NIMH NIH HHS/United States ; R01 MH094714/MH/NIMH NIH HHS/United States ; R01 CA136924/CA/NCI NIH HHS/United States ; R21 MH103877/MH/NIMH NIH HHS/United States ; U01 MH103365/MH/NIMH NIH HHS/United States ; R01 MH110905/MH/NIMH NIH HHS/United States ; R01 MH110927/MH/NIMH NIH HHS/United States ; R21 MH109956/MH/NIMH NIH HHS/United States ; K01 CA229995/CA/NCI NIH HHS/United States ; U01 MH103392/MH/NIMH NIH HHS/United States ; R01 MH109677/MH/NIMH NIH HHS/United States ; U01 MH103346/MH/NIMH NIH HHS/United States ; R01 MH086874/MH/NIMH NIH HHS/United States ; R01 MH111721/MH/NIMH NIH HHS/United States ; U01 MH103340/MH/NIMH NIH HHS/United States ; U01 MH103339/MH/NIMH NIH HHS/United States ; R01 MH110920/MH/NIMH NIH HHS/United States ; R21 MH102791/MH/NIMH NIH HHS/United States ; R01 MH105898/MH/NIMH NIH HHS/United States ; R21 MH105881/MH/NIMH NIH HHS/United States ; R01 MH110921/MH/NIMH NIH HHS/United States ; R21 MH105853/MH/NIMH NIH HHS/United States ; R01 MH109715/MH/NIMH NIH HHS/United States ; R01 MH110926/MH/NIMH NIH HHS/United States ; P50 MH106934/MH/NIMH NIH HHS/United States ; },
mesh = {Binding Sites ; Chromatin Immunoprecipitation ; Chromosome Mapping ; Computational Biology/methods ; Enhancer Elements, Genetic ; *Epigenesis, Genetic ; *Epigenomics/methods ; Gene Expression Profiling ; *Gene Expression Regulation ; Genetic Variation ; Heterochromatin/genetics ; High-Throughput Nucleotide Sequencing ; Humans ; Nucleotide Motifs ; Olfactory Receptor Neurons/*metabolism ; Protein Binding ; Regulatory Sequences, Nucleic Acid ; Transcription Factors/metabolism ; Transcriptome ; Workflow ; },
abstract = {As part of PsychENCODE, we developed a three-dimensional (3D) epigenomic map of primary cultured neuronal cells derived from olfactory neuroepithelium (CNON). We mapped topologically associating domains and high-resolution chromatin interactions using Hi-C and identified regulatory elements using chromatin immunoprecipitation and nucleosome positioning assays. Using epigenomic datasets from biopsies of 63 living individuals, we found that epigenetic marks at distal regulatory elements are more variable than marks at proximal regulatory elements. By integrating genotype and metadata, we identified enhancers that have different levels corresponding to differences in genetic variation, gender, smoking, and schizophrenia. Motif searches revealed that many CNON enhancers are bound by neuronal-related transcription factors. Last, we combined 3D epigenomic maps and gene expression profiles to predict enhancer-target gene interactions on a genome-wide scale. This study not only provides a framework for understanding individual epigenetic variation using a primary cell model system but also contributes valuable data resources for epigenomic studies of neuronal epithelium.},
}
@article {pmid30552103,
year = {2019},
author = {Le Dily, F and Vidal, E and Cuartero, Y and Quilez, J and Nacht, AS and Vicent, GP and Carbonell-Caballero, J and Sharma, P and Villanueva-Cañas, JL and Ferrari, R and De Llobet, LI and Verde, G and Wright, RHG and Beato, M},
title = {Hormone-control regions mediate steroid receptor-dependent genome organization.},
journal = {Genome research},
volume = {29},
number = {1},
pages = {29-39},
pmid = {30552103},
issn = {1549-5469},
mesh = {Estrogen Receptor alpha/*biosynthesis/genetics ; Estrogens/*pharmacology ; Gene Expression Regulation/*drug effects ; Humans ; MCF-7 Cells ; Progesterone/*pharmacology ; Receptors, Progesterone/*biosynthesis/genetics ; *Response Elements ; Signal Transduction/*drug effects ; },
abstract = {In breast cancer cells, some topologically associating domains (TADs) behave as hormonal gene regulation units, within which gene transcription is coordinately regulated in response to steroid hormones. Here we further describe that responsive TADs contain 20- to 100-kb-long clusters of intermingled estrogen receptor (ESR1) and progesterone receptor (PGR) binding sites, hereafter called hormone-control regions (HCRs). In T47D cells, we identified more than 200 HCRs, which are frequently bound by unliganded ESR1 and PGR. These HCRs establish steady long-distance inter-TAD interactions between them and organize characteristic looping structures with promoters in their TADs even in the absence of hormones in ESR1[+]-PGR[+] cells. This organization is dependent on the expression of the receptors and is further dynamically modulated in response to steroid hormones. HCRs function as platforms that integrate different signals, resulting in some cases in opposite transcriptional responses to estrogens or progestins. Altogether, these results suggest that steroid hormone receptors act not only as hormone-regulated sequence-specific transcription factors but also as local and global genome organizers.},
}
@article {pmid30545857,
year = {2018},
author = {Wang, D and Liu, S and Warrell, J and Won, H and Shi, X and Navarro, FCP and Clarke, D and Gu, M and Emani, P and Yang, YT and Xu, M and Gandal, MJ and Lou, S and Zhang, J and Park, JJ and Yan, C and Rhie, SK and Manakongtreecheep, K and Zhou, H and Nathan, A and Peters, M and Mattei, E and Fitzgerald, D and Brunetti, T and Moore, J and Jiang, Y and Girdhar, K and Hoffman, GE and Kalayci, S and Gümüş, ZH and Crawford, GE and , and Roussos, P and Akbarian, S and Jaffe, AE and White, KP and Weng, Z and Sestan, N and Geschwind, DH and Knowles, JA and Gerstein, MB},
title = {Comprehensive functional genomic resource and integrative model for the human brain.},
journal = {Science (New York, N.Y.)},
volume = {362},
number = {6420},
pages = {},
pmid = {30545857},
issn = {1095-9203},
support = {R01 MH110928/MH/NIMH NIH HHS/United States ; R37 MH057881/MH/NIMH NIH HHS/United States ; R21 MH103877/MH/NIMH NIH HHS/United States ; U01 MH103365/MH/NIMH NIH HHS/United States ; R00 MH113823/MH/NIMH NIH HHS/United States ; R01 MH110927/MH/NIMH NIH HHS/United States ; R21 MH109956/MH/NIMH NIH HHS/United States ; U01 MH103392/MH/NIMH NIH HHS/United States ; R01 MH109677/MH/NIMH NIH HHS/United States ; U01 MH103346/MH/NIMH NIH HHS/United States ; R01 MH105472/MH/NIMH NIH HHS/United States ; P50 MH084053/MH/NIMH NIH HHS/United States ; R21 MH105881/MH/NIMH NIH HHS/United States ; P50 MH066392/MH/NIMH NIH HHS/United States ; R01 MH110926/MH/NIMH NIH HHS/United States ; R01 MH085542/MH/NIMH NIH HHS/United States ; P50 MH096891/MH/NIMH NIH HHS/United States ; R01 MH094714/MH/NIMH NIH HHS/United States ; R01 MH110905/MH/NIMH NIH HHS/United States ; R01 MH075916/MH/NIMH NIH HHS/United States ; S10 OD018521/OD/NIH HHS/United States ; K01 CA229995/CA/NCI NIH HHS/United States ; R01 MH111721/MH/NIMH NIH HHS/United States ; U01 MH103340/MH/NIMH NIH HHS/United States ; U01 MH103339/MH/NIMH NIH HHS/United States ; R01 MH097276/MH/NIMH NIH HHS/United States ; P01 AG002219/AG/NIA NIH HHS/United States ; R01 MH110920/MH/NIMH NIH HHS/United States ; HHSN271201300031C/DA/NIDA NIH HHS/United States ; R01 MH093725/MH/NIMH NIH HHS/United States ; U19 AI118610/AI/NIAID NIH HHS/United States ; P50 AG005138/AG/NIA NIH HHS/United States ; R21 MH102791/MH/NIMH NIH HHS/United States ; R01 MH105898/MH/NIMH NIH HHS/United States ; S10 OD018164/OD/NIH HHS/United States ; R01 MH110921/MH/NIMH NIH HHS/United States ; R21 MH105853/MH/NIMH NIH HHS/United States ; R01 MH109715/MH/NIMH NIH HHS/United States ; R01 MH080405/MH/NIMH NIH HHS/United States ; U01 MH116492/MH/NIMH NIH HHS/United States ; P50 MH106934/MH/NIMH NIH HHS/United States ; },
mesh = {Brain/*metabolism ; Datasets as Topic ; Deep Learning ; Enhancer Elements, Genetic ; Epigenesis, Genetic ; Epigenomics ; *Gene Expression Regulation ; Gene Regulatory Networks ; Genome-Wide Association Study ; Humans ; Mental Disorders/*genetics ; Quantitative Trait Loci ; Single-Cell Analysis ; Transcriptome ; },
abstract = {Despite progress in defining genetic risk for psychiatric disorders, their molecular mechanisms remain elusive. Addressing this, the PsychENCODE Consortium has generated a comprehensive online resource for the adult brain across 1866 individuals. The PsychENCODE resource contains ~79,000 brain-active enhancers, sets of Hi-C linkages, and topologically associating domains; single-cell expression profiles for many cell types; expression quantitative-trait loci (QTLs); and further QTLs associated with chromatin, splicing, and cell-type proportions. Integration shows that varying cell-type proportions largely account for the cross-population variation in expression (with >88% reconstruction accuracy). It also allows building of a gene regulatory network, linking genome-wide association study variants to genes (e.g., 321 for schizophrenia). We embed this network into an interpretable deep-learning model, which improves disease prediction by ~6-fold versus polygenic risk scores and identifies key genes and pathways in psychiatric disorders.},
}
@article {pmid30523037,
year = {2019},
author = {Amat, R and Böttcher, R and Le Dily, F and Vidal, E and Quilez, J and Cuartero, Y and Beato, M and de Nadal, E and Posas, F},
title = {Rapid reversible changes in compartments and local chromatin organization revealed by hyperosmotic shock.},
journal = {Genome research},
volume = {29},
number = {1},
pages = {18-28},
pmid = {30523037},
issn = {1549-5469},
mesh = {Cell Line ; Chromatin/*metabolism ; *Chromatin Assembly and Disassembly ; Humans ; *Osmotic Pressure ; RNA Polymerase II/*metabolism ; *Transcription, Genetic ; },
abstract = {Nuclear architecture is decisive for the assembly of transcriptional responses. However, how chromosome organization is dynamically modulated to permit rapid and transient transcriptional changes in response to environmental challenges remains unclear. Here we show that hyperosmotic stress disrupts different levels of chromosome organization, ranging from A/B compartment changes to reduction in the number and insulation of topologically associating domains (TADs). Concomitantly, transcription is greatly affected, TAD borders weaken, and RNA Polymerase II runs off from hundreds of transcription end sites. Stress alters the binding profiles of architectural proteins, which explains the disappearance of local chromatin organization. These processes are dynamic, and cells rapidly reconstitute their default chromatin conformation after stress removal, uncovering an intrinsic organization. Transcription is not required for local chromatin reorganization, while compartment recovery is partially transcription-dependent. Thus, nuclear organization in mammalian cells can be rapidly modulated by environmental changes in a reversible manner.},
}
@article {pmid30539556,
year = {2019},
author = {Chen, X and Hao, Y and Cui, Y and Fan, Z and Chen, R},
title = {LncVar: Deciphering Genetic Variations Associated with Long Noncoding Genes.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1870},
number = {},
pages = {189-198},
doi = {10.1007/978-1-4939-8808-2_14},
pmid = {30539556},
issn = {1940-6029},
mesh = {*Computational Biology/methods ; Gene Expression Regulation ; *Genetic Variation ; Humans ; Methylation ; Open Reading Frames ; Polymorphism, Single Nucleotide ; Promoter Regions, Genetic ; *RNA, Long Noncoding/genetics/metabolism ; Software ; Transcription, Genetic ; },
abstract = {Long noncoding RNAs (lncRNAs) are pervasively transcribed in various species and play important roles in many biological processes. The biological functions of most lncRNAs remain to be explored. Previous studies have revealed that a large amount of disease-associated variations are located in the lncRNA gene regions. To evaluate the effects of genetic variations on lncRNAs, we constructed a database of genetic variations associated with long noncoding genes, LncVar. In this chapter, we describe the process of collecting data (including lncRNAs, transcription factor binding sites and m[6]A modification sites of lncRNAs, putatively translated open reading frames in lncRNAs) and steps of evaluating the effects of variations on the transcriptional regulation and modification of lncRNAs.},
}
@article {pmid30535005,
year = {2019},
author = {Nash, AJ and Lenhard, B},
title = {A novel measure of non-coding genome conservation identifies genomic regulatory blocks within primates.},
journal = {Bioinformatics (Oxford, England)},
volume = {35},
number = {14},
pages = {2354-2361},
pmid = {30535005},
issn = {1367-4811},
support = {MC_UP_1102/1/MRC_/Medical Research Council/United Kingdom ; 1584095/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Animals ; Biological Evolution ; Conserved Sequence ; *Genome ; *Genomics ; Primates ; },
abstract = {MOTIVATION: Clusters of extremely conserved non-coding elements (CNEs) mark genomic regions devoted to cis-regulation of key developmental genes in Metazoa. We have recently shown that their span coincides with that of topologically associating domains (TADs), making them useful for estimating conserved TAD boundaries in the absence of Hi-C data. The standard approach-detecting CNEs in genome alignments and then establishing the boundaries of their clusters-requires tuning of several parameters and breaks down when comparing closely related genomes.<br><br>RESULTS: We present a novel, kurtosis-based measure of pairwise non-coding conservation that requires no pre-set thresholds for conservation level and length of CNEs. We show that it performs robustly across a large span of evolutionary distances, including across the closely related genomes of primates for which standard approaches fail. The method is straightforward to implement and enables detection and comparison of clusters of CNEs and estimation of underlying TADs across a vastly increased range of Metazoan genomes.<br><br>The data generated for this study, and the scripts used to generate the data, can be found at https://github.com/alexander-nash/kurtosis_conservation.<br><br>SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},
}
@article {pmid30531872,
year = {2019},
author = {Fanucchi, S and Fok, ET and Dalla, E and Shibayama, Y and Börner, K and Chang, EY and Stoychev, S and Imakaev, M and Grimm, D and Wang, KC and Li, G and Sung, WK and Mhlanga, MM},
title = {Immune genes are primed for robust transcription by proximal long noncoding RNAs located in nuclear compartments.},
journal = {Nature genetics},
volume = {51},
number = {1},
pages = {138-150},
pmid = {30531872},
issn = {1546-1718},
mesh = {Animals ; Cell Line, Tumor ; Cell Nucleus/*genetics ; Cells, Cultured ; Chromatin/genetics ; Epigenesis, Genetic/genetics ; HeLa Cells ; Histone-Lysine N-Methyltransferase/genetics ; Histones/genetics ; Human Umbilical Vein Endothelial Cells ; Humans ; Macrophages/physiology ; Methylation ; Mice ; Myeloid-Lymphoid Leukemia Protein/genetics ; Promoter Regions, Genetic/genetics ; RAW 264.7 Cells ; RNA, Long Noncoding/*genetics ; Transcription, Genetic/*genetics ; Up-Regulation/genetics ; },
abstract = {Accumulation of trimethylation of histone H3 at lysine 4 (H3K4me3) on immune-related gene promoters underlies robust transcription during trained immunity. However, the molecular basis for this remains unknown. Here we show three-dimensional chromatin topology enables immune genes to engage in chromosomal contacts with a subset of long noncoding RNAs (lncRNAs) we have defined as immune gene-priming lncRNAs (IPLs). We show that the prototypical IPL, UMLILO, acts in cis to direct the WD repeat-containing protein 5 (WDR5)-mixed lineage leukemia protein 1 (MLL1) complex across the chemokine promoters, facilitating their H3K4me3 epigenetic priming. This mechanism is shared amongst several trained immune genes. Training mediated by β-glucan epigenetically reprograms immune genes by upregulating IPLs in manner dependent on nuclear factor of activated T cells. The murine chemokine topologically associating domain lacks an IPL, and the Cxcl genes are not trained. Strikingly, the insertion of UMLILO into the chemokine topologically associating domain in mouse macrophages resulted in training of Cxcl genes. This provides strong evidence that lncRNA-mediated regulation is central to the establishment of trained immunity.},
}
@article {pmid30527662,
year = {2019},
author = {Sun, F and Chronis, C and Kronenberg, M and Chen, XF and Su, T and Lay, FD and Plath, K and Kurdistani, SK and Carey, MF},
title = {Promoter-Enhancer Communication Occurs Primarily within Insulated Neighborhoods.},
journal = {Molecular cell},
volume = {73},
number = {2},
pages = {250-263.e5},
pmid = {30527662},
issn = {1097-4164},
support = {P01 GM099134/GM/NIGMS NIH HHS/United States ; R01 CA178415/CA/NCI NIH HHS/United States ; R01 GM074701/GM/NIGMS NIH HHS/United States ; T32 GM007185/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Binding Sites ; CCCTC-Binding Factor/genetics/metabolism ; Cell Cycle Proteins/genetics/metabolism ; Cell Line ; Chromosomal Proteins, Non-Histone/genetics/metabolism ; *Chromosomes, Mammalian ; Databases, Genetic ; Down-Regulation ; *Enhancer Elements, Genetic ; *Insulator Elements ; Mice ; Mouse Embryonic Stem Cells/*physiology ; *Promoter Regions, Genetic ; Protein Binding ; RNA, Messenger/biosynthesis/genetics ; Receptors, Estrogen/genetics/metabolism ; *Transcription, Genetic ; },
abstract = {Metazoan chromosomes are sequentially partitioned into topologically associating domains (TADs) and then into smaller sub-domains. One class of sub-domains, insulated neighborhoods, are proposed to spatially sequester and insulate the enclosed genes through self-association and chromatin looping. However, it has not been determined functionally whether promoter-enhancer interactions and gene regulation are broadly restricted to within these loops. Here, we employed published datasets from murine embryonic stem cells (mESCs) to identify insulated neighborhoods that confine promoter-enhancer interactions and demarcate gene regulatory regions. To directly address the functionality of these regions, we depleted estrogen-related receptor β (Esrrb), which binds the Mediator co-activator complex, to impair enhancers of genes within 222 insulated neighborhoods without causing mESC differentiation. Esrrb depletion reduces Mediator binding, promoter-enhancer looping, and expression of both nascent RNA and mRNA within the insulated neighborhoods without significantly affecting the flanking genes. Our data indicate that insulated neighborhoods represent functional regulons in mammalian genomes.},
}
@article {pmid30526631,
year = {2018},
author = {Zufferey, M and Tavernari, D and Oricchio, E and Ciriello, G},
title = {Comparison of computational methods for the identification of topologically associating domains.},
journal = {Genome biology},
volume = {19},
number = {1},
pages = {217},
pmid = {30526631},
issn = {1474-760X},
mesh = {Animals ; *Chromatin Assembly and Disassembly ; Chromosomes ; Genomics/*methods ; Humans ; Mice ; },
abstract = {BACKGROUND: Chromatin folding gives rise to structural elements among which are clusters of densely interacting DNA regions termed topologically associating domains (TADs). TADs have been characterized across multiple species, tissue types, and differentiation stages, sometimes in association with regulation of biological functions. The reliability and reproducibility of these findings are intrinsically related with the correct identification of these domains from high-throughput chromatin conformation capture (Hi-C) experiments.<br><br>RESULTS: Here, we test and compare 22 computational methods to identify TADs across 20 different conditions. We find that TAD sizes and numbers vary significantly among callers and data resolutions, challenging the definition of an average TAD size, but strengthening the hypothesis that TADs are hierarchically organized domains, rather than disjoint structural elements. Performances of these methods differ based on data resolution and normalization strategy, but a core set of TAD callers consistently retrieve reproducible domains, even at low sequencing depths, that are enriched for TAD-associated biological features.<br><br>CONCLUSIONS: This study provides a reference for the analysis of chromatin domains from Hi-C experiments and useful guidelines for choosing a suitable approach based on the experimental design, available data, and biological question of interest.},
}
@article {pmid30414923,
year = {2018},
author = {Pękowska, A and Klaus, B and Xiang, W and Severino, J and Daigle, N and Klein, FA and Oleś, M and Casellas, R and Ellenberg, J and Steinmetz, LM and Bertone, P and Huber, W},
title = {Gain of CTCF-Anchored Chromatin Loops Marks the Exit from Naive Pluripotency.},
journal = {Cell systems},
volume = {7},
number = {5},
pages = {482-495.e10},
pmid = {30414923},
issn = {2405-4712},
support = {203151/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; U01 DA047728/DA/NIDA NIH HHS/United States ; U01 EB021223/EB/NIBIB NIH HHS/United States ; BB/M004023/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; BB/G015678/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; 097922/Z/11/Z/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Animals ; CCCTC-Binding Factor/*metabolism ; Cell Cycle Proteins/*metabolism ; Cell Differentiation ; Chromatin/*metabolism/ultrastructure ; Chromosomal Proteins, Non-Histone/*metabolism ; Mice ; Mouse Embryonic Stem Cells/*metabolism/physiology/ultrastructure ; Neural Stem Cells/*metabolism/physiology/ultrastructure ; Protein Binding ; },
abstract = {The genome of pluripotent stem cells adopts a unique three-dimensional architecture featuring weakly condensed heterochromatin and large nucleosome-free regions. Yet, it is unknown whether structural loops and contact domains display characteristics that distinguish embryonic stem cells (ESCs) from differentiated cell types. We used genome-wide chromosome conformation capture and super-resolution imaging to determine nuclear organization in mouse ESC and neural stem cell (NSC) derivatives. We found that loss of pluripotency is accompanied by widespread gain of structural loops. This general architectural change correlates with enhanced binding of CTCF and cohesins and more pronounced insulation of contacts across chromatin boundaries in lineage-committed cells. Reprogramming NSCs to pluripotency restores the unique features of ESC domain topology. Domains defined by the anchors of loops established upon differentiation are enriched for developmental genes. Chromatin loop formation is a pervasive structural alteration to the genome that accompanies exit from pluripotency and delineates the spatial segregation of developmentally regulated genes.},
}
@article {pmid30401760,
year = {2018},
author = {Haloupek, N},
title = {Job Dekker: 2018 Edward Novitski Prize.},
journal = {Genetics},
volume = {210},
number = {3},
pages = {745-746},
pmid = {30401760},
issn = {1943-2631},
mesh = {*Awards and Prizes ; Genetics/*history ; History, 20th Century ; History, 21st Century ; },
abstract = {The Genetics Society of America's (GSA) Edward Novitski Prize is awarded to researchers who have solved challenging problems in genetics through experiments that demonstrate exceptional creativity and ingenuity. Job Dekker of the University of Massachusetts Medical School has been selected for the 2018 award in recognition of his innovative approach to understanding chromosome interactions and nuclear organization. Among Dekker's contributions are the development of the now-ubiquitous approach of chromosome conformation capture and the discovery of topologically associating domains.},
}
@article {pmid30395328,
year = {2019},
author = {Racko, D and Benedetti, F and Dorier, J and Stasiak, A},
title = {Are TADs supercoiled?.},
journal = {Nucleic acids research},
volume = {47},
number = {2},
pages = {521-532},
pmid = {30395328},
issn = {1362-4962},
mesh = {Chromatin ; Chromosomes/*chemistry ; *DNA, Superhelical ; Enhancer Elements, Genetic ; Models, Genetic ; Promoter Regions, Genetic ; Transcription, Genetic ; },
abstract = {Topologically associating domains (TADs) are megabase-sized building blocks of interphase chromosomes in higher eukaryotes. TADs are chromosomal regions with increased frequency of internal interactions. On average a pair of loci separated by a given genomic distance contact each other 2-3 times more frequently when they are in the same TAD as compared to a pair of loci located in two neighbouring TADs. TADs are also functional blocks of chromosomes as enhancers and their cognate promoters are normally located in the same TAD, even if their genomic distance from each other can be as large as a megabase. The internal structure of TADs, causing their increased frequency of internal interactions, is not established yet. We survey here experimental studies investigating presence of supercoiling in interphase chromosomes. We also review numerical simulation studies testing whether transcription-induced supercoiling of chromatin fibres can explain how TADs are formed and how they can assure very efficient interactions between enhancers and their cognate promoters located in the same TAD.},
}
@article {pmid30367165,
year = {2018},
author = {Rowley, MJ and Corces, VG},
title = {Organizational principles of 3D genome architecture.},
journal = {Nature reviews. Genetics},
volume = {19},
number = {12},
pages = {789-800},
pmid = {30367165},
issn = {1471-0064},
support = {K99 GM127671/GM/NIGMS NIH HHS/United States ; R00 GM127671/GM/NIGMS NIH HHS/United States ; R01 GM035463/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Chromatin/genetics/*metabolism ; Chromatin Assembly and Disassembly/*physiology ; Enhancer Elements, Genetic/*physiology ; Genome, Human/*physiology ; Humans ; Promoter Regions, Genetic/*physiology ; },
abstract = {Studies of 3D chromatin organization have suggested that chromosomes are hierarchically organized into large compartments composed of smaller domains called topologically associating domains (TADs). Recent evidence suggests that compartments are smaller than previously thought and that the transcriptional or chromatin state is responsible for interactions leading to the formation of small compartmental domains in all organisms. In vertebrates, CTCF forms loop domains, probably via an extrusion process involving cohesin. CTCF loops cooperate with compartmental domains to establish the 3D organization of the genome. The continuous extrusion of the chromatin fibre by cohesin may also be responsible for the establishment of enhancer-promoter interactions and stochastic aspects of the transcription process. These observations suggest that the 3D organization of the genome is an emergent property of chromatin and its components, and thus may not be only a determinant but also a consequence of its function.},
}
@article {pmid30361340,
year = {2018},
author = {Bintu, B and Mateo, LJ and Su, JH and Sinnott-Armstrong, NA and Parker, M and Kinrot, S and Yamaya, K and Boettiger, AN and Zhuang, X},
title = {Super-resolution chromatin tracing reveals domains and cooperative interactions in single cells.},
journal = {Science (New York, N.Y.)},
volume = {362},
number = {6413},
pages = {},
pmid = {30361340},
issn = {1095-9203},
support = {R35 GM122487/GM/NIGMS NIH HHS/United States ; T32 GM008313/GM/NIGMS NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; },
mesh = {CCCTC-Binding Factor/chemistry ; Cell Cycle Proteins/chemistry ; Chromatin/*chemistry/ultrastructure ; Chromosomal Proteins, Non-Histone/chemistry ; Genome, Human ; HCT116 Cells ; Humans ; In Situ Hybridization, Fluorescence ; Protein Binding ; Protein Domains ; Single-Cell Analysis/*methods ; },
abstract = {The spatial organization of chromatin is pivotal for regulating genome functions. We report an imaging method for tracing chromatin organization with kilobase- and nanometer-scale resolution, unveiling chromatin conformation across topologically associating domains (TADs) in thousands of individual cells. Our imaging data revealed TAD-like structures with globular conformation and sharp domain boundaries in single cells. The boundaries varied from cell to cell, occurring with nonzero probabilities at all genomic positions but preferentially at CCCTC-binding factor (CTCF)- and cohesin-binding sites. Notably, cohesin depletion, which abolished TADs at the population-average level, did not diminish TAD-like structures in single cells but eliminated preferential domain boundary positions. Moreover, we observed widespread, cooperative, multiway chromatin interactions, which remained after cohesin depletion. These results provide critical insight into the mechanisms underlying chromatin domain and hub formation.},
}
@article {pmid30352868,
year = {2019},
author = {Murcia Pienkowski, V and Kucharczyk, M and Młynek, M and Szczałuba, K and Rydzanicz, M and Poszewiecka, B and Skórka, A and Sykulski, M and Biernacka, A and Koppolu, AA and Posmyk, R and Walczak, A and Kosińska, J and Krajewski, P and Castaneda, J and Obersztyn, E and Jurkiewicz, E and Śmigiel, R and Gambin, A and Chrzanowska, K and Krajewska-Walasek, M and Płoski, R},
title = {Mapping of breakpoints in balanced chromosomal translocations by shallow whole-genome sequencing points to EFNA5, BAHD1 and PPP2R5E as novel candidates for genes causing human Mendelian disorders.},
journal = {Journal of medical genetics},
volume = {56},
number = {2},
pages = {104-112},
doi = {10.1136/jmedgenet-2018-105527},
pmid = {30352868},
issn = {1468-6244},
mesh = {Adolescent ; Adult ; Child ; Child, Preschool ; Chromosomal Proteins, Non-Histone/*genetics ; *Chromosome Breakpoints ; Chromosome Disorders/*genetics ; Ephrin-A5/*genetics ; Female ; Humans ; Infant ; Male ; Protein Phosphatase 2/*genetics ; *Translocation, Genetic ; Whole Genome Sequencing/*methods ; Young Adult ; },
abstract = {BACKGROUND: Mapping the breakpoints in de novo balanced chromosomal translocations (BCT) in symptomatic individuals provides a unique opportunity to identify in an unbiased way the likely causative genetic defect and thus find novel human disease candidate genes. Our aim was to fine-map breakpoints of de novo BCTs in a case series of nine patients.<br><br>METHODS: Shallow whole-genome mate pair sequencing (SGMPS) together with long-range PCR and Sanger sequencing. In one case (BCT disrupting BAHD1 and RET) cDNA analysis was used to verify expression of a fusion transcript in cultured fibroblasts.<br><br>RESULTS: In all nine probands 11 disrupted genes were found, that is, EFNA5, EBF3, LARGE, PPP2R5E, TXNDC5, ZNF423, NIPBL, BAHD1, RET, TRPS1 and SLC4A10. Five subjects had translocations that disrupted genes with so far unknown (EFNA5, BAHD1, PPP2R5E, TXNDC5) or poorly delineated impact on the phenotype (SLC4A10, two previous reports of BCT disrupting the gene). The four genes with no previous disease associations (EFNA5, BAHD1, PPP2R5E, TXNDC5), when compared with all human genes by a bootstrap test, had significantly higher pLI (p<0.017) and DOMINO (p<0.02) scores indicating enrichment in genes likely to be intolerant to single copy damage. Inspection of individual pLI and DOMINO scores, and local topologically associating domain structure suggested that EFNA5, BAHD1 and PPP2R5E were particularly good candidates for novel disease loci. The pathomechanism for BAHD1 may involve deregulation of expression due to fusion with RET promoter.<br><br>CONCLUSION: SGMPS in symptomatic carriers of BCTs is a powerful approach to delineate novel human gene-disease associations.},
}
@article {pmid30346395,
year = {2018},
author = {Hug, CB and Vaquerizas, JM},
title = {Generation of Genome-wide Chromatin Conformation Capture Libraries from Tightly Staged Early Drosophila Embryos.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {140},
pages = {},
pmid = {30346395},
issn = {1940-087X},
mesh = {Animals ; Cell Nucleus/genetics ; Chromatin/*chemistry/*genetics ; Drosophila melanogaster/cytology/*embryology/*genetics ; *Gene Library ; *Genomics ; Protein Conformation ; },
abstract = {Investigating the three-dimensional architecture of chromatin offers invaluable insight into the mechanisms of gene regulation. Here, we describe a protocol for performing the chromatin conformation capture technique in situ Hi-C on staged Drosophila melanogaster embryo populations. The result is a sequencing library that allows the mapping of all chromatin interactions that occur in the nucleus in a single experiment. Embryo sorting is done manually using a fluorescent stereo microscope and a transgenic fly line containing a nuclear marker. Using this technique, embryo populations from each nuclear division cycle, and with defined cell cycle status, can be obtained with very high purity. The protocol may also be adapted to sort older embryos beyond gastrulation. Sorted embryos are used as inputs for in situ Hi-C. All experiments, including sequencing library preparation, can be completed in five days. The protocol has low input requirements and works reliably using 20 blastoderm stage embryos as input material. The end result is a sequencing library for next generation sequencing. After sequencing, the data can be processed into genome-wide chromatin interaction maps that can be analyzed using a wide range of available tools to gain information about topologically associating domain (TAD) structure, chromatin loops, and chromatin compartments during Drosophila development.},
}
@article {pmid30315124,
year = {2018},
author = {Schuetzmann, D and Walter, C and van Riel, B and Kruse, S and König, T and Erdmann, T and Tönges, A and Bindels, E and Weilemann, A and Gebhard, C and Wethmar, K and Perrod, C and Minderjahn, J and Rehli, M and Delwel, R and Lenz, G and Gröschel, S and Dugas, M and Rosenbauer, F},
title = {Temporal autoregulation during human PU.1 locus SubTAD formation.},
journal = {Blood},
volume = {132},
number = {25},
pages = {2643-2655},
doi = {10.1182/blood-2018-02-834721},
pmid = {30315124},
issn = {1528-0020},
mesh = {Chromatin/genetics/metabolism ; *Epigenesis, Genetic ; *Gene Expression Regulation, Leukemic ; Genetic Loci ; High-Throughput Nucleotide Sequencing ; Humans ; *Leukemia, Myeloid, Acute/genetics/metabolism ; *Neoplasm Proteins/genetics/metabolism ; *Proto-Oncogene Proteins/genetics/metabolism ; *Trans-Activators/genetics/metabolism ; *Transcription, Genetic ; },
abstract = {Epigenetic control of gene expression occurs within discrete spatial chromosomal units called topologically associating domains (TADs), but the exact spatial requirements of most genes are unknown; this is of particular interest for genes involved in cancer. We therefore applied high-resolution chromosomal conformation capture sequencing to map the three-dimensional (3D) organization of the human locus encoding the key myeloid transcription factor PU.1 in healthy monocytes and acute myeloid leukemia (AML) cells. We identified a dynamic ∼75-kb unit (SubTAD) as the genomic region in which spatial interactions between PU.1 gene regulatory elements occur during myeloid differentiation and are interrupted in AML. Within this SubTAD, proper initiation of the spatial chromosomal interactions requires PU.1 autoregulation and recruitment of the chromatin-adaptor protein LDB1 (LIM domain-binding protein 1). However, once these spatial interactions have occurred, LDB1 stabilizes them independently of PU.1 autoregulation. Thus, our data support that PU.1 autoregulates its expression in a "hit-and-run" manner by initiating stable chromosomal loops that result in a transcriptionally active chromatin architecture.},
}
@article {pmid30297428,
year = {2018},
author = {Jorgenson, E and Matharu, N and Palmer, MR and Yin, J and Shan, J and Hoffmann, TJ and Thai, KK and Zhou, X and Hotaling, JM and Jarvik, GP and Ahituv, N and Wessells, H and Van Den Eeden, SK},
title = {Genetic variation in the SIM1 locus is associated with erectile dysfunction.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {115},
number = {43},
pages = {11018-11023},
pmid = {30297428},
issn = {1091-6490},
support = {RC2 AG036607/AG/NIA NIH HHS/United States ; UM1 HG009408/HG/NHGRI NIH HHS/United States ; P01 HD084387/HD/NICHD NIH HHS/United States ; R01 MH109907/MH/NIMH NIH HHS/United States ; MC_QA137853/MRC_/Medical Research Council/United Kingdom ; R01 DK104764/DK/NIDDK NIH HHS/United States ; R01 EY027004/EY/NEI NIH HHS/United States ; MC_PC_17228/MRC_/Medical Research Council/United Kingdom ; R01 DK090382/DK/NIDDK NIH HHS/United States ; R01 HL138424/HL/NHLBI NIH HHS/United States ; },
mesh = {Aged ; Alleles ; Body Mass Index ; Case-Control Studies ; Chromosomes, Human, Pair 6/genetics ; Cohort Studies ; Erectile Dysfunction/*genetics ; Genetic Predisposition to Disease/*genetics ; Genetic Variation/*genetics ; Humans ; Leptin/genetics ; Male ; Melanocortins/genetics ; Middle Aged ; Promoter Regions, Genetic/genetics ; },
abstract = {Erectile dysfunction affects millions of men worldwide. Twin studies support the role of genetic risk factors underlying erectile dysfunction, but no specific genetic variants have been identified. We conducted a large-scale genome-wide association study of erectile dysfunction in 36,649 men in the multiethnic Kaiser Permanente Northern California Genetic Epidemiology Research in Adult Health and Aging cohort. We also undertook replication analyses in 222,358 men from the UK Biobank. In the discovery cohort, we identified a single locus (rs17185536-T) on chromosome 6 near the single-minded family basic helix-loop-helix transcription factor 1 (SIM1) gene that was significantly associated with the risk of erectile dysfunction (odds ratio = 1.26, P = 3.4 × 10[-25]). The association replicated in the UK Biobank sample (odds ratio = 1.25, P = 6.8 × 10[-14]), and the effect is independent of known erectile dysfunction risk factors, including body mass index (BMI). The risk locus resides on the same topologically associating domain as SIM1 and interacts with the SIM1 promoter, and the rs17185536-T risk allele showed differential enhancer activity. SIM1 is part of the leptin-melanocortin system, which has an established role in body weight homeostasis and sexual function. Because the variants associated with erectile dysfunction are not associated with differences in BMI, our findings suggest a mechanism that is specific to sexual function.},
}
@article {pmid30275357,
year = {2018},
author = {Voutsadakis, IA},
title = {Molecular Lesions of Insulator CTCF and Its Paralogue CTCFL (BORIS) in Cancer: An Analysis from Published Genomic Studies.},
journal = {High-throughput},
volume = {7},
number = {4},
pages = {},
pmid = {30275357},
issn = {2571-5135},
abstract = {CTCF (CCCTC-binding factor) is a transcription regulator with hundreds of binding sites in the human genome. It has a main function as an insulator protein, defining together with cohesins the boundaries of areas of the genome called topologically associating domains (TADs). TADs contain regulatory elements such as enhancers which function as regulators of the transcription of genes inside the boundaries of the TAD while they are restricted from regulating genes outside these boundaries. This paper will examine the most common genetic lesions of CTCF as well as its related protein CTCFL (CTCF-like also called BORIS) in cancer using publicly available data from published genomic studies. Cancer types where abnormalities in the two genes are more common will be examined for possible associations with underlying repair defects or other prevalent genetic lesions. The putative functional effects in CTCF and CTCFL lesions will also be explored.},
}
@article {pmid30263009,
year = {2018},
author = {He, M and Li, Y and Tang, Q and Li, D and Jin, L and Tian, S and Che, T and He, S and Deng, L and Gao, G and Gu, Y and Jiang, Z and Li, X and Li, M},
title = {Genome-Wide Chromatin Structure Changes During Adipogenesis and Myogenesis.},
journal = {International journal of biological sciences},
volume = {14},
number = {11},
pages = {1571-1585},
pmid = {30263009},
issn = {1449-2288},
mesh = {3T3-L1 Cells ; Adipogenesis/genetics/*physiology ; Animals ; Cell Line ; Cell Nucleus/metabolism ; Chromatin/*metabolism ; Chromatin Assembly and Disassembly/genetics ; Genome/*genetics ; Mice ; Muscle Development/genetics/*physiology ; },
abstract = {The recently developed high-throughput chromatin conformation capture (Hi-C) technology enables us to explore the spatial architecture of genomes, which is increasingly considered an important regulator of gene expression. To investigate the changes in three-dimensional (3D) chromatin structure and its mediated gene expression during adipogenesis and myogenesis, we comprehensively mapped 3D chromatin organization for four cell types (3T3-L1 pre-adipocytes, 3T3-L1-D adipocytes, C2C12 myoblasts, and C2C12-D myotubes). We demonstrate that the dynamic spatial genome architecture affected gene expression during cell differentiation. A considerable proportion (~22%) of the mouse genome underwent compartment A/B rearrangement during adipogenic and myogenic differentiation, and most (~80%) upregulated marker genes exhibited an active chromatin state with B to A switch or stable A compartment. More than half (65.4%-73.2%) of the topologically associating domains (TADs) are dynamic. The newly formed TAD and intensified local interactions in the Fabp gene cluster indicated more precise structural regulation of the expression of pro-differentiation genes during adipogenesis. About half (32.39%-59.04%) of the differential chromatin interactions (DCIs) during differentiation are promoter interactions, although these DCIs only account for a small proportion of genome-wide interactions (~9.67% in adipogenesis and ~4.24% in myogenesis). These differential promoter interactions were enriched with promoter-enhancer interactions (PEIs), which were mediated by typical adipogenic and myogenic transcription factors. Differential promoter interactions also included more differentially expressed genes than nonpromoter interactions. Our results provide a global view of dynamic chromatin interactions during adipogenesis and myogenesis and are a resource for studying long-range chromatin interactions mediating the expression of pro-differentiation genes.},
}
@article {pmid30260021,
year = {2019},
author = {Luzhin, AV and Flyamer, IM and Khrameeva, EE and Ulianov, SV and Razin, SV and Gavrilov, AA},
title = {Quantitative differences in TAD border strength underly the TAD hierarchy in Drosophila chromosomes.},
journal = {Journal of cellular biochemistry},
volume = {120},
number = {3},
pages = {4494-4503},
doi = {10.1002/jcb.27737},
pmid = {30260021},
issn = {1097-4644},
mesh = {Animals ; CCCTC-Binding Factor/genetics/*metabolism ; Chromatin/genetics/*metabolism ; Chromosomes, Insect/genetics/*metabolism ; Drosophila Proteins/genetics/*metabolism ; Drosophila melanogaster ; },
abstract = {Chromosomes in many organisms, including Drosophila and mammals, are folded into topologically associating domains (TADs). Increasing evidence suggests that TAD folding is hierarchical, wherein subdomains combine to form larger superdomains, instead of a sequence of nonoverlapping domains. Here, we studied the hierarchical structure of TADs in Drosophila. We show that the boundaries of TADs of different hierarchical levels are characterized by the presence of different portions of active chromatin, but do not vary in the binding of architectural proteins, such as CCCTC binding factor or cohesin. The apparent hierarchy of TADs in Drosophila chromosomes is not likely to have functional importance but rather reflects various options of long-range chromatin folding directed by the distribution of active and inactive chromatin segments and may represent population average.},
}
@article {pmid30248133,
year = {2018},
author = {Shrestha, S and Oh, DH and McKowen, JK and Dassanayake, M and Hart, CM},
title = {4C-seq characterization of Drosophila BEAF binding regions provides evidence for highly variable long-distance interactions between active chromatin.},
journal = {PloS one},
volume = {13},
number = {9},
pages = {e0203843},
pmid = {30248133},
issn = {1932-6203},
mesh = {Animals ; Binding Sites ; Chromatin/genetics/physiology ; Chromatin Assembly and Disassembly/genetics ; Chromosome Mapping ; Chromosomes/metabolism ; DNA-Binding Proteins/*genetics/physiology ; Drosophila Proteins/*genetics/metabolism/physiology ; Drosophila melanogaster/genetics/metabolism ; Eye Proteins/*genetics/physiology ; Gene Expression Regulation/genetics ; Genome, Insect ; In Situ Hybridization, Fluorescence ; Insulator Elements/*genetics ; Promoter Regions, Genetic/genetics ; Sequence Analysis, DNA/methods ; Transcription Initiation Site ; Transcriptional Activation/*physiology ; },
abstract = {Chromatin organization is crucial for nuclear functions such as gene regulation, DNA replication and DNA repair. Insulator binding proteins, such as the Drosophila Boundary Element-Associated Factor (BEAF), are involved in chromatin organization. To further understand the role of BEAF, we detected cis- and trans-interaction partners of four BEAF binding regions (viewpoints) using 4C (circular chromosome conformation capture) and analyzed their association with different genomic features. Previous genome-wide mapping found that BEAF usually binds near transcription start sites, often of housekeeping genes, so our viewpoints were selected to reflect this. Our 4C data show the interaction partners of our viewpoints are highly variable and generally enriched for active chromatin marks. The most consistent association was with housekeeping genes, a feature in common with our viewpoints. Fluorescence in situ hybridization indicated that the long-distance interactions occur even in the absence of BEAF. These data are most consistent with a model in which BEAF is redundant with other factors found at active promoters. Our results point to principles of long-distance interactions made by active chromatin, supporting a previously proposed model in which condensed chromatin is sticky and associates into topologically associating domains (TADs) separated by active chromatin. We propose that the highly variable long-distance interactions we detect are driven by redundant factors that open chromatin to promote transcription, combined with active chromatin filling spaces between TADs while packing of TADs relative to each other varies from cell to cell.},
}
@article {pmid30239812,
year = {2018},
author = {Cook, PR and Marenduzzo, D},
title = {Transcription-driven genome organization: a model for chromosome structure and the regulation of gene expression tested through simulations.},
journal = {Nucleic acids research},
volume = {46},
number = {19},
pages = {9895-9906},
pmid = {30239812},
issn = {1362-4962},
support = {MR/K010867/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Animals ; Chromatin Assembly and Disassembly ; Chromosome Structures/*physiology ; Computational Biology/methods ; Computer Simulation ; *Gene Expression Regulation ; Genome/*genetics ; Humans ; *Models, Genetic ; Transcription, Genetic/*physiology ; },
abstract = {Current models for the folding of the human genome see a hierarchy stretching down from chromosome territories, through A/B compartments and topologically-associating domains (TADs), to contact domains stabilized by cohesin and CTCF. However, molecular mechanisms underlying this folding, and the way folding affects transcriptional activity, remain obscure. Here we review physical principles driving proteins bound to long polymers into clusters surrounded by loops, and present a parsimonious yet comprehensive model for the way the organization determines function. We argue that clusters of active RNA polymerases and their transcription factors are major architectural features; then, contact domains, TADs and compartments just reflect one or more loops and clusters. We suggest tethering a gene close to a cluster containing appropriate factors-a transcription factory-increases the firing frequency, and offer solutions to many current puzzles concerning the actions of enhancers, super-enhancers, boundaries and eQTLs (expression quantitative trait loci). As a result, the activity of any gene is directly influenced by the activity of other transcription units around it in 3D space, and this is supported by Brownian-dynamics simulations of transcription factors binding to cognate sites on long polymers.},
}
@article {pmid30218370,
year = {2018},
author = {Miura, H and Poonperm, R and Takahashi, S and Hiratani, I},
title = {Practical Analysis of Hi-C Data: Generating A/B Compartment Profiles.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1861},
number = {},
pages = {221-245},
doi = {10.1007/978-1-4939-8766-5_16},
pmid = {30218370},
issn = {1940-6029},
mesh = {Animals ; Chromatin/metabolism/*ultrastructure ; Computational Biology ; DNA/chemistry/metabolism ; Genomics/*methods ; High-Throughput Nucleotide Sequencing/*methods ; Humans ; Mice ; *Nucleic Acid Conformation ; Sequence Analysis, DNA/methods ; *Software ; },
abstract = {Recent advances in next-generation sequencing (NGS) and chromosome conformation capture (3C) analysis have led to the development of Hi-C, a genome-wide version of the 3C method. Hi-C has identified new levels of chromosome organization such as A/B compartments, topologically associating domains (TADs) as well as large megadomains on the inactive X chromosome, while allowing the identification of chromatin loops at the genome scale. Despite its powerfulness, Hi-C data analysis is much more involved compared to conventional NGS applications such as RNA-seq or ChIP-seq and requires many more steps. This presents a significant hurdle for those who wish to implement Hi-C technology into their laboratory. On the other hand, genomics data repository sites sometimes contain processed Hi-C data sets, allowing researchers to perform further analysis without the need for high-spec workstations and servers. In this chapter, we provide a detailed description on how to calculate A/B compartment profiles from processed Hi-C data on the autosomes and the active/inactive X chromosomes.},
}
@article {pmid30173918,
year = {2018},
author = {Sun, JH and Zhou, L and Emerson, DJ and Phyo, SA and Titus, KR and Gong, W and Gilgenast, TG and Beagan, JA and Davidson, BL and Tassone, F and Phillips-Cremins, JE},
title = {Disease-Associated Short Tandem Repeats Co-localize with Chromatin Domain Boundaries.},
journal = {Cell},
volume = {175},
number = {1},
pages = {224-238.e15},
pmid = {30173918},
issn = {1097-4172},
support = {T32 HL007954/HL/NHLBI NIH HHS/United States ; DP2 MH110247/MH/NIMH NIH HHS/United States ; R01 GM113929/GM/NIGMS NIH HHS/United States ; U01 HL129998/HL/NHLBI NIH HHS/United States ; T32 HG000046/HG/NHGRI NIH HHS/United States ; },
mesh = {Adult ; Brain/cytology/pathology ; CCCTC-Binding Factor/genetics/physiology ; Cell Line ; Chromatin/*genetics/physiology ; Chromatin Assembly and Disassembly/genetics/physiology ; CpG Islands/genetics/physiology ; DNA/genetics ; Disease/etiology/genetics ; Female ; Fragile X Mental Retardation Protein/genetics/metabolism/physiology ; Fragile X Syndrome/genetics/metabolism ; Genome, Human/genetics ; Humans ; Male ; Microsatellite Repeats/genetics/*physiology ; Trinucleotide Repeat Expansion/genetics/*physiology ; },
abstract = {More than 25 inherited human disorders are caused by the unstable expansion of repetitive DNA sequences termed short tandem repeats (STRs). A fundamental unresolved question is why some STRs are susceptible to pathologic expansion, whereas thousands of repeat tracts across the human genome are relatively stable. Here, we discover that nearly all disease-associated STRs (daSTRs) are located at boundaries demarcating 3D chromatin domains. We identify a subset of boundaries with markedly higher CpG island density compared to the rest of the genome. daSTRs specifically localize to ultra-high-density CpG island boundaries, suggesting they might be hotspots for epigenetic misregulation or topological disruption linked to STR expansion. Fragile X syndrome patients exhibit severe boundary disruption in a manner that correlates with local loss of CTCF occupancy and the degree of FMR1 silencing. Our data uncover higher-order chromatin architecture as a new dimension in understanding repeat expansion disorders.},
}
@article {pmid30157436,
year = {2018},
author = {Karki, S and Kennedy, DE and Mclean, K and Grzybowski, AT and Maienschein-Cline, M and Banerjee, S and Xu, H and Davis, E and Mandal, M and Labno, C and Powers, SE and Le Beau, MM and Dinner, AR and Singh, H and Ruthenburg, AJ and Clark, MR},
title = {Regulated Capture of Vκ Gene Topologically Associating Domains by Transcription Factories.},
journal = {Cell reports},
volume = {24},
number = {9},
pages = {2443-2456},
pmid = {30157436},
issn = {2211-1247},
support = {R01 AI120715/AI/NIAID NIH HHS/United States ; R01 GM052736/GM/NIGMS NIH HHS/United States ; T32 GM007281/GM/NIGMS NIH HHS/United States ; UL1 TR002003/TR/NCATS NIH HHS/United States ; },
mesh = {Animals ; Humans ; Immunoglobulin Variable Region/*genetics ; Transcription, Genetic/*genetics ; },
abstract = {Expression of vast repertoires of antigen receptors by lymphocytes, with each cell expressing a single receptor, requires stochastic activation of individual variable (V) genes for transcription and recombination. How this occurs remains unknown. Using single-cell RNA sequencing (scRNA-seq) and allelic variation, we show that individual pre-B cells monoallelically transcribe divergent arrays of Vκ genes, thereby opening stochastic repertoires for subsequent Vκ-Jκ recombination. Transcription occurs upon translocation of Vκ genes to RNA polymerase II arrayed on the nuclear matrix in transcription factories. Transcription is anchored by CTCF-bound sites or E2A-loaded Vκ promotors and continues over large genomic distances delimited only by topological associating domains (TADs). Prior to their monoallelic activation, Vκ loci are transcriptionally repressed by cyclin D3, which prevents capture of Vκ gene containing TADs by transcription factories. Cyclin D3 also represses protocadherin, olfactory, and other monoallelically expressed genes, suggesting a widely deployed mechanism for coupling monoallelic gene activation with cell cycle exit.},
}
@article {pmid30143639,
year = {2018},
author = {Pascual-Reguant, L and Blanco, E and Galan, S and Le Dily, F and Cuartero, Y and Serra-Bardenys, G and Di Carlo, V and Iturbide, A and Cebrià-Costa, JP and Nonell, L and de Herreros, AG and Di Croce, L and Marti-Renom, MA and Peiró, S},
title = {Lamin B1 mapping reveals the existence of dynamic and functional euchromatin lamin B1 domains.},
journal = {Nature communications},
volume = {9},
number = {1},
pages = {3420},
pmid = {30143639},
issn = {2041-1723},
support = {609989/ERC_/European Research Council/International ; },
mesh = {Animals ; Cell Nucleus/metabolism ; Chromatin Immunoprecipitation ; Epithelial-Mesenchymal Transition/genetics/physiology ; Euchromatin/chemistry/genetics/metabolism ; Fluorescence Recovery After Photobleaching ; Humans ; Lamin Type B/chemistry/genetics/*metabolism ; Mice ; },
abstract = {Lamins (A/C and B) are major constituents of the nuclear lamina (NL). Structurally conserved lamina-associated domains (LADs) are formed by genomic regions that contact the NL. Lamins are also found in the nucleoplasm, with a yet unknown function. Here we map the genome-wide localization of lamin B1 in an euchromatin-enriched fraction of the mouse genome and follow its dynamics during the epithelial-to-mesenchymal transition (EMT). Lamin B1 associates with actively expressed and open euchromatin regions, forming dynamic euchromatin lamin B1-associated domains (eLADs) of about 0.3 Mb. Hi-C data link eLADs to the 3D organization of the mouse genome during EMT and correlate lamin B1 enrichment at topologically associating domain (TAD) borders with increased border strength. Having reduced levels of lamin B1 alters the EMT transcriptional signature and compromises the acquisition of mesenchymal traits. Thus, during EMT, the process of genome reorganization in mouse involves dynamic changes in eLADs.},
}
@article {pmid30115746,
year = {2018},
author = {Petryk, N and Dalby, M and Wenger, A and Stromme, CB and Strandsby, A and Andersson, R and Groth, A},
title = {MCM2 promotes symmetric inheritance of modified histones during DNA replication.},
journal = {Science (New York, N.Y.)},
volume = {361},
number = {6409},
pages = {1389-1392},
doi = {10.1126/science.aau0294},
pmid = {30115746},
issn = {1095-9203},
support = {//European Research Council/International ; },
mesh = {Animals ; Cell Division ; Cell Line ; Chromatids/metabolism ; *DNA Replication ; Embryonic Stem Cells ; *Histone Code ; Histones/*metabolism ; Mice ; Minichromosome Maintenance Complex Component 2/genetics/*metabolism ; Protein Processing, Post-Translational ; },
abstract = {During genome replication, parental histones are recycled to newly replicated DNA with their posttranslational modifications (PTMs). Whether sister chromatids inherit modified histones evenly remains unknown. We measured histone PTM partition to sister chromatids in embryonic stem cells. We found that parental histones H3-H4 segregate to both daughter DNA strands with a weak leading-strand bias, skewing partition at topologically associating domain (TAD) borders and enhancers proximal to replication initiation zones. Segregation of parental histones to the leading strand increased markedly in cells with histone-binding mutations in MCM2, part of the replicative helicase, exacerbating histone PTM sister chromatid asymmetry. This work reveals how histones are inherited to sister chromatids and identifies a mechanism by which the replication machinery ensures symmetric cell division.},
}
@article {pmid30111883,
year = {2018},
author = {Li, A and Yin, X and Xu, B and Wang, D and Han, J and Wei, Y and Deng, Y and Xiong, Y and Zhang, Z},
title = {Decoding topologically associating domains with ultra-low resolution Hi-C data by graph structural entropy.},
journal = {Nature communications},
volume = {9},
number = {1},
pages = {3265},
pmid = {30111883},
issn = {2041-1723},
abstract = {Submegabase-size topologically associating domains (TAD) have been observed in high-throughput chromatin interaction data (Hi-C). However, accurate detection of TADs depends on ultra-deep sequencing and sophisticated normalization procedures. Here we propose a fast and normalization-free method to decode the domains of chromosomes (deDoc) that utilizes structural information theory. By treating Hi-C contact matrix as a representation of a graph, deDoc partitions the graph into segments with minimal structural entropy. We show that structural entropy can also be used to determine the proper bin size of the Hi-C data. By applying deDoc to pooled Hi-C data from 10 single cells, we detect megabase-size TAD-like domains. This result implies that the modular structure of the genome spatial organization may be fundamental to even a small cohort of single cells. Our algorithms may facilitate systematic investigations of chromosomal domains on a larger scale than hitherto have been possible.},
}
@article {pmid30109602,
year = {2018},
author = {Crémazy, FG and Rashid, FM and Haycocks, JR and Lamberte, LE and Grainger, DC and Dame, RT},
title = {Determination of the 3D Genome Organization of Bacteria Using Hi-C.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1837},
number = {},
pages = {3-18},
doi = {10.1007/978-1-4939-8675-0_1},
pmid = {30109602},
issn = {1940-6029},
mesh = {Chromosomes, Bacterial/*chemistry/*genetics ; Escherichia coli/genetics ; Gene Library ; *Genome, Bacterial ; *Genomics/methods ; *High-Throughput Nucleotide Sequencing ; Imaging, Three-Dimensional ; *Molecular Conformation ; },
abstract = {The spatial organization of genomes is based on their hierarchical compartmentalization in topological domains. There is growing evidence that bacterial genomes are organized into insulated domains similar to the Topologically Associating Domains (TADs) detected in eukaryotic cells. Chromosome conformation capture (3C) technologies are used to analyze in vivo DNA proximity based on ligation of distal DNA segments crossed-linked by bridging proteins. By combining 3C and high-throughput sequencing, the Hi-C method reveals genome-wide interactions within topological domains and global genome structure as a whole. This chapter provides detailed guidelines for the preparation of Hi-C sequencing libraries for bacteria.},
}
@article {pmid30089831,
year = {2018},
author = {Shi, G and Liu, L and Hyeon, C and Thirumalai, D},
title = {Interphase human chromosome exhibits out of equilibrium glassy dynamics.},
journal = {Nature communications},
volume = {9},
number = {1},
pages = {3161},
pmid = {30089831},
issn = {2041-1723},
mesh = {Algorithms ; Chromosomes, Human/*chemistry ; Chromosomes, Human, Pair 10/chemistry ; Chromosomes, Human, Pair 5/chemistry ; Cluster Analysis ; Computational Biology ; Computer Simulation ; Epigenomics ; Euchromatin/chemistry ; Genome ; Heterochromatin/chemistry ; Humans ; *Interphase ; Models, Genetic ; *Molecular Dynamics Simulation ; *Nucleic Acid Conformation ; },
abstract = {Fingerprints of the three-dimensional organization of genomes have emerged using advances in Hi-C and imaging techniques. However, genome dynamics is poorly understood. Here, we create the chromosome copolymer model (CCM) by representing chromosomes as a copolymer with two epigenetic loci types corresponding to euchromatin and heterochromatin. Using novel clustering techniques, we establish quantitatively that the simulated contact maps and topologically associating domains (TADs) for chromosomes 5 and 10 and those inferred from Hi-C experiments are in good agreement. Chromatin exhibits glassy dynamics with coherent motion on micron scale. The broad distribution of the diffusion exponents of the individual loci, which quantitatively agrees with experiments, is suggestive of highly heterogeneous dynamics. This is reflected in the cell-to-cell variations in the contact maps. Chromosome organization is hierarchical, involving the formation of chromosome droplets (CDs) on genomic scale, coinciding with the TAD size, followed by coalescence of the CDs, reminiscent of Ostwald ripening.},
}
@article {pmid30086749,
year = {2018},
author = {Krefting, J and Andrade-Navarro, MA and Ibn-Salem, J},
title = {Evolutionary stability of topologically associating domains is associated with conserved gene regulation.},
journal = {BMC biology},
volume = {16},
number = {1},
pages = {87},
pmid = {30086749},
issn = {1741-7007},
mesh = {Animals ; *Chromatin Assembly and Disassembly ; *Evolution, Molecular ; *Gene Expression ; *Gene Expression Regulation ; *Genome ; Genome, Human ; Humans ; Mice ; },
abstract = {BACKGROUND: The human genome is highly organized in the three-dimensional nucleus. Chromosomes fold locally into topologically associating domains (TADs) defined by increased intra-domain chromatin contacts. TADs contribute to gene regulation by restricting chromatin interactions of regulatory sequences, such as enhancers, with their target genes. Disruption of TADs can result in altered gene expression and is associated to genetic diseases and cancers. However, it is not clear to which extent TAD regions are conserved in evolution and whether disruption of TADs by evolutionary rearrangements can alter gene expression.<br><br>RESULTS: Here, we hypothesize that TADs represent essential functional units of genomes, which are stable against rearrangements during evolution. We investigate this using whole-genome alignments to identify evolutionary rearrangement breakpoints of different vertebrate species. Rearrangement breakpoints are strongly enriched at TAD boundaries and depleted within TADs across species. Furthermore, using gene expression data across many tissues in mouse and human, we show that genes within TADs have more conserved expression patterns. Disruption of TADs by evolutionary rearrangements is associated with changes in gene expression profiles, consistent with a functional role of TADs in gene expression regulation.<br><br>CONCLUSIONS: Together, these results indicate that TADs are conserved building blocks of genomes with regulatory functions that are often reshuffled as a whole instead of being disrupted by rearrangements.},
}
@article {pmid30028293,
year = {2018},
author = {Majumder, K and Wang, J and Boftsi, M and Fuller, MS and Rede, JE and Joshi, T and Pintel, DJ},
title = {Parvovirus minute virus of mice interacts with sites of cellular DNA damage to establish and amplify its lytic infection.},
journal = {eLife},
volume = {7},
number = {},
pages = {},
pmid = {30028293},
issn = {2050-084X},
support = {F32 AI131468/AI/NIAID NIH HHS/United States ; R01 AI046458/AI/NIAID NIH HHS/United States ; R01 AI116595/AI/NIAID NIH HHS/United States ; AI046458//National Institute of Allergy and Infectious Diseases/International ; R56 AI046458/AI/NIAID NIH HHS/United States ; AI131468//National Institute of Allergy and Infectious Diseases/International ; AI116595//National Institute of Allergy and Infectious Diseases/International ; },
mesh = {Animals ; *DNA Damage ; DNA Repair ; Genetic Engineering ; Genome, Viral ; Histones/metabolism ; Male ; Mice ; Minute Virus of Mice/genetics/*physiology ; Rats ; Virus Replication ; },
abstract = {We have developed a generally adaptable, novel high-throughput Viral Chromosome Conformation Capture assay (V3C-seq) for use in trans that allows genome-wide identification of the direct interactions of a lytic virus genome with distinct regions of the cellular chromosome. Upon infection, we found that the parvovirus Minute Virus of Mice (MVM) genome initially associated with sites of cellular DNA damage that in mock-infected cells also exhibited DNA damage as cells progressed through S-phase. As infection proceeded, new DNA damage sites were induced, and virus subsequently also associated with these. Sites of association identified biochemically were confirmed microscopically and MVM could be targeted specifically to artificially induced sites of DNA damage. Thus, MVM established replication at cellular DNA damage sites, which provide replication and expression machinery, and as cellular DNA damage accrued, virus spread additionally to newly damaged sites to amplify infection. MVM-associated sites overlap significantly with previously identified topologically-associated domains (TADs).},
}
@article {pmid30017478,
year = {2018},
author = {Menghi, F and Barthel, FP and Yadav, V and Tang, M and Ji, B and Tang, Z and Carter, GW and Ruan, Y and Scully, R and Verhaak, RGW and Jonkers, J and Liu, ET},
title = {The Tandem Duplicator Phenotype Is a Prevalent Genome-Wide Cancer Configuration Driven by Distinct Gene Mutations.},
journal = {Cancer cell},
volume = {34},
number = {2},
pages = {197-210.e5},
pmid = {30017478},
issn = {1878-3686},
support = {R01 CA095175/CA/NCI NIH HHS/United States ; P30 CA034196/CA/NCI NIH HHS/United States ; U54 DK107967/DK/NIDDK NIH HHS/United States ; R25 HG007631/HG/NHGRI NIH HHS/United States ; R01 CA190121/CA/NCI NIH HHS/United States ; R01 CA186714/CA/NCI NIH HHS/United States ; R01 CA217991/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cyclin E/genetics ; Female ; *Gene Duplication ; Genes, BRCA1 ; Genes, p53 ; *Genomic Instability ; Humans ; Mice ; *Mutation ; Neoplasms/*genetics ; Oncogene Proteins/genetics ; Phenotype ; *Tandem Repeat Sequences ; Triple Negative Breast Neoplasms/genetics ; Whole Genome Sequencing ; },
abstract = {The tandem duplicator phenotype (TDP) is a genome-wide instability configuration primarily observed in breast, ovarian, and endometrial carcinomas. Here, we stratify TDP tumors by classifying their tandem duplications (TDs) into three span intervals, with modal values of 11 kb, 231 kb, and 1.7 Mb, respectively. TDPs with ∼11 kb TDs feature loss of TP53 and BRCA1. TDPs with ∼231 kb and ∼1.7 Mb TDs associate with CCNE1 pathway activation and CDK12 disruptions, respectively. We demonstrate that p53 and BRCA1 conjoint abrogation drives TDP induction by generating short-span TDP mammary tumors in genetically modified mice lacking them. Lastly, we show how TDs in TDP tumors disrupt heterogeneous combinations of tumor suppressors and chromatin topologically associating domains while duplicating oncogenes and super-enhancers.},
}
@article {pmid30008320,
year = {2018},
author = {Ogiyama, Y and Schuettengruber, B and Papadopoulos, GL and Chang, JM and Cavalli, G},
title = {Polycomb-Dependent Chromatin Looping Contributes to Gene Silencing during Drosophila Development.},
journal = {Molecular cell},
volume = {71},
number = {1},
pages = {73-88.e5},
doi = {10.1016/j.molcel.2018.05.032},
pmid = {30008320},
issn = {1097-4164},
mesh = {Animals ; CRISPR-Cas Systems ; Chromatin/genetics/*metabolism ; Drosophila Proteins/genetics/*metabolism ; Drosophila melanogaster ; *Gene Silencing ; Polycomb-Group Proteins/genetics/*metabolism ; },
abstract = {Interphase chromatin is organized into topologically associating domains (TADs). Within TADs, chromatin looping interactions are formed between DNA regulatory elements, but their functional importance for the establishment of the 3D genome organization and gene regulation during development is unclear. Using high-resolution Hi-C experiments, we analyze higher order 3D chromatin organization during Drosophila embryogenesis and identify active and repressive chromatin loops that are established with different kinetics and depend on distinct factors: Zelda-dependent active loops are formed before the midblastula transition between transcribed genes over long distances. Repressive loops within polycomb domains are formed after the midblastula transition between polycomb response elements by the action of GAGA factor and polycomb proteins. Perturbation of PRE function by CRISPR/Cas9 genome engineering affects polycomb domain formation and destabilizes polycomb-mediated silencing. Preventing loop formation without removal of polycomb components also decreases silencing efficiency, suggesting that chromatin architecture can play instructive roles in gene regulation during development. VIDEO ABSTRACT.},
}
@article {pmid30006052,
year = {2018},
author = {Franke, M and Gómez-Skarmeta, JL},
title = {An evolutionary perspective of regulatory landscape dynamics in development and disease.},
journal = {Current opinion in cell biology},
volume = {55},
number = {},
pages = {24-29},
doi = {10.1016/j.ceb.2018.06.009},
pmid = {30006052},
issn = {1879-0410},
mesh = {Animals ; *Biological Evolution ; Cell Differentiation/genetics ; Disease/*genetics ; Embryonic Development/*genetics ; *Gene Expression Regulation, Developmental ; Genome ; Humans ; },
abstract = {The organization of animal genomes into topologically associating domains (TADs) provides a structural scaffold in which cis-regulatory elements (CREs) operate on their target genes. Determining the position of CREs and genes relative to TADs has become instrumental to trace gene expression changes during evolution and in diseases. Here we will review recent studies and discuss TADs as structural units with respect to their conservation and stability during genome reorganization. Furthermore, we describe how TAD restructuring contributed to morphological novelties during evolution but also their deleterious effects associated with disease. Despite considering TADs as structural units, the nested and dynamic scaffold within TADs contributes to tissue-specific gene expression, implying that such changes can also account for gene expression differences during evolution.},
}
@article {pmid30004017,
year = {2019},
author = {Hou, J and Wang, X},
title = {The polycomb group proteins functions in epithelial to mesenchymal transition in lung cancer.},
journal = {Seminars in cell &amp; developmental biology},
volume = {90},
number = {},
pages = {138-143},
doi = {10.1016/j.semcdb.2018.07.010},
pmid = {30004017},
issn = {1096-3634},
mesh = {Chromatin/genetics/metabolism ; *Epithelial-Mesenchymal Transition/genetics ; Humans ; Lung Neoplasms/genetics/*metabolism/pathology ; Polycomb-Group Proteins/*metabolism ; },
abstract = {Polycomb group proteins (PcG) play important roles in the maintenance of DNA sequencing and multi-dimensional organization of genome. The main PcG complexes are consisted of Polycomb repressive complex 1 and 2, of which the diversity is dependent upon target gene sequences and functions. The present review initially explores the mechanism-based relationship and functional roles of PcG proteins in the interplay between epithelial mesenchymal transition (EMT) and chromatin dynamics in lung cancer. PcG proteins regulate the target genes by modifying histone and chromosome conformation and influencing chromatin looping and long-range interactions between topologically associating domains (TADs). PcG proteins regulate target genes expression and long-distance interactions between TADs in nucleus in the development of EMT and lung cancer. PcG plays decisive regulatory roles in epithelial differentiation and transition or signaling and activation of oncogenes, by promoting the isoforms at the transcriptional levels, to drive EMT to greater invasive ability and carcinogenesis. With the development of single cell systems biology and gene editing, PcG roles in 3D genome organization, heterogeneity, and EMT will be furthermore understood at single cell levels.},
}
@article {pmid29994683,
year = {2019},
author = {Malik, L and Patro, R},
title = {Rich Chromatin Structure Prediction from Hi-C Data.},
journal = {IEEE/ACM transactions on computational biology and bioinformatics},
volume = {16},
number = {5},
pages = {1448-1458},
doi = {10.1109/TCBB.2018.2851200},
pmid = {29994683},
issn = {1557-9964},
mesh = {Algorithms ; Animals ; *Chromatin/chemistry/genetics ; Cluster Analysis ; Drosophila/genetics ; Genomics/*methods ; High-Throughput Nucleotide Sequencing/*methods ; Humans ; Mice ; },
abstract = {Recent studies involving the 3-dimensional conformation of chromatin have revealed the important role it has to play in different processes within the cell. These studies have also led to the discovery of densely interacting segments of the chromosome, called topologically associating domains. The accurate identification of these domains from Hi-C interaction data is an interesting and important computational problem for which numerous methods have been proposed. Unfortunately, most existing algorithms designed to identify these domains assume that they are non-overlapping whereas there is substantial evidence to believe a nested structure exists. We present a methodology to predict hierarchical chromatin domains using chromatin conformation capture data. Our method predicts domains at different resolutions, calculated using intrinsic properties of the chromatin data, and effectively clusters these to construct the hierarchy. At each individual level, the domains are non-overlapping in such a way that the intra-domain interaction frequencies are maximized. We show that our predicted structure is highly enriched for actively transcribing housekeeping genes and various chromatin markers, including CTCF, around the domain boundaries. We also show that large-scale domains, at multiple resolutions within our hierarchy, are conserved across cell types and species. We also provide comparisons against existing tools for extracting hierarchical domains. Our software, Matryoshka, is written in C++11 and licensed under GPL v3; it is available at https://github.com/COMBINE-lab/matryoshka.},
}
@article {pmid29981443,
year = {2019},
author = {Zhang, L and Song, D and Zhu, B and Wang, X},
title = {The role of nuclear matrix protein HNRNPU in maintaining the architecture of 3D genome.},
journal = {Seminars in cell &amp; developmental biology},
volume = {90},
number = {},
pages = {161-167},
doi = {10.1016/j.semcdb.2018.07.006},
pmid = {29981443},
issn = {1096-3634},
mesh = {Chromatin/*genetics/metabolism ; Genome, Human/*genetics ; Heterogeneous-Nuclear Ribonucleoprotein U/*metabolism ; Humans ; },
abstract = {The complexity of higher eukaryote genomes is far from being explained by linear information. There is a need to understand roles of genome regulation at the organism level through defining a comprehensive profile of chromosomal organization. Chromosome conformation capture (3C)-based studies reveal that higher-order of chromatin include not only long-range chromatin loops, but also compartments and topologically associating domains as the basis of genome structure and functions. However, the molecular machinery how the genome is spatially organized is still inadequate. Exciting progress has been made with the development of today's technology, we find that heterogeneous nuclear ribonucleoprotein U, initially identified as a structural nuclear protein, plays important role in three-dimensional (3D) genome organization by high-throughput assays. The disruption of this protein not only results in compartment switching on of the genome, it also reduces of TAD boundary strengths at borders between two types of compartments, and regulates chromatin loop by decrease its intensities. In addition, HNRNPU mainly binds to active chromatin. Most of HNRNPU peaks is consistent with CTCF or RAD21.It also plays an irreplaceable role in the processes of mitosis. This review aims to discuss the role of HNRNPU in maintaining the 3D chromatin architecture, as well as the recent development and human diseases involved in this nuclear matrix (NM)-associated protein.},
}
@article {pmid29972771,
year = {2018},
author = {Kaaij, LJT and van der Weide, RH and Ketting, RF and de Wit, E},
title = {Systemic Loss and Gain of Chromatin Architecture throughout Zebrafish Development.},
journal = {Cell reports},
volume = {24},
number = {1},
pages = {1-10.e4},
pmid = {29972771},
issn = {2211-1247},
mesh = {Animals ; Chromatin/*metabolism ; Embryonic Development/*genetics ; Enhancer Elements, Genetic/genetics ; Epigenomics ; Genome ; Histone Code ; Zebrafish/*embryology/*genetics ; },
abstract = {The spatial organization of chromosomes is critical in establishing gene expression programs. We generated in situ Hi-C maps throughout zebrafish development to gain insight into higher-order chromatin organization and dynamics. Zebrafish chromosomes segregate in active and inactive chromatin (A/B compartments), which are further organized into topologically associating domains (TADs). Zebrafish A/B compartments and TADs have genomic features similar to those of their mammalian counterparts, including evolutionary conservation and enrichment of CTCF binding sites at TAD borders. At the earliest time point, when there is no zygotic transcription, the genome is highly structured. After zygotic genome activation (ZGA), the genome loses structural features, which are re-established throughout early development. Despite the absence of structural features, we see clustering of super-enhancers in the 3D genome. Our results provide insight into vertebrate genome organization and demonstrate that the developing zebrafish embryo is a powerful model system to study the dynamics of nuclear organization.},
}
@article {pmid29967174,
year = {2018},
author = {Nuebler, J and Fudenberg, G and Imakaev, M and Abdennur, N and Mirny, LA},
title = {Chromatin organization by an interplay of loop extrusion and compartmental segregation.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {115},
number = {29},
pages = {E6697-E6706},
pmid = {29967174},
issn = {1091-6490},
support = {R01 GM114190/GM/NIGMS NIH HHS/United States ; U54 CA193419/CA/NCI NIH HHS/United States ; U54 DK107980/DK/NIDDK NIH HHS/United States ; },
mesh = {Animals ; Cell Cycle Proteins/metabolism ; Chromatin/*metabolism ; Chromatin Assembly and Disassembly/*physiology ; Chromosomal Proteins, Non-Histone/metabolism ; Chromosomes, Mammalian/*metabolism ; *Models, Biological ; },
abstract = {Mammalian chromatin is spatially organized at many scales showing two prominent features in interphase: (i) alternating regions (1-10 Mb) of active and inactive chromatin that spatially segregate into different compartments, and (ii) domains (<1 Mb), that is, regions that preferentially interact internally [topologically associating domains (TADs)] and are central to gene regulation. There is growing evidence that TADs are formed by active extrusion of chromatin loops by cohesin, whereas compartmentalization is established according to local chromatin states. Here, we use polymer simulations to examine how loop extrusion and compartmental segregation work collectively and potentially interfere in shaping global chromosome organization. A model with differential attraction between euchromatin and heterochromatin leads to phase separation and reproduces compartmentalization as observed in Hi-C. Loop extrusion, essential for TAD formation, in turn, interferes with compartmentalization. Our integrated model faithfully reproduces Hi-C data from puzzling experimental observations where altering loop extrusion also led to changes in compartmentalization. Specifically, depletion of chromatin-associated cohesin reduced TADs and revealed finer compartments, while increased processivity of cohesin strengthened large TADs and reduced compartmentalization; and depletion of the TAD boundary protein CTCF weakened TADs while leaving compartments unaffected. We reveal that these experimental perturbations are special cases of a general polymer phenomenon of active mixing by loop extrusion. Our results suggest that chromatin organization on the megabase scale emerges from competition of nonequilibrium active loop extrusion and epigenetically defined compartment structure.},
}
@article {pmid29949963,
year = {2018},
author = {Sauerwald, N and Kingsford, C},
title = {Quantifying the similarity of topological domains across normal and cancer human cell types.},
journal = {Bioinformatics (Oxford, England)},
volume = {34},
number = {13},
pages = {i475-i483},
pmid = {29949963},
issn = {1367-4811},
support = {P41 GM103712/GM/NIGMS NIH HHS/United States ; R01 GM122935/GM/NIGMS NIH HHS/United States ; R01 HG007104/HG/NHGRI NIH HHS/United States ; },
mesh = {Cell Line ; Cell Line, Tumor ; Chromatin/metabolism/*ultrastructure ; Chromosomes, Human/metabolism/ultrastructure ; Genomics/*methods ; Humans ; Neoplasms/metabolism/ultrastructure ; Sequence Analysis, DNA/methods ; *Software ; },
abstract = {MOTIVATION: Three-dimensional chromosome structure has been increasingly shown to influence various levels of cellular and genomic functions. Through Hi-C data, which maps contact frequency on chromosomes, it has been found that structural elements termed topologically associating domains (TADs) are involved in many regulatory mechanisms. However, we have little understanding of the level of similarity or variability of chromosome structure across cell types and disease states. In this study, we present a method to quantify resemblance and identify structurally similar regions between any two sets of TADs.<br><br>RESULTS: We present an analysis of 23 human Hi-C samples representing various tissue types in normal and cancer cell lines. We quantify global and chromosome-level structural similarity, and compare the relative similarity between cancer and non-cancer cells. We find that cancer cells show higher structural variability around commonly mutated pan-cancer genes than normal cells at these same locations.<br><br>Software for the methods and analysis can be found at https://github.com/Kingsford-Group/localtadsim.},
}
@article {pmid29932245,
year = {2018},
author = {Lumley, T and Brody, J and Peloso, G and Morrison, A and Rice, K},
title = {FastSKAT: Sequence kernel association tests for very large sets of markers.},
journal = {Genetic epidemiology},
volume = {42},
number = {6},
pages = {516-527},
pmid = {29932245},
issn = {1098-2272},
support = {RC2 HL102419/HL/NHLBI NIH HHS/United States ; U01HL137162/HL/NHLBI NIH HHS/United States ; R01 HL103612/HL/NHLBI NIH HHS/United States ; R01 HL120393/HL/NHLBI NIH HHS/United States ; U01 HL080295/HL/NHLBI NIH HHS/United States ; HHSN268200800007C/HL/NHLBI NIH HHS/United States ; R01 HL087652/HL/NHLBI NIH HHS/United States ; N01HC55222/HL/NHLBI NIH HHS/United States ; U54 HG003273/HG/NHGRI NIH HHS/United States ; N01HC85086/HL/NHLBI NIH HHS/United States ; N02 HL64278/HL/NHLBI NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; HHSN268201200036C/HL/NHLBI NIH HHS/United States ; HHSN268201700001I/HL/NHLBI NIH HHS/United States ; HHSN268201700004I/HL/NHLBI NIH HHS/United States ; R01AG023629/AG/NIA NIH HHS/United States ; U01 HL137162/HL/NHLBI NIH HHS/United States ; N01HC85082/HL/NHLBI NIH HHS/United States ; N01HC85083/HL/NHLBI NIH HHS/United States ; N01HC25195/HL/NHLBI NIH HHS/United States ; HHSN268201700002I/HL/NHLBI NIH HHS/United States ; HHSN268201700005I/HL/NHLBI NIH HHS/United States ; N01HC85079/HL/NHLBI NIH HHS/United States ; R01 AG023629/AG/NIA NIH HHS/United States ; N01HC85080/HL/NHLBI NIH HHS/United States ; HHSN268201700003I/HL/NHLBI NIH HHS/United States ; N01HC85081/HL/NHLBI NIH HHS/United States ; },
mesh = {*Algorithms ; Chromosomes, Human/metabolism ; *Genetic Association Studies ; Genetic Markers ; Histones/metabolism ; Humans ; *Sequence Analysis, DNA ; Statistics as Topic ; Time Factors ; },
abstract = {The sequence kernel association test (SKAT) is widely used to test for associations between a phenotype and a set of genetic variants that are usually rare. Evaluating tail probabilities or quantiles of the null distribution for SKAT requires computing the eigenvalues of a matrix related to the genotype covariance between markers. Extracting the full set of eigenvalues of this matrix (an <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi>n</mml:mi><mml:mo>×</mml:mo><mml:mi>n</mml:mi></mml:mrow></mml:math> matrix, for n subjects) has computational complexity proportional to n[3] . As SKAT is often used when <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi>n</mml:mi><mml:mo>></mml:mo><mml:msup><mml:mn>10</mml:mn><mml:mn>4</mml:mn></mml:msup></mml:mrow></mml:math> , this step becomes a major bottleneck in its use in practice. We therefore propose fastSKAT, a new computationally inexpensive but accurate approximations to the tail probabilities, in which the k largest eigenvalues of a weighted genotype covariance matrix or the largest singular values of a weighted genotype matrix are extracted, and a single term based on the Satterthwaite approximation is used for the remaining eigenvalues. While the method is not particularly sensitive to the choice of k, we also describe how to choose its value, and show how fastSKAT can automatically alert users to the rare cases where the choice may affect results. As well as providing faster implementation of SKAT, the new method also enables entirely new applications of SKAT that were not possible before; we give examples grouping variants by topologically associating domains, and comparing chromosome-wide association by class of histone marker.},
}
@article {pmid29914971,
year = {2018},
author = {Lazar, NH and Nevonen, KA and O'Connell, B and McCann, C and O'Neill, RJ and Green, RE and Meyer, TJ and Okhovat, M and Carbone, L},
title = {Epigenetic maintenance of topological domains in the highly rearranged gibbon genome.},
journal = {Genome research},
volume = {28},
number = {7},
pages = {983-997},
pmid = {29914971},
issn = {1549-5469},
support = {P51 OD011092/OD/NIH HHS/United States ; T15 LM007088/LM/NLM NIH HHS/United States ; U24 HG009084/HG/NHGRI NIH HHS/United States ; },
mesh = {Animals ; Chromatin/genetics ; CpG Islands/genetics ; Epigenesis, Genetic/*genetics ; Epigenomics/methods ; Genome/*genetics ; Genomics/methods ; Humans ; Synteny/genetics ; },
abstract = {The relationship between evolutionary genome remodeling and the three-dimensional structure of the genome remain largely unexplored. Here, we use the heavily rearranged gibbon genome to examine how evolutionary chromosomal rearrangements impact genome-wide chromatin interactions, topologically associating domains (TADs), and their epigenetic landscape. We use high-resolution maps of gibbon-human breaks of synteny (BOS), apply Hi-C in gibbon, measure an array of epigenetic features, and perform cross-species comparisons. We find that gibbon rearrangements occur at TAD boundaries, independent of the parameters used to identify TADs. This overlap is supported by a remarkable genetic and epigenetic similarity between BOS and TAD boundaries, namely presence of CpG islands and SINE elements, and enrichment in CTCF and H3K4me3 binding. Cross-species comparisons reveal that regions orthologous to BOS also correspond with boundaries of large (400-600 kb) TADs in human and other mammalian species. The colocalization of rearrangement breakpoints and TAD boundaries may be due to higher chromatin fragility at these locations and/or increased selective pressure against rearrangements that disrupt TAD integrity. We also examine the small portion of BOS that did not overlap with TAD boundaries and gave rise to novel TADs in the gibbon genome. We postulate that these new TADs generally lack deleterious consequences. Last, we show that limited epigenetic homogenization occurs across breakpoints, irrespective of their time of occurrence in the gibbon lineage. Overall, our findings demonstrate remarkable conservation of chromatin interactions and epigenetic landscape in gibbons, in spite of extensive genomic shuffling.},
}
@article {pmid29887375,
year = {2018},
author = {Wang, CY and Jégu, T and Chu, HP and Oh, HJ and Lee, JT},
title = {SMCHD1 Merges Chromosome Compartments and Assists Formation of Super-Structures on the Inactive X.},
journal = {Cell},
volume = {174},
number = {2},
pages = {406-421.e25},
pmid = {29887375},
issn = {1097-4172},
support = {R01 GM090278/GM/NIGMS NIH HHS/United States ; R37 GM058839/GM/NIGMS NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; },
mesh = {Alleles ; Animals ; Cell Line ; Chromosomal Proteins, Non-Histone/genetics/*metabolism ; Chromosomes, Mammalian/*chemistry/metabolism ; DNA Methylation ; Female ; Heterochromatin/metabolism ; Histones/genetics/metabolism ; Male ; Mice ; Mouse Embryonic Stem Cells/cytology/metabolism ; Principal Component Analysis ; RNA, Long Noncoding/genetics/metabolism ; *X Chromosome Inactivation ; },
abstract = {Mammalian chromosomes are partitioned into A/B compartments and topologically associated domains (TADs). The inactive X (Xi) chromosome, however, adopts a distinct conformation without evident compartments or TADs. Here, through exploration of an architectural protein, structural-maintenance-of-chromosomes hinge domain containing 1 (SMCHD1), we probe how the Xi is reconfigured during X chromosome inactivation. A/B compartments are first fused into "S1" and "S2" compartments, coinciding with Xist spreading into gene-rich domains. SMCHD1 then binds S1/S2 compartments and merges them to create a compartment-less architecture. Contrary to current views, TADs remain on the Xi but in an attenuated state. Ablating SMCHD1 results in a persistent S1/S2 organization and strengthening of TADs. Furthermore, loss of SMCHD1 causes regional defects in Xist spreading and erosion of heterochromatic silencing. We present a stepwise model for Xi folding, where SMCHD1 attenuates a hidden layer of Xi architecture to facilitate Xist spreading.},
}
@article {pmid29875794,
year = {2018},
author = {daSilva, LF and Beckedorff, FC and Ayupe, AC and Amaral, MS and Mesel, V and Videira, A and Reis, EM and Setubal, JC and Verjovski-Almeida, S},
title = {Chromatin Landscape Distinguishes the Genomic Loci of Hundreds of Androgen-Receptor-Associated LincRNAs From the Loci of Non-associated LincRNAs.},
journal = {Frontiers in genetics},
volume = {9},
number = {},
pages = {132},
pmid = {29875794},
issn = {1664-8021},
abstract = {Cell signaling events triggered by androgen hormone in prostate cells is dependent on activation of the androgen receptor (AR) transcription factor. Androgen hormone binding to AR promotes its displacement from the cytoplasm to the nucleus and AR binding to DNA motifs, thus inducing activatory and inhibitory transcriptional programs through a complex regulatory mechanism not yet fully understood. In this work, we performed RNA-seq deep-sequencing of LNCaP prostate cancer cells and found over 7000 expressed long intergenic non-coding RNAs (lincRNAs), of which ∼4000 are novel lincRNAs, and 258 lincRNAs have their expression activated by androgen. Immunoprecipitation of AR, followed by large-scale sequencing of co-immunoprecipitated RNAs (RIP-Seq) has identified in the LNCaP cell line a total of 619 lincRNAs that were significantly enriched (FDR < 10%, DESeq2) in the anti-Androgen Receptor (antiAR) fraction in relation to the control fraction (non-specific IgG), and we named them Androgen-Receptor-Associated lincRNAs (ARA-lincRNAs). A genome-wide analysis showed that protein-coding gene neighbors to ARA-lincRNAs had a significantly higher androgen-induced change in expression than protein-coding genes neighboring lincRNAs not associated to AR. To find relevant epigenetic signatures enriched at the ARA-lincRNAs' transcription start sites (TSSs) we used a machine learning approach and identified that the ARA-lincRNA genomic loci in LNCaP cells are significantly enriched with epigenetic marks that are characteristic of in cis enhancer RNA regulators, and that the H3K27ac mark of active enhancers is conspicuously enriched at the TSS of ARA-lincRNAs adjacent to androgen-activated protein-coding genes. In addition, LNCaP topologically associating domains (TADs) that comprise chromatin regions with ARA-lincRNAs exhibit transcription factor contents, epigenetic marks and gene transcriptional activities that are significantly different from TADs not containing ARA-lincRNAs. This work highlights the possible involvement of hundreds of lincRNAs working in synergy with the AR on the genome-wide androgen-induced gene regulatory program in prostate cells.},
}
@article {pmid29871881,
year = {2018},
author = {Lecellier, CH and Wasserman, WW and Mathelier, A},
title = {Human Enhancers Harboring Specific Sequence Composition, Activity, and Genome Organization Are Linked to the Immune Response.},
journal = {Genetics},
volume = {209},
number = {4},
pages = {1055-1071},
pmid = {29871881},
issn = {1943-2631},
mesh = {Base Composition ; Base Sequence ; Chromatin/*genetics ; *Enhancer Elements, Genetic ; Gene Regulatory Networks ; Genome, Human ; Humans ; *Immunity, Cellular ; },
abstract = {The FANTOM5 consortium recently characterized 65,423 human enhancers from 1829 cell and tissue samples using the Cap Analysis of Gene Expression technology. We showed that the guanine and cytosine content at enhancer regions distinguishes two classes of enhancers harboring distinct DNA structural properties at flanking regions. A functional analysis of their predicted gene targets highlighted one class of enhancers as significantly enriched for associations with immune response genes. Moreover, these enhancers were specifically enriched for regulatory motifs recognized by transcription factors involved in immune response. We observed that enhancers enriched for links to immune response genes were more cell-type specific, preferentially activated upon bacterial infection, and with specific response activity. Looking at chromatin capture data, we found that the two classes of enhancers were lying in distinct topologically associating domains and chromatin loops. Our results suggest that specific nucleotide compositions encode for classes of enhancers that are functionally distinct and specifically organized in the human genome.},
}
@article {pmid29867216,
year = {2018},
author = {Kojic, A and Cuadrado, A and De Koninck, M and Giménez-Llorente, D and Rodríguez-Corsino, M and Gómez-López, G and Le Dily, F and Marti-Renom, MA and Losada, A},
title = {Distinct roles of cohesin-SA1 and cohesin-SA2 in 3D chromosome organization.},
journal = {Nature structural &amp; molecular biology},
volume = {25},
number = {6},
pages = {496-504},
pmid = {29867216},
issn = {1545-9985},
support = {609989/ERC_/European Research Council/International ; },
mesh = {CCCTC-Binding Factor/genetics/metabolism ; Cell Cycle Proteins/metabolism/*physiology ; Chromosomal Proteins, Non-Histone/metabolism/*physiology ; *Chromosomes, Human ; Down-Regulation/physiology ; Enhancer Elements, Genetic ; Gene Expression Regulation/physiology ; Humans ; Protein Binding ; Transcription, Genetic ; },
abstract = {Two variant cohesin complexes containing SMC1, SMC3, RAD21 and either SA1 (also known as STAG1) or SA2 (also known as STAG2) are present in all cell types. We report here their genomic distribution and specific contributions to genome organization in human cells. Although both variants are found at CCCTC-binding factor (CTCF) sites, a distinct population of the SA2-containing cohesin complexes (hereafter referred to as cohesin-SA2) localize to enhancers lacking CTCF, are linked to tissue-specific transcription and cannot be replaced by the SA1-containing cohesin complex (cohesin-SA1) when SA2 is absent, a condition that has been observed in several tumors. Downregulation of each of these variants has different consequences for gene expression and genome architecture. Our results suggest that cohesin-SA1 preferentially contributes to the stabilization of topologically associating domain boundaries together with CTCF, whereas cohesin-SA2 promotes cell-type-specific contacts between enhancers and promoters independently of CTCF. Loss of cohesin-SA2 rewires local chromatin contacts and alters gene expression. These findings provide insights into how cohesin mediates chromosome folding and establish a novel framework to address the consequences of mutations in cohesin genes in cancer.},
}
@article {pmid29858282,
year = {2018},
author = {Rada-Iglesias, A and Grosveld, FG and Papantonis, A},
title = {Forces driving the three-dimensional folding of eukaryotic genomes.},
journal = {Molecular systems biology},
volume = {14},
number = {6},
pages = {e8214},
pmid = {29858282},
issn = {1744-4292},
mesh = {Animals ; Chromatin/*chemistry ; *Chromatin Assembly and Disassembly ; Eukaryota/*genetics ; *Genome ; Humans ; Nucleic Acid Conformation ; Protein Folding ; Transcription, Genetic ; },
abstract = {The last decade has radically renewed our understanding of higher order chromatin folding in the eukaryotic nucleus. As a result, most current models are in support of a mostly hierarchical and relatively stable folding of chromosomes dividing chromosomal territories into A- (active) and B- (inactive) compartments, which are then further partitioned into topologically associating domains (TADs), each of which is made up from multiple loops stabilized mainly by the CTCF and cohesin chromatin-binding complexes. Nonetheless, the structure-to-function relationship of eukaryotic genomes is still not well understood. Here, we focus on recent work highlighting the biophysical and regulatory forces that contribute to the spatial organization of genomes, and we propose that the various conformations that chromatin assumes are not so much the result of a linear hierarchy, but rather of both converging and conflicting dynamic forces that act on it.},
}
@article {pmid29854282,
year = {2018},
author = {Chyr, J and Guo, D and Zhou, X},
title = {LSCC SNP variant regulates SOX2 modulation of VDAC3.},
journal = {Oncotarget},
volume = {9},
number = {32},
pages = {22340-22352},
pmid = {29854282},
issn = {1949-2553},
support = {R01 GM123037/GM/NIGMS NIH HHS/United States ; U01 AR069395/AR/NIAMS NIH HHS/United States ; U01 CA166886/CA/NCI NIH HHS/United States ; },
abstract = {Lung squamous cell carcinoma (LSCC) is a genomically complex malignancy with no effective treatments. Recent studies have found a large number of DNA alterations such as SOX2 amplification in LSCC patients. As a stem cell transcription factor, SOX2 is important for the maintenance of pluripotent cells and may play a role in cancer. To study the downstream mechanisms of SOX2, we employed expression quantitative trait loci (eQTLs) technology to investigate how the presence of SOX2 affects the expression of target genes. We discovered unique eQTLs, such as rs798827-VDAC3 (FDR p-value = 0.0034), that are only found in SOX2-active patients but not in SOX2-inactive patients. SNP rs798827 is within strong linkage disequilibrium (r[2] = 1) to rs58163073, where rs58163073 [T] allele increases the binding affinity of SOX2 and allele [TA] decreases it. In our analysis, SOX2 silencing downregulates VDAC3 in two LSCC cell lines. Chromatin conformation capturing data indicates that this SNP is located within the same Topologically Associating Domain (TAD) of VDAC3, further suggesting SOX2's role in the regulation of VDAC3 through the binding of rs58163073. By first subgrouping patients based on SOX2 activity, we made more relevant eQTL discoveries and our analysis can be applied to other diseases.},
}
@article {pmid29804679,
year = {2018},
author = {Gassler, J and Flyamer, IM and Tachibana, K},
title = {Single-nucleus Hi-C of mammalian oocytes and zygotes.},
journal = {Methods in cell biology},
volume = {144},
number = {},
pages = {389-407},
doi = {10.1016/bs.mcb.2018.03.032},
pmid = {29804679},
issn = {0091-679X},
mesh = {Animals ; Cell Nucleus/*metabolism ; Cytological Techniques/*methods ; DNA/metabolism ; DNA Fragmentation ; Humans ; Mammals/*metabolism ; Nucleic Acid Amplification Techniques ; *Nucleic Acid Conformation ; Oocytes/*cytology ; Restriction Mapping ; Sonication ; Zygote/*cytology ; },
abstract = {The 3D folding of the genome is linked to essential nuclear processes including gene expression, DNA repair, and replication. Chromatin conformation capture assays such as Hi-C are providing unprecedented insights into higher-order chromatin structure. Bulk Hi-C of millions of cells enables detection of average chromatin features at high resolution but is challenging to apply to rare cell types. This chapter describes our recently developed single-nucleus Hi-C (snHi-C) approach for detection of chromatin contacts in single nuclei of murine oocytes and one-cell embryos (zygotes). The step-by-step protocol includes isolation of these cells, extraction of nuclei, fixation, restriction digestion, ligation, and whole genome amplification. Contacts obtained by snHi-C allow detection of chromatin features including loops, topologically associating domains, and compartments when averaged over the genome. The combination of snHi-C with other single-cell techniques in these and other rare cell types will likely provide a comprehensive picture of how chromatin architecture shapes cell identity.},
}
@article {pmid29797095,
year = {2018},
author = {Manduchi, E and Williams, SM and Chesi, A and Johnson, ME and Wells, AD and Grant, SFA and Moore, JH},
title = {Leveraging epigenomics and contactomics data to investigate SNP pairs in GWAS.},
journal = {Human genetics},
volume = {137},
number = {5},
pages = {413-425},
pmid = {29797095},
issn = {1432-1203},
support = {R21 HD089824/HD/NICHD NIH HHS/United States ; P30 ES013508/ES/NIEHS NIH HHS/United States ; R01 LM010098/LM/NLM NIH HHS/United States ; UC4 DK112217/DK/NIDDK NIH HHS/United States ; },
mesh = {Diabetes Mellitus, Type 2/*genetics/physiopathology ; *Epigenomics ; Genome-Wide Association Study/*statistics &amp; numerical data ; Genotype ; Humans ; Phenotype ; Polymorphism, Single Nucleotide/genetics ; Quantitative Trait Loci/*genetics ; },
abstract = {Although Genome Wide Association Studies (GWAS) have led to many valuable insights into the genetic bases of common diseases over the past decade, the issue of missing heritability has surfaced, as the discovered main effect genetic variants found to date do not account for much of a trait's predicted genetic component. We present a workflow, integrating epigenomics and topologically associating domain data, aimed at discovering trait-associated SNP pairs from GWAS where neither SNP achieved independent genome-wide significance. Each analyzed SNP pair consists of one SNP in a putative active enhancer and another SNP in a putative physically interacting gene promoter in a trait-relevant tissue. As a proof-of-principle case study, we used this approach to identify focused collections of SNP pairs that we analyzed in three independent Type 2 diabetes (T2D) GWAS. This approach led us to discover 35 significant SNP pairs, encompassing both novel signals and signals for which we have found orthogonal support from other sources. Nine of these pairs are consistent with eQTL results, two are consistent with our own capture C experiments, and seven involve signals supported by recent T2D literature.},
}
@article {pmid29790956,
year = {2018},
author = {Cheng, Y and Li, Z and Manupipatpong, S and Lin, L and Li, X and Xu, T and Jiang, YH and Shu, Q and Wu, H and Jin, P},
title = {5-Hydroxymethylcytosine alterations in the human postmortem brains of autism spectrum disorder.},
journal = {Human molecular genetics},
volume = {27},
number = {17},
pages = {2955-2964},
pmid = {29790956},
issn = {1460-2083},
support = {R21 HD087795/HD/NICHD NIH HHS/United States ; R21 MH104316/MH/NIMH NIH HHS/United States ; P01 NS097206/NS/NINDS NIH HHS/United States ; R01 GM122083/GM/NIGMS NIH HHS/United States ; R01 MH098114/MH/NIMH NIH HHS/United States ; R01 NS079625/NS/NINDS NIH HHS/United States ; R21 HD077197/HD/NICHD NIH HHS/United States ; R01 HD088007/HD/NICHD NIH HHS/United States ; R01 NS051630/NS/NINDS NIH HHS/United States ; R01 MH102690/MH/NIMH NIH HHS/United States ; },
mesh = {5-Methylcytosine/*analogs &amp; derivatives/metabolism ; Adolescent ; Adult ; Autism Spectrum Disorder/genetics/*metabolism/*pathology ; Autopsy ; Case-Control Studies ; *DNA Methylation ; *Epigenesis, Genetic ; Female ; Humans ; Male ; Young Adult ; },
abstract = {Autism spectrum disorders (ASDs) include a group of syndromes characterized by impaired language, social and communication skills, in addition to restrictive behaviors or stereotypes. However, with a prevalence of 1.5% in developed countries and high comorbidity rates, no clear underlying mechanism that unifies the heterogeneous phenotypes of ASD exists. 5-hydroxymethylcytosine (5hmC) is highly enriched in the brain and recognized as an essential epigenetic mark in developmental and brain disorders. To explore the role of 5hmC in ASD, we used the genomic DNA isolated from the postmortem cerebellum of both ASD patients and age-matched controls to profile genome-wide distribution of 5hmC. We identified 797 age-dependent differentially hydroxymethylated regions (DhMRs) in the young group (age ≤ 18), while no significant DhMR was identified in the groups over 18 years of age. Pathway and disease association analyses demonstrated that the intragenic DhMRs were in the genes involved in cell-cell communication and neurological disorders. Also, we saw significant 5hmC changes in the larger group of psychiatric genes. Interestingly, we found that the predicted cis functions of non-coding intergenic DhMRs strikingly associate with ASD and intellectual disorders. A significant fraction of intergenic DhMRs overlapped with topologically associating domains. These results together suggest that 5hmC alteration is associated with ASD, particularly in the early development stage, and could contribute to the pathogenesis of ASD.},
}
@article {pmid29772275,
year = {2018},
author = {Kim, JH and Titus, KR and Gong, W and Beagan, JA and Cao, Z and Phillips-Cremins, JE},
title = {5C-ID: Increased resolution Chromosome-Conformation-Capture-Carbon-Copy with in situ 3C and double alternating primer design.},
journal = {Methods (San Diego, Calif.)},
volume = {142},
number = {},
pages = {39-46},
pmid = {29772275},
issn = {1095-9130},
support = {DP2 MH110247/MH/NIMH NIH HHS/United States ; U01 HL129998/HL/NHLBI NIH HHS/United States ; },
mesh = {Animals ; Cell Culture Techniques/methods ; Cells, Cultured ; Chromosome Mapping/*methods ; Chromosomes/chemistry/*genetics ; DNA Primers/*genetics ; Genome/*genetics ; Mice ; Mice, Inbred C57BL ; Mouse Embryonic Stem Cells ; *Nucleic Acid Conformation ; Polymerase Chain Reaction ; Sequence Analysis, DNA ; },
abstract = {Mammalian genomes are folded in a hierarchy of compartments, topologically associating domains (TADs), subTADs, and looping interactions. Currently, there is a great need to evaluate the link between chromatin topology and genome function across many biological conditions and genetic perturbations. Hi-C can generate genome-wide maps of looping interactions but is intractable for high-throughput comparison of loops across multiple conditions due to the enormous number of reads (>6 Billion) required per library. Here, we describe 5C-ID, a new version of Chromosome-Conformation-Capture-Carbon-Copy (5C) with restriction digest and ligation performed in the nucleus (in situ Chromosome-Conformation-Capture (3C)) and ligation-mediated amplification performed with a double alternating primer design. We demonstrate that 5C-ID produces higher-resolution 3D genome folding maps with reduced spatial noise using markedly lower cell numbers than canonical 5C. 5C-ID enables the creation of high-resolution, high-coverage maps of chromatin loops in up to a 30 Megabase subset of the genome at a fraction of the cost of Hi-C.},
}
@article {pmid29763432,
year = {2018},
author = {Huang, AY and Yang, X and Wang, S and Zheng, X and Wu, Q and Ye, AY and Wei, L},
title = {Distinctive types of postzygotic single-nucleotide mosaicisms in healthy individuals revealed by genome-wide profiling of multiple organs.},
journal = {PLoS genetics},
volume = {14},
number = {5},
pages = {e1007395},
pmid = {29763432},
issn = {1553-7404},
mesh = {Adult ; DNA Replication Timing ; Embryonic Development/genetics ; Female ; Genome, Human/*genetics ; Humans ; Male ; Middle Aged ; *Mosaicism ; Mutation ; Organ Specificity/genetics ; *Polymorphism, Single Nucleotide ; Postmortem Changes ; Whole Genome Sequencing/*methods ; Young Adult ; Zygote/*metabolism ; },
abstract = {Postzygotic single-nucleotide mosaicisms (pSNMs) have been extensively studied in tumors and are known to play critical roles in tumorigenesis. However, the patterns and origin of pSNMs in normal organs of healthy humans remain largely unknown. Using whole-genome sequencing and ultra-deep amplicon re-sequencing, we identified and validated 164 pSNMs from 27 postmortem organ samples obtained from five healthy donors. The mutant allele fractions ranged from 1.0% to 29.7%. Inter- and intra-organ comparison revealed two distinctive types of pSNMs, with about half originating during early embryogenesis (embryonic pSNMs) and the remaining more likely to result from clonal expansion events that had occurred more recently (clonal expansion pSNMs). Compared to clonal expansion pSNMs, embryonic pSNMs had higher proportion of C>T mutations with elevated mutation rate at CpG sites. We observed differences in replication timing between these two types of pSNMs, with embryonic and clonal expansion pSNMs enriched in early- and late-replicating regions, respectively. An increased number of embryonic pSNMs were located in open chromatin states and topologically associating domains that transcribed embryonically. Our findings provide new insights into the origin and spatial distribution of postzygotic mosaicism during normal human development.},
}
@article {pmid29757144,
year = {2018},
author = {Matthews, BJ and Waxman, DJ},
title = {Computational prediction of CTCF/cohesin-based intra-TAD loops that insulate chromatin contacts and gene expression in mouse liver.},
journal = {eLife},
volume = {7},
number = {},
pages = {},
pmid = {29757144},
issn = {2050-084X},
support = {R01 DK033765/DK/NIDDK NIH HHS/United States ; R56 DK033765/DK/NIDDK NIH HHS/United States ; R01 ES024421/ES/NIEHS NIH HHS/United States ; ES024421/NH/NIH HHS/United States ; DK33765/NH/NIH HHS/United States ; },
mesh = {Animals ; Binding Sites ; CCCTC-Binding Factor/*metabolism ; Cell Cycle Proteins/*metabolism ; Chromatin/*metabolism ; Chromosomal Proteins, Non-Histone/*metabolism ; Computer Simulation ; DNA/*metabolism ; Female ; *Gene Expression ; Liver/*metabolism ; Male ; Mice ; Protein Binding ; },
abstract = {CTCF and cohesin are key drivers of 3D-nuclear organization, anchoring the megabase-scale Topologically Associating Domains (TADs) that segment the genome. Here, we present and validate a computational method to predict cohesin-and-CTCF binding sites that form intra-TAD DNA loops. The intra-TAD loop anchors identified are structurally indistinguishable from TAD anchors regarding binding partners, sequence conservation, and resistance to cohesin knockdown; further, the intra-TAD loops retain key functional features of TADs, including chromatin contact insulation, blockage of repressive histone mark spread, and ubiquity across tissues. We propose that intra-TAD loops form by the same loop extrusion mechanism as the larger TAD loops, and that their shorter length enables finer regulatory control in restricting enhancer-promoter interactions, which enables selective, high-level expression of gene targets of super-enhancers and genes located within repressive nuclear compartments. These findings elucidate the role of intra-TAD cohesin-and-CTCF binding in nuclear organization associated with widespread insulation of distal enhancer activity.},
}
@article {pmid29729833,
year = {2018},
author = {Zinchenko, A and Berezhnoy, NV and Chen, Q and Nordenskiöld, L},
title = {Compaction of Single-Molecule Megabase-Long Chromatin under the Influence of Macromolecular Crowding.},
journal = {Biophysical journal},
volume = {114},
number = {10},
pages = {2326-2335},
pmid = {29729833},
issn = {1542-0086},
mesh = {Bacteriophage T4 ; Chromatin/drug effects/*metabolism ; DNA, Viral/*metabolism ; Histones/metabolism ; Humans ; Magnesium/pharmacology ; Nucleosomes/drug effects/metabolism ; Polyethylene Glycols/pharmacology ; Sodium/pharmacology ; },
abstract = {The megabase-sized length of chromatin is highly relevant to the state of chromatin in vivo, where it is subject to a highly crowded environment and is organized in topologically associating domains of similar dimension. We developed an in vitro experimental chromatin model system reconstituted from T4 DNA (approximately 166 kbp) and histone octamers and studied the monomolecular compaction of this megabase-sized chromatin fiber under the influence of macromolecular crowding. We used single-molecule fluorescence microscopy and observed compaction in aqueous solutions containing poly(ethylene glycol) in the presence of monovalent (Na[+] and K[+]) and divalent (Mg[2+]) cations. Both DNA and chromatin demonstrated compaction under comparable conditions in the presence of poly(ethylene glycol) and Na[+] or Mg[2+] salt. However, the mechanism of the compaction changed from a first-order phase transition for DNA to a continuous folding for megabase-sized chromatin fibers. A more efficient and pronounced chromatin compaction was observed in the presence of Na[+] compared to K[+]. A flow-stretching technique to unfold DNA and chromatin coils was used to gain further insight into the morphology of partially folded chromatin fibers. The results revealed a distribution of partially folded chromatin fibers. This variability is likely the result of the heterogeneous distribution of nucleosomes on the DNA chain. The packaging of DNA in the form of chromatin in the crowded nuclear environment appears essential to ensure gradual conformational changes of DNA.},
}
@article {pmid29713370,
year = {2018},
author = {Liu, T and Wang, Z},
title = {SOV_refine: A further refined definition of segment overlap score and its significance for protein structure similarity.},
journal = {Source code for biology and medicine},
volume = {13},
number = {},
pages = {1},
pmid = {29713370},
issn = {1751-0473},
support = {R15 GM120650/GM/NIGMS NIH HHS/United States ; },
abstract = {BACKGROUND: The segment overlap score (SOV) has been used to evaluate the predicted protein secondary structures, a sequence composed of helix (H), strand (E), and coil (C), by comparing it with the native or reference secondary structures, another sequence of H, E, and C. SOV's advantage is that it can consider the size of continuous overlapping segments and assign extra allowance to longer continuous overlapping segments instead of only judging from the percentage of overlapping individual positions as Q3 score does. However, we have found a drawback from its previous definition, that is, it cannot ensure increasing allowance assignment when more residues in a segment are further predicted accurately.<br><br>RESULTS: A new way of assigning allowance has been designed, which keeps all the advantages of the previous SOV score definitions and ensures that the amount of allowance&#xa0;assigned is incremental when more elements in a segment are predicted&#xa0;accurately. Furthermore, our improved SOV has achieved a higher correlation with the quality of protein models measured by GDT-TS score&#xa0;and TM-score, indicating its better abilities to evaluate tertiary structure quality at the secondary structure level. We analyzed&#xa0;the&#xa0;statistical significance of&#xa0;SOV scores&#xa0;and found the&#xa0;threshold values&#xa0;for distinguishing&#xa0;two protein structures (SOV_refine&#xa0; >&#xa0;0.19)&#xa0;and indicating&#xa0;whether two proteins&#xa0;are under&#xa0;the same CATH fold (SOV_refine&#xa0;>&#xa0;0.94 and >&#xa0;0.90 for three- and eight-state secondary structures respectively). We provided another&#xa0;two example&#xa0;applications, which are&#xa0;when used as a&#xa0;machine learning feature&#xa0;for protein model quality assessment and&#xa0;comparing different definitions of topologically associating domains.&#xa0;We proved that our newly defined SOV score resulted in better performance.<br><br>CONCLUSIONS: The SOV score can be widely used&#xa0;in bioinformatics research&#xa0;and&#xa0;other&#xa0;fields that need to compare two sequences&#xa0;of letters&#xa0;in which continuous segments have important&#xa0;meanings. We also generalized the previous SOV definitions so that it can work for sequences composed of more than three states (e.g., it can work for the eight-state definition of&#xa0;protein secondary structures). A standalone software package has been implemented in Perl with source code released. The software can be downloaded&#xa0;from http://dna.cs.miami.edu/SOV/.},
}
@article {pmid29692413,
year = {2018},
author = {Spielmann, M and Lupiáñez, DG and Mundlos, S},
title = {Structural variation in the 3D genome.},
journal = {Nature reviews. Genetics},
volume = {19},
number = {7},
pages = {453-467},
doi = {10.1038/s41576-018-0007-0},
pmid = {29692413},
issn = {1471-0064},
mesh = {Chromatin/*genetics/*metabolism ; *DNA Copy Number Variations ; *Gene Dosage ; Gene Expression Regulation/*physiology ; Genome, Human/*physiology ; Humans ; },
abstract = {Structural and quantitative chromosomal rearrangements, collectively referred to as structural variation (SV), contribute to a large extent to the genetic diversity of the human genome and thus are of high relevance for cancer genetics, rare diseases and evolutionary genetics. Recent studies have shown that SVs can not only affect gene dosage but also modulate basic mechanisms of gene regulation. SVs can alter the copy number of regulatory elements or modify the 3D genome by disrupting higher-order chromatin organization such as topologically associating domains. As a result of these position effects, SVs can influence the expression of genes distant from the SV breakpoints, thereby causing disease. The impact of SVs on the 3D genome and on gene expression regulation has to be considered when interpreting the pathogenic potential of these variant types.},
}
@article {pmid29686034,
year = {2017},
author = {Galupa, R and Heard, E},
title = {Topologically Associating Domains in Chromosome Architecture and Gene Regulatory Landscapes during Development, Disease, and Evolution.},
journal = {Cold Spring Harbor symposia on quantitative biology},
volume = {82},
number = {},
pages = {267-278},
doi = {10.1101/sqb.2017.82.035030},
pmid = {29686034},
issn = {1943-4456},
abstract = {The packaging of genetic material into chromatin and chromosomes has been recognized for more than a century, thanks to microscopy and biochemical approaches. This was followed by the progressive realization that chromatin organization is critical for genome functions such as transcription and DNA replication and repair. The recent discovery that chromosomes are partitioned at the submegabase scale into topologically associating domains (TADs) has implications for our understanding of gene regulation during developmental processes such as X-chromosome inactivation, as well as for evolution and for the search for disease-associated loci. Here we discuss our current knowledge about this recently recognized level of mammalian chromosome organization, with a special emphasis on the potential role of TADs as a structural basis for the function and evolution of mammalian regulatory landscapes.},
}
@article {pmid29685368,
year = {2018},
author = {Eagen, KP},
title = {Principles of Chromosome Architecture Revealed by Hi-C.},
journal = {Trends in biochemical sciences},
volume = {43},
number = {6},
pages = {469-478},
pmid = {29685368},
issn = {0968-0004},
support = {DP5 OD024587/OD/NIH HHS/United States ; },
mesh = {Animals ; *Chromosome Mapping ; Chromosomes/*chemistry ; High-Throughput Nucleotide Sequencing ; Humans ; Nucleic Acid Conformation ; },
abstract = {Chromosomes are folded and compacted in interphase nuclei, but the molecular basis of this folding is poorly understood. Chromosome conformation capture methods, such as Hi-C, combine chemical crosslinking of chromatin with fragmentation, DNA ligation, and high-throughput DNA sequencing to detect neighboring loci genome-wide. Hi-C has revealed the segregation of chromatin into active and inactive compartments and the folding of DNA into self-associating domains and loops. Depletion of CTCF, cohesin, or cohesin-associated proteins was recently shown to affect the majority of domains and loops in a manner that is consistent with a model of DNA folding through extrusion of chromatin loops. Compartmentation was not dependent on CTCF or cohesin. Hi-C contact maps represent the superimposition of CTCF/cohesin-dependent and -independent folding states.},
}
@article {pmid29662163,
year = {2018},
author = {Bianco, S and Lupiáñez, DG and Chiariello, AM and Annunziatella, C and Kraft, K and Schöpflin, R and Wittler, L and Andrey, G and Vingron, M and Pombo, A and Mundlos, S and Nicodemi, M},
title = {Polymer physics predicts the effects of structural variants on chromatin architecture.},
journal = {Nature genetics},
volume = {50},
number = {5},
pages = {662-667},
pmid = {29662163},
issn = {1546-1718},
mesh = {Animals ; CCCTC-Binding Factor/genetics ; Cell Line ; Chromatin/*chemistry/*genetics ; Chromatin Assembly and Disassembly/*genetics ; Chromosomes/genetics ; Enhancer Elements, Genetic/genetics ; Gene Expression/genetics ; Humans ; Mice ; Mice, Inbred C57BL ; Polymers/*chemistry ; Promoter Regions, Genetic/genetics ; Receptor, EphA4/genetics ; },
abstract = {Structural variants (SVs) can result in changes in gene expression due to abnormal chromatin folding and cause disease. However, the prediction of such effects remains a challenge. Here we present a polymer-physics-based approach (PRISMR) to model 3D chromatin folding and to predict enhancer-promoter contacts. PRISMR predicts higher-order chromatin structure from genome-wide chromosome conformation capture (Hi-C) data. Using the EPHA4 locus as a model, the effects of pathogenic SVs are predicted in silico and compared to Hi-C data generated from mouse limb buds and patient-derived fibroblasts. PRISMR deconvolves the folding complexity of the EPHA4 locus and identifies SV-induced ectopic contacts and alterations of 3D genome organization in homozygous or heterozygous states. We show that SVs can reconfigure topologically associating domains, thereby producing extensive rewiring of regulatory interactions and causing disease by gene misexpression. PRISMR can be used to predict interactions in silico, thereby providing a tool for analyzing the disease-causing potential of SVs.},
}
@article {pmid29631108,
year = {2018},
author = {Serizay, J and Ahringer, J},
title = {Genome organization at different scales: nature, formation and function.},
journal = {Current opinion in cell biology},
volume = {52},
number = {},
pages = {145-153},
doi = {10.1016/j.ceb.2018.03.009},
pmid = {29631108},
issn = {1879-0410},
support = {092096/WT_/Wellcome Trust/United Kingdom ; C6946/A14492/CRUK_/Cancer Research UK/United Kingdom ; 101863/WT_/Wellcome Trust/United Kingdom ; /MRC_/Medical Research Council/United Kingdom ; },
mesh = {Animals ; Gene Expression Regulation/*genetics ; Genome/*genetics ; Humans ; },
abstract = {Since the discovery of chromosome territories, it has been clear that DNA within the nucleus is spatially organized. During the last decade, a tremendous body of work has described architectural features of chromatin at different spatial scales, such as A/B compartments, topologically associating domains (TADs), and chromatin loops. These features correlate with domains of chromatin marking and gene expression, supporting their relevance for gene regulation. Recent work has highlighted the dynamic nature of spatial folding and investigated mechanisms of their formation. Here we discuss current understanding and highlight key open questions in chromosome organization in animals.},
}
@article {pmid29626919,
year = {2018},
author = {Cremer, T and Cremer, M and Cremer, C},
title = {The 4D Nucleome: Genome Compartmentalization in an Evolutionary Context.},
journal = {Biochemistry. Biokhimiia},
volume = {83},
number = {4},
pages = {313-325},
doi = {10.1134/S000629791804003X},
pmid = {29626919},
issn = {1608-3040},
mesh = {Animals ; *Biological Evolution ; Cell Nucleus/*genetics/metabolism ; Chromatin/genetics/metabolism ; *Chromosome Positioning ; Chromosomes/genetics/metabolism ; *Genome ; Humans ; },
abstract = {4D nucleome research aims to understand the impact of nuclear organization in space and time on nuclear functions, such as gene expression patterns, chromatin replication, and the maintenance of genome integrity. In this review we describe evidence that the origin of 4D genome compartmentalization can be traced back to the prokaryotic world. In cell nuclei of animals and plants chromosomes occupy distinct territories, built up from ~1 Mb chromatin domains, which in turn are composed of smaller chromatin subdomains and also form larger chromatin domain clusters. Microscopic evidence for this higher order chromatin landscape was strengthened by chromosome conformation capture studies, in particular Hi-C. This approach demonstrated ~1 Mb sized, topologically associating domains in mammalian cell nuclei separated by boundaries. Mutations, which destroy boundaries, can result in developmental disorders and cancer. Nucleosomes appeared first as tetramers in the Archaea kingdom and later evolved to octamers built up each from two H2A, two H2B, two H3, and two H4 proteins. Notably, nucleosomes were lost during the evolution of the Dinoflagellata phylum. Dinoflagellate chromosomes remain condensed during the entire cell cycle, but their chromosome architecture differs radically from the architecture of other eukaryotes. In summary, the conservation of fundamental features of higher order chromatin arrangements throughout the evolution of metazoan animals suggests the existence of conserved, but still unknown mechanism(s) controlling this architecture. Notwithstanding this conservation, a comparison of metazoans and protists also demonstrates species-specific structural and functional features of nuclear organization.},
}
@article {pmid29617930,
year = {2018},
author = {Lodato, NJ and Rampersaud, A and Waxman, DJ},
title = {Impact of CAR Agonist Ligand TCPOBOP on Mouse Liver Chromatin Accessibility.},
journal = {Toxicological sciences : an official journal of the Society of Toxicology},
volume = {164},
number = {1},
pages = {115-128},
pmid = {29617930},
issn = {1096-0929},
support = {R01 ES024421/ES/NIEHS NIH HHS/United States ; },
mesh = {Animals ; Chromatin Assembly and Disassembly/*drug effects/genetics ; Constitutive Androstane Receptor ; Female ; Gene Expression Regulation/drug effects ; Ligands ; Liver/*drug effects/metabolism ; Male ; Mice, Inbred Strains ; Promoter Regions, Genetic ; Pyridines/*toxicity ; RNA, Long Noncoding/genetics ; Receptors, Cytoplasmic and Nuclear/*agonists/genetics ; Sex Factors ; },
abstract = {Activation of the nuclear receptor and transcription factor CAR (Nr1i3) by its specific agonist ligand TCPOBOP (1, 4-bis[2-(3, 5-dichloropyridyloxy)]benzene) dysregulates hundreds of genes in mouse liver and is linked to male-biased hepatocarcinogenesis. To elucidate the genomic organization of CAR-induced gene responses, we investigated the distribution of TCPOBOP-responsive RefSeq coding and long noncoding RNA (lncRNA) genes across the megabase-scale topologically associating domains (TADs) that segment the genome, and which provide a structural framework that functionally constrains enhancer-promoter interactions. We show that a subset of TCPOBOP-responsive genes cluster within TADs, and that TCPOBOP-induced genes and TCPOBOP-repressed genes are often found in different TADs. Further, using DNase-seq and DNase hypersensitivity site (DHS) analysis, we identified several thousand genomic regions (ΔDHS) where short-term exposure to TCPOBOP induces localized changes (increases or decreases) in mouse liver chromatin accessibility, many of which cluster in TADs together with TCPOBOP-responsive genes. Sites of chromatin opening were highly enriched nearby genes induced by TCPOBOP and chromatin closing was highly enriched nearby genes repressed by TCPOBOP, consistent with TCPOBOP-responsive ΔDHS serving as enhancers and promoters that positively regulate CAR-responsive genes. Gene expression changes lagged behind chromatin opening or closing for a subset of TCPOBOP-responsive ΔDHS. ΔDHS that were specifically responsive to TCPOBOP in male liver were significantly enriched for genomic regions with a basal male bias in chromatin accessibility; however, the male-biased response of hepatocellular carcinoma-related genes to TCPOBOP was not associated with a correspondingly male-biased ΔDHS response. These studies elucidate the genome-wide organization of CAR-responsive genes and of the thousands of associated genomic sites where TCPOBOP exposure induces both rapid and persistent changes in chromatin accessibility.},
}
@article {pmid29581440,
year = {2018},
author = {Al Bkhetan, Z and Plewczynski, D},
title = {Three-dimensional Epigenome Statistical Model: Genome-wide Chromatin Looping Prediction.},
journal = {Scientific reports},
volume = {8},
number = {1},
pages = {5217},
pmid = {29581440},
issn = {2045-2322},
support = {U54 DK107967/DK/NIDDK NIH HHS/United States ; },
mesh = {Animals ; CCCTC-Binding Factor/*genetics ; Cell Line ; Chromatin/*genetics ; Epigenomics ; Gene Expression Regulation/genetics ; Genome, Human/*genetics ; Histone Code/genetics ; Humans ; Mice ; Promoter Regions, Genetic/genetics ; RNA Polymerase II/*genetics ; },
abstract = {This study aims to understand through statistical learning the basic biophysical mechanisms behind three-dimensional folding of epigenomes. The 3DEpiLoop algorithm predicts three-dimensional chromatin looping interactions within topologically associating domains (TADs) from one-dimensional epigenomics and transcription factor profiles using the statistical learning. The predictions obtained by 3DEpiLoop are highly consistent with the reported experimental interactions. The complex signatures of epigenomic and transcription factors within the physically interacting chromatin regions (anchors) are similar across all genomic scales: genomic domains, chromosomal territories, cell types, and different individuals. We report the most important epigenetic and transcription factor features used for interaction identification either shared, or unique for each of sixteen (16) cell lines. The analysis shows that CTCF interaction anchors are enriched by transcription factors yet deficient in histone modifications, while the opposite is true in the case of RNAP II mediated interactions. The code is available at the repository https://bitbucket.org/4dnucleome/3depiloop .},
}
@article {pmid29572382,
year = {2018},
author = {Xiang, W and Roberti, MJ and Hériché, JK and Huet, S and Alexander, S and Ellenberg, J},
title = {Correlative live and super-resolution imaging reveals the dynamic structure of replication domains.},
journal = {The Journal of cell biology},
volume = {217},
number = {6},
pages = {1973-1984},
pmid = {29572382},
issn = {1540-8140},
support = {U01 DA047728/DA/NIDA NIH HHS/United States ; U01 EB021223/EB/NIBIB NIH HHS/United States ; },
mesh = {Animals ; Cell Line ; DNA/chemistry ; *DNA Replication ; Fluorescent Dyes/metabolism ; *Imaging, Three-Dimensional ; Microscopy, Confocal ; Models, Biological ; Rats ; Staining and Labeling ; },
abstract = {Chromosome organization in higher eukaryotes controls gene expression, DNA replication, and DNA repair. Genome mapping has revealed the functional units of chromatin at the submegabase scale as self-interacting regions called topologically associating domains (TADs) and showed they correspond to replication domains (RDs). A quantitative structural and dynamic description of RD behavior in the nucleus is, however, missing because visualization of dynamic subdiffraction-sized RDs remains challenging. Using fluorescence labeling of RDs combined with correlative live and super-resolution microscopy in situ, we determined biophysical parameters to characterize the internal organization, spacing, and mechanical coupling of RDs. We found that RDs are typically 150 nm in size and contain four co-replicating regions spaced 60 nm apart. Spatially neighboring RDs are spaced 300 nm apart and connected by highly flexible linker regions that couple their motion only <550 nm. Our pipeline allows a robust quantitative characterization of chromosome structure in situ and provides important biophysical parameters to understand general principles of chromatin organization.},
}
@article {pmid29541161,
year = {2018},
author = {Han, J and Zhang, Z and Wang, K},
title = {3C and 3C-based techniques: the powerful tools for spatial genome organization deciphering.},
journal = {Molecular cytogenetics},
volume = {11},
number = {},
pages = {21},
pmid = {29541161},
issn = {1755-8166},
abstract = {It is well known that the chromosomes are organized in the nucleus and this spatial arrangement of genome play a crucial role in gene regulation and genome stability. Different techniques have been developed and applied to uncover the intrinsic mechanism of genome architecture, especially the chromosome conformation capture (3C) and 3C-derived methods. 3C and 3C-derived techniques provide us approaches to perform high-throughput chromatin architecture assays at the genome scale. However, the advantage and disadvantage of current methodologies of C-technologies have not been discussed extensively. In this review, we described and compared the methodologies of C-technologies used in genome organization studies with an emphasis on Hi-C method. We also discussed the crucial challenges facing current genome architecture studies based on 3C and 3C-derived technologies and the direction of future technologies to address currently outstanding questions in the field. These latest news contribute to our current understanding of genome structure, and provide a comprehensive reference for researchers to choose the appropriate method in future application. We consider that these constantly improving technologies will offer a finer and more accurate contact profiles of entire genome and ultimately reveal specific molecular machines govern its shape and function.},
}
@article {pmid29540241,
year = {2018},
author = {Amaral, PP and Leonardi, T and Han, N and Viré, E and Gascoigne, DK and Arias-Carrasco, R and Büscher, M and Pandolfini, L and Zhang, A and Pluchino, S and Maracaja-Coutinho, V and Nakaya, HI and Hemberg, M and Shiekhattar, R and Enright, AJ and Kouzarides, T},
title = {Genomic positional conservation identifies topological anchor point RNAs linked to developmental loci.},
journal = {Genome biology},
volume = {19},
number = {1},
pages = {32},
pmid = {29540241},
issn = {1474-760X},
support = {092096/WT_/Wellcome Trust/United Kingdom ; 268569/ERC_/European Research Council/International ; 10827/CRUK_/Cancer Research UK/United Kingdom ; R01 GM078455/GM/NIGMS NIH HHS/United States ; C6/A18796/CRUK_/Cancer Research UK/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; C6946/A14492/CRUK_/Cancer Research UK/United Kingdom ; },
mesh = {Animals ; Base Sequence ; Chromatin/chemistry ; Conserved Sequence ; *Gene Expression Regulation, Developmental ; *Genetic Loci ; Genome ; Humans ; Mice ; Neoplasms/genetics ; Nucleotide Motifs ; Promoter Regions, Genetic ; RNA, Long Noncoding/chemistry/*genetics ; Transcription Factors/genetics ; },
abstract = {BACKGROUND: The mammalian genome is transcribed into large numbers of long noncoding RNAs (lncRNAs), but the definition of functional lncRNA groups has proven difficult, partly due to their low sequence conservation and lack of identified shared properties. Here we consider promoter conservation and positional conservation as indicators of functional commonality.<br><br>RESULTS: We identify 665 conserved lncRNA promoters in mouse and human that are preserved in genomic position relative to orthologous coding genes. These positionally conserved lncRNA genes are primarily associated with developmental transcription factor loci with which they are coexpressed in a tissue-specific manner. Over half of positionally conserved RNAs in this set are linked to chromatin organization structures, overlapping binding sites for the CTCF chromatin organiser and located at chromatin loop anchor points and borders of topologically associating domains (TADs). We define these RNAs as topological anchor point RNAs (tapRNAs). Characterization of these noncoding RNAs and their associated coding genes shows that they are functionally connected: they regulate each other's expression and influence the metastatic phenotype of cancer cells in vitro in a similar fashion. Furthermore, we find that tapRNAs contain conserved sequence domains that are enriched in motifs for zinc finger domain-containing RNA-binding proteins and transcription factors, whose binding sites are found mutated in cancers.<br><br>CONCLUSIONS: This work leverages positional conservation to identify lncRNAs with potential importance in genome organization, development and disease. The evidence that many developmental transcription factors are physically and functionally connected to lncRNAs represents an exciting stepping-stone to further our understanding of genome regulation.},
}
@article {pmid29538766,
year = {2018},
author = {Yan, Y and Ding, Y and Leng, F and Dunlap, D and Finzi, L},
title = {Protein-mediated loops in supercoiled DNA create large topological domains.},
journal = {Nucleic acids research},
volume = {46},
number = {9},
pages = {4417-4424},
pmid = {29538766},
issn = {1362-4962},
support = {R01 GM084070/GM/NIGMS NIH HHS/United States ; R15 GM109254/GM/NIGMS NIH HHS/United States ; R21 AI125973/AI/NIAID NIH HHS/United States ; },
mesh = {DNA, Superhelical/*chemistry/metabolism ; Lac Repressors/*metabolism ; Torsion, Mechanical ; },
abstract = {Supercoiling can alter the form and base pairing of the double helix and directly impact protein binding. More indirectly, changes in protein binding and the stress of supercoiling also influence the thermodynamic stability of regulatory, protein-mediated loops and shift the equilibria of fundamental DNA/chromatin transactions. For example, supercoiling affects the hierarchical organization and function of chromatin in topologically associating domains (TADs) in both eukaryotes and bacteria. On the other hand, a protein-mediated loop in DNA can constrain supercoiling within a plectonemic structure. To characterize the extent of constrained supercoiling, 400 bp, lac repressor-secured loops were formed in extensively over- or under-wound DNA under gentle tension in a magnetic tweezer. The protein-mediated loops constrained variable amounts of supercoiling that often exceeded the maximum writhe expected for a 400 bp plectoneme. Loops with such high levels of supercoiling appear to be entangled with flanking domains. Thus, loop-mediating proteins operating on supercoiled substrates can establish topological domains that may coordinate gene regulation and other DNA transactions across spans in the genome that are larger than the separation between the binding sites.},
}
@article {pmid29503869,
year = {2018},
author = {Szabo, Q and Jost, D and Chang, JM and Cattoni, DI and Papadopoulos, GL and Bonev, B and Sexton, T and Gurgo, J and Jacquier, C and Nollmann, M and Bantignies, F and Cavalli, G},
title = {TADs are 3D structural units of higher-order chromosome organization in Drosophila.},
journal = {Science advances},
volume = {4},
number = {2},
pages = {eaar8082},
pmid = {29503869},
issn = {2375-2548},
mesh = {Animals ; Biopolymers/chemistry ; Chromatin/chemistry ; Chromosomes, Insect/*chemistry/*genetics ; Drosophila/*genetics ; *Imaging, Three-Dimensional ; Nanoparticles/chemistry ; },
abstract = {Deciphering the rules of genome folding in the cell nucleus is essential to understand its functions. Recent chromosome conformation capture (Hi-C) studies have revealed that the genome is partitioned into topologically associating domains (TADs), which demarcate functional epigenetic domains defined by combinations of specific chromatin marks. However, whether TADs are true physical units in each cell nucleus or whether they reflect statistical frequencies of measured interactions within cell populations is unclear. Using a combination of Hi-C, three-dimensional (3D) fluorescent in situ hybridization, super-resolution microscopy, and polymer modeling, we provide an integrative view of chromatin folding in Drosophila. We observed that repressed TADs form a succession of discrete nanocompartments, interspersed by less condensed active regions. Single-cell analysis revealed a consistent TAD-based physical compartmentalization of the chromatin fiber, with some degree of heterogeneity in intra-TAD conformations and in cis and trans inter-TAD contact events. These results indicate that TADs are fundamental 3D genome units that engage in dynamic higher-order inter-TAD connections. This domain-based architecture is likely to play a major role in regulatory transactions during DNA-dependent processes.},
}
@article {pmid29466755,
year = {2018},
author = {Hu, G and Cui, K and Fang, D and Hirose, S and Wang, X and Wangsa, D and Jin, W and Ried, T and Liu, P and Zhu, J and Rothenberg, EV and Zhao, K},
title = {Transformation of Accessible Chromatin and 3D Nucleome Underlies Lineage Commitment of Early T Cells.},
journal = {Immunity},
volume = {48},
number = {2},
pages = {227-242.e8},
pmid = {29466755},
issn = {1097-4180},
support = {R01 AI083514/AI/NIAID NIH HHS/United States ; Z01 HL005801-05//Intramural NIH HHS/United States ; },
mesh = {Animals ; Cell Differentiation ; *Cell Lineage ; Cell Nucleus/*physiology ; Chromatin/*physiology ; Humans ; Repressor Proteins/physiology ; T-Lymphocytes/*physiology ; Tumor Suppressor Proteins/physiology ; },
abstract = {How chromatin reorganization coordinates differentiation and lineage commitment from hematopoietic stem and progenitor cells (HSPCs) to mature immune cells has not been well understood. Here, we carried out an integrative analysis of chromatin accessibility, topologically associating domains, AB compartments, and gene expression from HSPCs to CD4[+]CD8[+] T cells. We found that abrupt genome-wide changes at all three levels of chromatin organization occur during the transition from double-negative stage 2 (DN2) to DN3, accompanying the T lineage commitment. The transcription factor BCL11B, a critical regulator of T cell commitment, is associated with increased chromatin interaction, and Bcl11b deletion compromised chromatin interaction at its target genes. We propose that these large-scale and concerted changes in chromatin organization present an energy barrier to prevent the cell from reversing its fate to earlier stages or redirecting to alternatives and thus lock the cell fate into the T lineages.},
}
@article {pmid29429976,
year = {2018},
author = {Comoglio, F and Park, HJ and Schoenfelder, S and Barozzi, I and Bode, D and Fraser, P and Green, AR},
title = {Thrombopoietin signaling to chromatin elicits rapid and pervasive epigenome remodeling within poised chromatin architectures.},
journal = {Genome research},
volume = {28},
number = {3},
pages = {295-309},
pmid = {29429976},
issn = {1549-5469},
support = {//Wellcome Trust/United Kingdom ; MC_PC_12009/MRC_/Medical Research Council/United Kingdom ; },
abstract = {Thrombopoietin (TPO) is a critical cytokine regulating hematopoietic stem cell maintenance and differentiation into the megakaryocytic lineage. However, the transcriptional and chromatin dynamics elicited by TPO signaling are poorly understood. Here, we study the immediate early transcriptional and cis-regulatory responses to TPO in hematopoietic stem/progenitor cells (HSPCs) and use this paradigm of cytokine signaling to chromatin to dissect the relation between cis- regulatory activity and chromatin architecture. We show that TPO profoundly alters the transcriptome of HSPCs, with key hematopoietic regulators being transcriptionally repressed within 30 minutes of TPO. By examining cis-regulatory dynamics and chromatin architectures, we demonstrate that these changes are accompanied by rapid and extensive epigenome remodeling of cis-regulatory landscapes that is spatially coordinated within topologically associating domains (TADs). Moreover, TPO-responsive enhancers are spatially clustered and engage in preferential homotypic intra- and inter-TAD interactions that are largely refractory to TPO signaling. By further examining the link between cis-regulatory dynamics and chromatin looping, we show that rapid modulation of cis-regulatory activity is largely independent of chromatin looping dynamics. Finally, we show that, although activated and repressed cis-regulatory elements share remarkably similar DNA sequence compositions, transcription factor binding patterns accurately predict rapid cis-regulatory responses to TPO.},
}
@article {pmid29419817,
year = {2018},
author = {Kolovos, P and Brouwer, RWW and Kockx, CEM and Lesnussa, M and Kepper, N and Zuin, J and Imam, AMA and van de Werken, HJG and Wendt, KS and Knoch, TA and van IJcken, WFJ and Grosveld, F},
title = {Investigation of the spatial structure and interactions of the genome at sub-kilobase-pair resolution using T2C.},
journal = {Nature protocols},
volume = {13},
number = {3},
pages = {459-477},
pmid = {29419817},
issn = {1750-2799},
mesh = {Animals ; Chromatin/ultrastructure ; Chromatin Assembly and Disassembly/physiology ; Chromosome Mapping/methods ; Computational Biology/*methods ; DNA ; Gene Expression Regulation ; Genome/genetics ; Genome, Human/genetics/physiology ; Genomics ; High-Throughput Nucleotide Sequencing/methods ; Humans ; Mice ; Nucleosomes ; Physical Chromosome Mapping/*methods ; Sequence Analysis, DNA/*methods ; Software ; },
abstract = {Chromosome conformation capture (3C) and its derivatives (e.g., 4C, 5C and Hi-C) are used to analyze the 3D organization of genomes. We recently developed targeted chromatin capture (T2C), an inexpensive method for studying the 3D organization of genomes, interactomes and structural changes associated with gene regulation, the cell cycle, and cell survival and development. Here, we present the protocol for T2C based on capture, describing all experimental steps and bio-informatic tools in full detail. T2C offers high resolution, a large dynamic interaction frequency range and a high signal-to-noise ratio. Its resolution is determined by the resulting fragment size of the chosen restriction enzyme, which can lead to sub-kilobase-pair resolution. T2C's high coverage allows the identification of the interactome of each individual DNA fragment, which makes binning of reads (often used in other methods) basically unnecessary. Notably, T2C requires low sequencing efforts. T2C also allows multiplexing of samples for the direct comparison of multiple samples. It can be used to study topologically associating domains (TADs), determining their position, shape, boundaries, and intra- and inter-domain interactions, as well as the composition of aggregated loops, interactions between nucleosomes, individual transcription factor binding sites, and promoters and enhancers. T2C can be performed by any investigator with basic skills in molecular biology techniques in ∼7-8 d. Data analysis requires basic expertise in bioinformatics and in Linux and Python environments.},
}
@article {pmid29416042,
year = {2018},
author = {Gong, Y and Lazaris, C and Sakellaropoulos, T and Lozano, A and Kambadur, P and Ntziachristos, P and Aifantis, I and Tsirigos, A},
title = {Stratification of TAD boundaries reveals preferential insulation of super-enhancers by strong boundaries.},
journal = {Nature communications},
volume = {9},
number = {1},
pages = {542},
pmid = {29416042},
issn = {2041-1723},
support = {P30 CA016087/CA/NCI NIH HHS/United States ; R01 CA216421/CA/NCI NIH HHS/United States ; R00 CA188293/CA/NCI NIH HHS/United States ; R01 CA194923/CA/NCI NIH HHS/United States ; U54 CA193419/CA/NCI NIH HHS/United States ; R01 CA169784/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; CCCTC-Binding Factor ; Chromatin ; Enhancer Elements, Genetic/*genetics ; Epigenomics ; Gene Expression Regulation, Neoplastic/*genetics ; Humans ; Insulator Elements/*genetics ; Machine Learning ; Neoplasms/*genetics ; },
abstract = {The metazoan genome is compartmentalized in areas of highly interacting chromatin known as topologically associating domains (TADs). TADs are demarcated by boundaries mostly conserved across cell types and even across species. However, a genome-wide characterization of TAD boundary strength in mammals is still lacking. In this study, we first use fused two-dimensional lasso as a machine learning method to improve Hi-C contact matrix reproducibility, and, subsequently, we categorize TAD boundaries based on their insulation score. We demonstrate that higher TAD boundary insulation scores are associated with elevated CTCF levels and that they may differ across cell types. Intriguingly, we observe that super-enhancers are preferentially insulated by strong boundaries. Furthermore, we demonstrate that strong TAD boundaries and super-enhancer elements are frequently co-duplicated in cancer patients. Taken together, our findings suggest that super-enhancers insulated by strong TAD boundaries may be exploited, as a functional unit, by cancer cells to promote oncogenesis.},
}
@article {pmid29378768,
year = {2018},
author = {Kurtas, N and Arrigoni, F and Errichiello, E and Zucca, C and Maghini, C and D'Angelo, MG and Beri, S and Giorda, R and Bertuzzo, S and Delledonne, M and Xumerle, L and Rossato, M and Zuffardi, O and Bonaglia, MC},
title = {Chromothripsis and ring chromosome 22: a paradigm of genomic complexity in the Phelan-McDermid syndrome (22q13 deletion syndrome).},
journal = {Journal of medical genetics},
volume = {55},
number = {4},
pages = {269-277},
pmid = {29378768},
issn = {1468-6244},
mesh = {Cesarean Section ; Child, Preschool ; Chromosome Deletion ; Chromosome Disorders/epidemiology/*genetics/pathology ; Chromosomes, Human, Pair 22/genetics ; *Chromothripsis ; Comparative Genomic Hybridization ; Female ; Genomics ; Haploinsufficiency/genetics ; Humans ; Infant ; Membrane Proteins/genetics ; Nerve Tissue Proteins/genetics ; Pregnancy ; Ring Chromosomes ; Transcription Factors/genetics ; *Translocation, Genetic ; },
abstract = {INTRODUCTION: Phelan-McDermid syndrome (PMS) is caused by SHANK3 haploinsufficiency. Its wide phenotypic variation is attributed partly to the type and size of 22q13 genomic lesion (deletion, unbalanced translocation, ring chromosome), partly to additional undefined factors. We investigated a child with severe global neurodevelopmental delay (NDD) compatible with her distal 22q13 deletion, complicated by bilateral perisylvian polymicrogyria (BPP) and urticarial rashes, unreported in PMS.<br><br>METHODS: Following the cytogenetic and array-comparative genomic hybridization (CGH) detection of a r(22) with SHANK3 deletion and two upstream duplications, whole-genome sequencing (WGS) in blood and whole-exome sequencing (WES) in blood and saliva were performed to highlight potential chromothripsis/chromoanagenesis events and any possible BPP-associated variants, even in low-level mosaicism.<br><br>RESULTS: WGS confirmed the deletion and highlighted inversion and displaced order of eight fragments, three of them duplicated. The microhomology-mediated insertion of partial Alu-elements at one breakpoint junction disrupted the topological associating domain joining NFAM1 to the transcriptional coregulator TCF20. WES failed to detect BPP-associated variants.<br><br>CONCLUSIONS: Although we were unable to highlight the molecular basis of BPP, our data suggest that SHANK3 haploinsufficiency and TCF20 misregulation, both associated with intellectual disability, contributed to the patient's NDD, while NFAM1 interruption likely caused her skin rashes, as previously reported. We provide the first example of chromoanasynthesis in a constitutional ring chromosome and reinforce the growing evidence that chromosomal rearrangements may be more complex than estimated by conventional diagnostic approaches and affect the phenotype by global alteration of the topological chromatin organisation rather than simply by deletion or duplication of dosage-sensitive genes.},
}
@article {pmid29365171,
year = {2018},
author = {Jost, D and Vaillant, C},
title = {Epigenomics in 3D: importance of long-range spreading and specific interactions in epigenomic maintenance.},
journal = {Nucleic acids research},
volume = {46},
number = {5},
pages = {2252-2264},
pmid = {29365171},
issn = {1362-4962},
mesh = {Acetylation ; Algorithms ; Animals ; Chromatin/chemistry/*genetics/metabolism ; *Epigenesis, Genetic ; Epigenomics/*methods ; Gene Expression Regulation ; Genome/*genetics ; Histones/metabolism ; Humans ; Methylation ; Models, Genetic ; },
abstract = {Recent progresses of genome-wide chromatin conformation capture techniques have shown that the genome is segmented into hierarchically organized spatial compartments. However, whether this non-random 3D organization only reflects or indeed contributes-and how-to the regulation of genome function remain to be elucidated. The observation in many species that 3D domains correlate strongly with the 1D epigenomic information along the genome suggests a dynamic coupling between chromatin organization and epigenetic regulation. Here, we posit that chromosome folding may contribute to the maintenance of a robust epigenomic identity via the formation of spatial compartments like topologically-associating domains. Using a novel theoretical framework, the living chromatin model, we show that 3D compartmentalization leads to the spatial colocalization of epigenome regulators, thus increasing their local concentration and enhancing their ability to spread an epigenomic signal at long-range. Interestingly, we find that the presence of 1D insulator elements, like CTCF, may contribute greatly to the stable maintenance of adjacent antagonistic epigenomic domains. We discuss the generic implications of our findings in the light of various biological contexts from yeast to human. Our approach provides a modular framework to improve our understanding and to investigate in details the coupling between the structure and function of chromatin.},
}
@article {pmid29357061,
year = {2017},
author = {Zhao, PA and Rivera-Mulia, JC and Gilbert, DM},
title = {Replication Domains: Genome Compartmentalization into Functional Replication Units.},
journal = {Advances in experimental medicine and biology},
volume = {1042},
number = {},
pages = {229-257},
doi = {10.1007/978-981-10-6955-0_11},
pmid = {29357061},
issn = {0065-2598},
mesh = {Animals ; Binding Sites/genetics ; *Chromatin/chemistry/genetics/metabolism ; Chromatin Assembly and Disassembly ; DNA Replication/*physiology ; DNA Replication Timing ; DNA-Binding Proteins/metabolism ; Gene Expression Regulation ; Genome/*genetics/physiology ; Humans ; Replicon/*physiology ; },
abstract = {DNA replication occurs in a defined temporal order during S phase, known as the replication timing programme, which is regulated not only during the cell cycle but also during the process of development and differentiation. The units of replication timing regulation, known as replication domains (RDs), frequently comprise several nearly synchronously firing replication origins. Replication domains correspond to topologically associating domains (TADs) mapped by chromatin conformation capture methods and are likely to be the molecular equivalents of replication foci observed using cytogenetic methods. Both TAD and replication foci are considered to be stable structural units of chromosomes, conserved through the cell cycle and development, and accordingly, the boundaries of RDs also appear to be stable in different cell types. During both normal development and progression of disease, distinct cell states are characterized by unique replication timing signatures, with approximately half of genomic RDs switching replication timing between these cell states. Advances in functional genomics provide hope that we can soon gain an understanding of the cause and consequence of the replication timing programme and its myriad correlations with chromatin context and gene regulation.},
}
@article {pmid29335803,
year = {2018},
author = {Glinsky, GV},
title = {Contribution of transposable elements and distal enhancers to evolution of human-specific features of interphase chromatin architecture in embryonic stem cells.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {26},
number = {1-2},
pages = {61-84},
pmid = {29335803},
issn = {1573-6849},
mesh = {Chromatin/metabolism/*ultrastructure ; DNA Transposable Elements/*genetics ; Enhancer Elements, Genetic/*genetics ; *Evolution, Molecular ; Gene Regulatory Networks ; Genome, Human ; Human Embryonic Stem Cells/*ultrastructure ; Humans ; Interphase ; },
abstract = {Transposable elements have made major evolutionary impacts on creation of primate-specific and human-specific genomic regulatory loci and species-specific genomic regulatory networks (GRNs). Molecular and genetic definitions of human-specific changes to GRNs contributing to development of unique to human phenotypes remain a highly significant challenge. Genome-wide proximity placement analysis of diverse families of human-specific genomic regulatory loci (HSGRL) identified topologically associating domains (TADs) that are significantly enriched for HSGRL and designated rapidly evolving in human TADs. Here, the analysis of HSGRL, hESC-enriched enhancers, super-enhancers (SEs), and specific sub-TAD structures termed super-enhancer domains (SEDs) has been performed. In the hESC genome, 331 of 504 (66%) of SED-harboring TADs contain HSGRL and 68% of SEDs co-localize with HSGRL, suggesting that emergence of HSGRL may have rewired SED-associated GRNs within specific TADs by inserting novel and/or erasing existing non-coding regulatory sequences. Consequently, markedly distinct features of the principal regulatory structures of interphase chromatin evolved in the hESC genome compared to mouse: the SED quantity is 3-fold higher and the median SED size is significantly larger. Concomitantly, the overall TAD quantity is increased by 42% while the median TAD size is significantly decreased (p = 9.11E-37) in the hESC genome. Present analyses illustrate a putative global role for transposable elements and HSGRL in shaping the human-specific features of the interphase chromatin organization and functions, which are facilitated by accelerated creation of novel transcription factor binding sites and new enhancers driven by targeted placement of HSGRL at defined genomic coordinates. A trend toward the convergence of TAD and SED architectures of interphase chromatin in the hESC genome may reflect changes of 3D-folding patterns of linear chromatin fibers designed to enhance both regulatory complexity and functional precision of GRNs by creating predominantly a single gene (or a set of functionally linked genes) per regulatory domain structures. Collectively, present analyses reveal critical evolutionary contributions of transposable elements and distal enhancers to creation of thousands primate- and human-specific elements of a chromatin folding code, which defines the 3D context of interphase chromatin both restricting and facilitating biological functions of GRNs.},
}
@article {pmid29335486,
year = {2018},
author = {Ramírez, F and Bhardwaj, V and Arrigoni, L and Lam, KC and Grüning, BA and Villaveces, J and Habermann, B and Akhtar, A and Manke, T},
title = {High-resolution TADs reveal DNA sequences underlying genome organization in flies.},
journal = {Nature communications},
volume = {9},
number = {1},
pages = {189},
pmid = {29335486},
issn = {2041-1723},
mesh = {Animals ; Biological Evolution ; CCCTC-Binding Factor/genetics/metabolism ; Chromatin/chemistry/*ultrastructure ; Chromatin Assembly and Disassembly ; Chromosome Mapping/*methods ; Chromosomes, Insect/chemistry/*ultrastructure ; DNA-Binding Proteins/genetics/metabolism ; Databases, Genetic ; Drosophila Proteins/genetics/metabolism ; Drosophila melanogaster/*genetics/ultrastructure ; Eye Proteins/genetics/metabolism ; Gene Expression ; *Genome, Insect ; Humans ; Mice ; Molecular Conformation ; Nucleotide Motifs ; Software ; Transcription Factors/genetics/metabolism ; },
abstract = {Despite an abundance of new studies about topologically associating domains (TADs), the role of genetic information in TAD formation is still not fully understood. Here we use our software, HiCExplorer (hicexplorer.readthedocs.io) to annotate >2800 high-resolution (570 bp) TAD boundaries in Drosophila melanogaster. We identify eight DNA motifs enriched at boundaries, including a motif bound by the M1BP protein, and two new boundary motifs. In contrast to mammals, the CTCF motif is only enriched on a small fraction of boundaries flanking inactive chromatin while most active boundaries contain the motifs bound by the M1BP or Beaf-32 proteins. We demonstrate that boundaries can be accurately predicted using only the motif sequences at open chromatin sites. We propose that DNA sequence guides the genome architecture by allocation of boundary proteins in the genome. Finally, we present an interactive online database to access and explore the spatial organization of fly, mouse and human genomes, available at http://chorogenome.ie-freiburg.mpg.de .},
}
@article {pmid29335463,
year = {2018},
author = {Wang, Q and Sun, Q and Czajkowsky, DM and Shao, Z},
title = {Sub-kb Hi-C in D. melanogaster reveals conserved characteristics of TADs between insect and mammalian cells.},
journal = {Nature communications},
volume = {9},
number = {1},
pages = {188},
pmid = {29335463},
issn = {2041-1723},
mesh = {Animals ; Biological Evolution ; CCCTC-Binding Factor/genetics/metabolism ; Cell Cycle Proteins/genetics/metabolism ; Chromatin/chemistry/*ultrastructure ; Chromatin Assembly and Disassembly ; Chromosomal Proteins, Non-Histone/genetics/metabolism ; Chromosome Mapping/instrumentation/*methods ; Chromosomes, Insect/chemistry/*ultrastructure ; DNA-Binding Proteins/genetics/metabolism ; Drosophila Proteins/genetics/metabolism ; Drosophila melanogaster/*genetics/ultrastructure ; Eye Proteins/genetics/metabolism ; Gene Expression ; *Genome, Insect ; Humans ; Mammals/*genetics ; Microtubule-Associated Proteins/genetics/metabolism ; Molecular Conformation ; Nuclear Matrix-Associated Proteins/genetics/metabolism ; Nuclear Proteins/genetics/metabolism ; },
abstract = {Topologically associating domains (TADs) are fundamental elements of the eukaryotic genomic structure. However, recent studies suggest that the insulating complexes, CTCF/cohesin, present at TAD borders in mammals are absent from those in Drosophila melanogaster, raising the possibility that border elements are not conserved among metazoans. Using in situ Hi-C with sub-kb resolution, here we show that the D. melanogaster genome is almost completely partitioned into >4000 TADs, nearly sevenfold more than previously identified. The overwhelming majority of these TADs are demarcated by the insulator complexes, BEAF-32/CP190, or BEAF-32/Chromator, indicating that these proteins may play an analogous role in flies as that of CTCF/cohesin in mammals. Moreover, extended regions previously thought to be unstructured are shown to consist of small contiguous TADs, a property also observed in mammals upon re-examination. Altogether, our work demonstrates that fundamental features associated with the higher-order folding of the genome are conserved from insects to mammals.},
}
@article {pmid29334377,
year = {2018},
author = {Norton, HK and Emerson, DJ and Huang, H and Kim, J and Titus, KR and Gu, S and Bassett, DS and Phillips-Cremins, JE},
title = {Detecting hierarchical genome folding with network modularity.},
journal = {Nature methods},
volume = {15},
number = {2},
pages = {119-122},
pmid = {29334377},
issn = {1548-7105},
support = {DP2 MH110247/MH/NIMH NIH HHS/United States ; U01 HL129998/HL/NHLBI NIH HHS/United States ; },
mesh = {Chromatin/*genetics/*metabolism ; Computational Biology/*methods ; *Computer Graphics ; *Genome, Human ; High-Throughput Nucleotide Sequencing ; Humans ; },
abstract = {Mammalian genomes are folded in a hierarchy of compartments, topologically associating domains (TADs), subTADs and looping interactions. Here, we describe 3DNetMod, a graph theory-based method for sensitive and accurate detection of chromatin domains across length scales in Hi-C data. We identify nested, partially overlapping TADs and subTADs genome wide by optimizing network modularity and varying a single resolution parameter. 3DNetMod can be applied broadly to understand genome reconfiguration in development and disease.},
}
@article {pmid29289958,
year = {2018},
author = {Mehrjouy, MM and Fonseca, ACS and Ehmke, N and Paskulin, G and Novelli, A and Benedicenti, F and Mencarelli, MA and Renieri, A and Busa, T and Missirian, C and Hansen, C and Abe, KT and Speck-Martins, CE and Vianna-Morgante, AM and Bak, M and Tommerup, N},
title = {Regulatory variants of FOXG1 in the context of its topological domain organisation.},
journal = {European journal of human genetics : EJHG},
volume = {26},
number = {2},
pages = {186-196},
pmid = {29289958},
issn = {1476-5438},
mesh = {Cells, Cultured ; Child ; Child, Preschool ; *Chromosomal Position Effects ; Chromosome Breakpoints ; Embryonic Stem Cells/metabolism ; *Enhancer Elements, Genetic ; Female ; Forkhead Transcription Factors/*genetics ; Humans ; Infant ; Male ; Nerve Tissue Proteins/*genetics ; Neural Stem Cells/metabolism ; Phenotype ; Rett Syndrome/*genetics/pathology ; Sequence Deletion ; Translocation, Genetic ; },
abstract = {FOXG1 syndrome is caused by FOXG1 intragenic point mutations, or by long-range position effects (LRPE) of intergenic structural variants. However, the size of the FOXG1 regulatory landscape is uncertain, because the associated topologically associating domain (TAD) in fibroblasts is split into two domains in embryonic stem cells (hESC). Indeed, it has been suggested that the pathogenetic mechanism of deletions that remove the stem-cell-specific TAD boundary may be enhancer adoption due to ectopic activity of enhancer(s) located in the distal hESC-TAD. Herein we map three de novo translocation breakpoints to the proximal regulatory domain of FOXG1. The classical FOXG1 syndrome in these and in other translocation patients, and in a patient with an intergenic deletion that removes the hESC-specific TAD boundary, do not support the hypothesised enhancer adoption as a main contributor to the FOXG1 syndrome. Also, virtual 4 C and HiC-interaction data suggest that the hESC-specific TAD boundary may not be critical for FOXG1 regulation in a majority of human cells and tissues, including brain tissues and a neuronal progenitor cell line. Our data support the importance of a critical regulatory region (SRO) proximal to the hESC-specific TAD boundary. We further narrow this critical region by a deletion distal to the hESC-specific boundary, associated with a milder clinical phenotype. The distance from FOXG1 to the SRO (> 500 kb) highlight a limitation of ENCODE DNase hypersensitivity data for functional prediction of LRPE. Moreover, the SRO has little overlap with a cluster of frequently associating regions (FIREs) located in the proximal hESC-TAD.},
}
@article {pmid29284669,
year = {2018},
author = {Zimmerman, MW and Liu, Y and He, S and Durbin, AD and Abraham, BJ and Easton, J and Shao, Y and Xu, B and Zhu, S and Zhang, X and Li, Z and Weichert-Leahey, N and Young, RA and Zhang, J and Look, AT},
title = {MYC Drives a Subset of High-Risk Pediatric Neuroblastomas and Is Activated through Mechanisms Including Enhancer Hijacking and Focal Enhancer Amplification.},
journal = {Cancer discovery},
volume = {8},
number = {3},
pages = {320-335},
pmid = {29284669},
issn = {2159-8290},
support = {P30 CA021765/CA/NCI NIH HHS/United States ; R01 CA180692/CA/NCI NIH HHS/United States ; R35 CA210064/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Animals, Genetically Modified ; Cell Line, Tumor ; Child ; *Enhancer Elements, Genetic ; Gene Amplification ; Gene Expression Regulation, Neoplastic ; Humans ; Luminescent Proteins/genetics ; N-Myc Proto-Oncogene Protein/genetics ; Neoplasms, Experimental/genetics ; Neuroblastoma/*genetics/mortality/pathology ; Proto-Oncogene Proteins c-myc/*genetics ; Survival Analysis ; Translocation, Genetic ; Zebrafish/genetics ; },
abstract = {The amplified MYCN gene serves as an oncogenic driver in approximately 20% of high-risk pediatric neuroblastomas. Here, we show that the family member MYC is a potent transforming gene in a separate subset of high-risk neuroblastoma cases (∼10%), based on (i) its upregulation by focal enhancer amplification or genomic rearrangements leading to enhancer hijacking, and (ii) its ability to transform neuroblastoma precursor cells in a transgenic animal model. The aberrant regulatory elements associated with oncogenic MYC activation include focally amplified distal enhancers and translocation of highly active enhancers from other genes to within topologically associating domains containing the MYC gene locus. The clinical outcome for patients with high levels of MYC expression is virtually identical to that of patients with amplification of the MYCN gene, a known high-risk feature of this disease. Together, these findings establish MYC as a bona fide oncogene in a clinically significant group of high-risk childhood neuroblastomas.Significance: Amplification of the MYCN oncogene is a recognized hallmark of high-risk pediatric neuroblastoma. Here, we demonstrate that MYC is also activated as a potent oncogene in a distinct subset of neuroblastoma cases through either focal amplification of distal enhancers or enhancer hijacking mediated by chromosomal translocation. Cancer Discov; 8(3); 320-35. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 253.},
}
@article {pmid29273679,
year = {2017},
author = {Rodríguez-Carballo, E and Lopez-Delisle, L and Zhan, Y and Fabre, PJ and Beccari, L and El-Idrissi, I and Huynh, THN and Ozadam, H and Dekker, J and Duboule, D},
title = {The HoxD cluster is a dynamic and resilient TAD boundary controlling the segregation of antagonistic regulatory landscapes.},
journal = {Genes &amp; development},
volume = {31},
number = {22},
pages = {2264-2281},
pmid = {29273679},
issn = {1549-5477},
support = {R01 HG003141/HG/NHGRI NIH HHS/United States ; R01 HG003143/HG/NHGRI NIH HHS/United States ; },
mesh = {Animals ; CCCTC-Binding Factor/metabolism ; Cell Cycle Proteins/metabolism ; Chromosomal Proteins, Non-Histone/metabolism ; Enhancer Elements, Genetic ; *Genes, Homeobox ; Limb Buds/metabolism ; Mice ; *Multigene Family ; *Regulatory Sequences, Nucleic Acid ; Sequence Deletion ; Transcription, Genetic ; },
abstract = {The mammalian HoxD cluster lies between two topologically associating domains (TADs) matching distinct enhancer-rich regulatory landscapes. During limb development, the telomeric TAD controls the early transcription of Hoxd genes in forearm cells, whereas the centromeric TAD subsequently regulates more posterior Hoxd genes in digit cells. Therefore, the TAD boundary prevents the terminal Hoxd13 gene from responding to forearm enhancers, thereby allowing proper limb patterning. To assess the nature and function of this CTCF-rich DNA region in embryos, we compared chromatin interaction profiles between proximal and distal limb bud cells isolated from mutant stocks where various parts of this boundary region were removed. The resulting progressive release in boundary effect triggered inter-TAD contacts, favored by the activity of the newly accessed enhancers. However, the boundary was highly resilient, and only a 400-kb deletion, including the whole-gene cluster, was eventually able to merge the neighboring TADs into a single structure. In this unified TAD, both proximal and distal limb enhancers nevertheless continued to work independently over a targeted transgenic reporter construct. We propose that the whole HoxD cluster is a dynamic TAD border and that the exact boundary position varies depending on both the transcriptional status and the developmental context.},
}
@article {pmid29273625,
year = {2018},
author = {Fan, H and Lv, P and Huo, X and Wu, J and Wang, Q and Cheng, L and Liu, Y and Tang, QQ and Zhang, L and Zhang, F and Zheng, X and Wu, H and Wen, B},
title = {The nuclear matrix protein HNRNPU maintains 3D genome architecture globally in mouse hepatocytes.},
journal = {Genome research},
volume = {28},
number = {2},
pages = {192-202},
pmid = {29273625},
issn = {1549-5469},
mesh = {Animals ; Chromatin/genetics ; Chromatin Assembly and Disassembly/*genetics ; Chromosomes/*genetics ; Genome/*genetics ; Hepatocytes/metabolism ; Heterogeneous-Nuclear Ribonucleoprotein U/*genetics ; Mice ; Nuclear Matrix/genetics ; },
abstract = {Eukaryotic chromosomes are folded into higher-order conformations to coordinate genome functions. In addition to long-range chromatin loops, recent chromosome conformation capture (3C)-based studies have indicated higher levels of chromatin structures including compartments and topologically associating domains (TADs), which may serve as units of genome organization and functions. However, the molecular machinery underlying these hierarchically three-dimensional (3D) chromatin architectures remains poorly understood. Via high-throughput assays, including in situ Hi-C, DamID, ChIP-seq, and RNA-seq, we investigated roles of the Heterogeneous Nuclear Ribonucleoprotein U (HNRNPU), a nuclear matrix (NM)-associated protein, in 3D genome organization. Upon the depletion of HNRNPU in mouse hepatocytes, the coverage of lamina-associated domains (LADs) in the genome increases from 53.1% to 68.6%, and a global condensation of chromatin was observed. Furthermore, disruption of HNRNPU leads to compartment switching on 7.5% of the genome, decreases TAD boundary strengths at borders between A (active) and B (inactive) compartments, and reduces chromatin loop intensities. Long-range chromatin interactions between and within compartments or TADs are also significantly remodeled upon HNRNPU depletion. Intriguingly, HNRNPU mainly associates with active chromatin, and 80% of HNRNPU peaks coincide with the binding of CTCF or RAD21. Collectively, we demonstrated that HNRNPU functions as a major factor maintaining 3D chromatin architecture, suggesting important roles of NM-associated proteins in genome organization.},
}
@article {pmid29272504,
year = {2018},
author = {Mourad, R and Cuvier, O},
title = {TAD-free analysis of architectural proteins and insulators.},
journal = {Nucleic acids research},
volume = {46},
number = {5},
pages = {e27},
pmid = {29272504},
issn = {1362-4962},
mesh = {Algorithms ; Animals ; Binding Sites/genetics ; Drosophila Proteins/metabolism ; Drosophila melanogaster ; Gene Expression Profiling ; Gene Expression Regulation ; Gene Regulatory Networks ; Genome/*genetics ; Humans ; Insulator Elements/*genetics ; Models, Genetic ; Protein Binding ; Regulatory Sequences, Nucleic Acid/*genetics ; Transcription Factors/*metabolism ; },
abstract = {The three-dimensional (3D) organization of the genome is intimately related to numerous key biological functions including gene expression and DNA replication regulations. The mechanisms by which molecular drivers functionally organize the 3D genome, such as topologically associating domains (TADs), remain to be explored. Current approaches consist in assessing the enrichments or influences of proteins at TAD borders. Here, we propose a TAD-free model to directly estimate the blocking effects of architectural proteins, insulators and DNA motifs on long-range contacts, making the model intuitive and biologically meaningful. In addition, the model allows analyzing the whole Hi-C information content (2D information) instead of only focusing on TAD borders (1D information). The model outperforms multiple logistic regression at TAD borders in terms of parameter estimation accuracy and is validated by enhancer-blocking assays. In Drosophila, the results support the insulating role of simple sequence repeats and suggest that the blocking effects depend on the number of repeats. Motif analysis uncovered the roles of the transcriptional factors pannier and tramtrack in blocking long-range contacts. In human, the results suggest that the blocking effects of the well-known architectural proteins CTCF, cohesin and ZNF143 depend on the distance between loci, where each protein may participate at different scales of the 3D chromatin organization.},
}
@article {pmid29269730,
year = {2017},
author = {Ron, G and Globerson, Y and Moran, D and Kaplan, T},
title = {Promoter-enhancer interactions identified from Hi-C data using probabilistic models and hierarchical topological domains.},
journal = {Nature communications},
volume = {8},
number = {1},
pages = {2237},
pmid = {29269730},
issn = {2041-1723},
mesh = {Animals ; Chromatin ; Computational Biology ; DNA/*genetics ; Enhancer Elements, Genetic/*genetics ; Epigenesis, Genetic/*genetics ; Gene Expression Regulation ; High-Throughput Nucleotide Sequencing ; Humans ; Mice ; Models, Statistical ; Nucleic Acid Conformation ; Promoter Regions, Genetic/*genetics ; },
abstract = {Proximity-ligation methods such as Hi-C allow us to map physical DNA-DNA interactions along the genome, and reveal its organization into topologically associating domains (TADs). As the Hi-C data accumulate, computational methods were developed for identifying domain borders in multiple cell types and organisms. Here, we present PSYCHIC, a computational approach for analyzing Hi-C data and identifying promoter-enhancer interactions. We use a unified probabilistic model to segment the genome into domains, which we then merge hierarchically and fit using a local background model, allowing us to identify over-represented DNA-DNA interactions across the genome. By analyzing the published Hi-C data sets in human and mouse, we identify hundreds of thousands of putative enhancers and their target genes, and compile an extensive genome-wide catalog of gene regulation in human and mouse. As we show, our predictions are highly enriched for ChIP-seq and DNA accessibility data, evolutionary conservation, eQTLs and other DNA-DNA interaction data.},
}
@article {pmid29253110,
year = {2018},
author = {Tang, B and Li, F and Li, J and Zhao, W and Zhang, Z},
title = {Delta: a new web-based 3D genome visualization and analysis platform.},
journal = {Bioinformatics (Oxford, England)},
volume = {34},
number = {8},
pages = {1409-1410},
doi = {10.1093/bioinformatics/btx805},
pmid = {29253110},
issn = {1367-4811},
mesh = {*Chromatin ; *Data Visualization ; Genome, Human ; Genomics/*methods ; Humans ; Imaging, Three-Dimensional/*methods ; Internet ; *Software ; beta-Globins ; },
abstract = {SUMMARY: Delta is an integrative visualization and analysis platform to facilitate visually annotating and exploring the 3D physical architecture of genomes. Delta takes Hi-C or ChIA-PET contact matrix as input and predicts the topologically associating domains and chromatin loops in the genome. It then generates a physical 3D model which represents the plausible consensus 3D structure of the genome. Delta features a highly interactive visualization tool which enhances the integration of genome topology/physical structure with extensive genome annotation by juxtaposing the 3D model with diverse genomic assay outputs. Finally, by visually comparing the 3D model of the β-globin gene locus and its annotation, we speculated a plausible transitory interaction pattern in the locus. Experimental evidence was found to support this speculation by literature survey. This served as an example of intuitive hypothesis testing with the help of Delta.<br><br>Delta is freely accessible from http://delta.big.ac.cn, and the source code is available at https://github.com/zhangzhwlab/delta.<br><br>CONTACT: zhangzhihua@big.ac.cn.<br><br>SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},
}
@article {pmid29217591,
year = {2017},
author = {Wutz, G and Várnai, C and Nagasaka, K and Cisneros, DA and Stocsits, RR and Tang, W and Schoenfelder, S and Jessberger, G and Muhar, M and Hossain, MJ and Walther, N and Koch, B and Kueblbeck, M and Ellenberg, J and Zuber, J and Fraser, P and Peters, JM},
title = {Topologically associating domains and chromatin loops depend on cohesin and are regulated by CTCF, WAPL, and PDS5 proteins.},
journal = {The EMBO journal},
volume = {36},
number = {24},
pages = {3573-3599},
pmid = {29217591},
issn = {1460-2075},
support = {U01 DA047728/DA/NIDA NIH HHS/United States ; U01 EB021223/EB/NIBIB NIH HHS/United States ; BB/J004480/1//Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {CCCTC-Binding Factor/genetics/*metabolism ; Carrier Proteins/genetics/*metabolism ; Cell Cycle Proteins/genetics/*metabolism ; Chromatin/*genetics ; Chromosomal Proteins, Non-Histone/genetics/*metabolism ; Chromosomes/genetics ; DNA-Binding Proteins/genetics/*metabolism ; Genome, Human/genetics ; HeLa Cells ; Humans ; Nuclear Proteins/genetics/*metabolism ; Proto-Oncogene Proteins/genetics/*metabolism ; Transcription Factors/genetics/*metabolism ; },
abstract = {Mammalian genomes are spatially organized into compartments, topologically associating domains (TADs), and loops to facilitate gene regulation and other chromosomal functions. How compartments, TADs, and loops are generated is unknown. It has been proposed that cohesin forms TADs and loops by extruding chromatin loops until it encounters CTCF, but direct evidence for this hypothesis is missing. Here, we show that cohesin suppresses compartments but is required for TADs and loops, that CTCF defines their boundaries, and that the cohesin unloading factor WAPL and its PDS5 binding partners control the length of loops. In the absence of WAPL and PDS5 proteins, cohesin forms extended loops, presumably by passing CTCF sites, accumulates in axial chromosomal positions (vermicelli), and condenses chromosomes. Unexpectedly, PDS5 proteins are also required for boundary function. These results show that cohesin has an essential genome-wide function in mediating long-range chromatin interactions and support the hypothesis that cohesin creates these by loop extrusion, until it is delayed by CTCF in a manner dependent on PDS5 proteins, or until it is released from DNA by WAPL.},
}
@article {pmid29203764,
year = {2017},
author = {Wu, P and Li, T and Li, R and Jia, L and Zhu, P and Liu, Y and Chen, Q and Tang, D and Yu, Y and Li, C},
title = {3D genome of multiple myeloma reveals spatial genome disorganization associated with copy number variations.},
journal = {Nature communications},
volume = {8},
number = {1},
pages = {1937},
pmid = {29203764},
issn = {2041-1723},
mesh = {B-Lymphocytes ; Cell Line, Tumor ; Chromatin/*genetics ; Chromosome Mapping ; DNA Copy Number Variations/*genetics ; *Gene Expression ; Gene Expression Regulation, Neoplastic/*genetics ; Genome/*genetics ; High-Throughput Nucleotide Sequencing ; Humans ; Molecular Conformation ; Multiple Myeloma/*genetics ; Nucleic Acid Conformation ; Whole Genome Sequencing ; },
abstract = {The Hi-C method is widely used to study the functional roles of the three-dimensional (3D) architecture of genomes. Here, we integrate Hi-C, whole-genome sequencing (WGS) and RNA-seq to study the 3D genome architecture of multiple myeloma (MM) and how it associates with genomic variation and gene expression. Our results show that Hi-C interaction matrices are biased by copy number variations (CNVs) and can be used to detect CNVs. Also, combining Hi-C and WGS data can improve the detection of translocations. We find that CNV breakpoints significantly overlap with topologically associating domain (TAD) boundaries. Compared to normal B cells, the numbers of TADs increases by 25% in MM, the average size of TADs is smaller, and about 20% of genomic regions switch their chromatin A/B compartment types. In summary, we report a 3D genome interaction map of aneuploid MM cells and reveal the relationship among CNVs, translocations, 3D genome reorganization, and gene expression regulation.},
}
@article {pmid29149264,
year = {2018},
author = {DeMaere, MZ and Darling, AE},
title = {Sim3C: simulation of Hi-C and Meta3C proximity ligation sequencing technologies.},
journal = {GigaScience},
volume = {7},
number = {2},
pages = {1-12},
pmid = {29149264},
issn = {2047-217X},
mesh = {Algorithms ; Bacteria/*genetics ; Chromosome Mapping ; Computer Simulation ; Fungi/*genetics ; *Genome ; High-Throughput Nucleotide Sequencing/*statistics &amp; numerical data ; *Models, Statistical ; },
abstract = {BACKGROUND: Chromosome conformation capture (3C) and Hi-C DNA sequencing methods have rapidly advanced our understanding of the spatial organization of genomes and metagenomes. Many variants of these protocols have been developed, each with their own strengths. Currently there is no systematic means for simulating sequence data from this family of sequencing protocols, potentially hindering the advancement of algorithms to exploit this new datatype.<br><br>FINDINGS: We describe a computational simulator that, given simple parameters and reference genome sequences, will simulate Hi-C sequencing on those sequences. The simulator models the basic spatial structure in genomes that is commonly observed in Hi-C and 3C datasets, including the distance-decay relationship in proximity ligation, differences in the frequency of interaction within and across chromosomes, and the structure imposed by cells. A means to model the 3D structure of randomly generated topologically associating domains is provided. The simulator considers several sources of error common to 3C and Hi-C library preparation and sequencing methods, including spurious proximity ligation events and sequencing error.<br><br>CONCLUSIONS: We have introduced the first comprehensive simulator for 3C and Hi-C sequencing protocols. We expect the simulator to have use in testing of Hi-C data analysis algorithms, as well as more general value for experimental design, where questions such as the required depth of sequencing, enzyme choice, and other decisions can be made in advance in order to ensure adequate statistical power with respect to experimental hypothesis testing.},
}
@article {pmid29140466,
year = {2018},
author = {Racko, D and Benedetti, F and Dorier, J and Stasiak, A},
title = {Transcription-induced supercoiling as the driving force of chromatin loop extrusion during formation of TADs in interphase chromosomes.},
journal = {Nucleic acids research},
volume = {46},
number = {4},
pages = {1648-1660},
pmid = {29140466},
issn = {1362-4962},
mesh = {Cell Cycle Proteins/metabolism ; Chromatin/*chemistry ; Chromosomal Proteins, Non-Histone/metabolism ; Chromosomes/chemistry ; DNA, Superhelical/*chemistry ; Interphase/genetics ; Models, Genetic ; Molecular Dynamics Simulation ; Rotation ; *Transcription, Genetic ; },
abstract = {Using molecular dynamics simulations, we show here that growing plectonemes resulting from transcription-induced supercoiling have the ability to actively push cohesin rings along chromatin fibres. The pushing direction is such that within each topologically associating domain (TAD) cohesin rings forming handcuffs move from the source of supercoiling, constituted by RNA polymerase with associated DNA topoisomerase TOP1, towards borders of TADs, where supercoiling is released by topoisomerase TOPIIB. Cohesin handcuffs are pushed by continuous flux of supercoiling that is generated by transcription and is then progressively released by action of TOPIIB located at TADs borders. Our model explains what can be the driving force of chromatin loop extrusion and how it can be ensured that loops grow quickly and in a good direction. In addition, the supercoiling-driven loop extrusion mechanism is consistent with earlier explanations proposing why TADs flanked by convergent CTCF binding sites form more stable chromatin loops than TADs flanked by divergent CTCF binding sites. We discuss the role of supercoiling in stimulating enhancer promoter contacts and propose that transcription of eRNA sends the first wave of supercoiling that can activate mRNA transcription in a given TAD.},
}
@article {pmid29078370,
year = {2017},
author = {Ronquist, S and Patterson, G and Muir, LA and Lindsly, S and Chen, H and Brown, M and Wicha, MS and Bloch, A and Brockett, R and Rajapakse, I},
title = {Algorithm for cellular reprogramming.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {114},
number = {45},
pages = {11832-11837},
pmid = {29078370},
issn = {1091-6490},
mesh = {*Algorithms ; Binding Sites/genetics ; Cell Cycle/genetics ; Cell Differentiation ; Cells, Cultured ; Cellular Reprogramming/*genetics/physiology ; Computational Biology/*methods ; Fibroblasts/*cytology ; Gene Expression Profiling ; Genome, Human/genetics ; Humans ; Models, Genetic ; Transcription Factors/*genetics ; },
abstract = {The day we understand the time evolution of subcellular events at a level of detail comparable to physical systems governed by Newton's laws of motion seems far away. Even so, quantitative approaches to cellular dynamics add to our understanding of cell biology. With data-guided frameworks we can develop better predictions about, and methods for, control over specific biological processes and system-wide cell behavior. Here we describe an approach for optimizing the use of transcription factors (TFs) in cellular reprogramming, based on a device commonly used in optimal control. We construct an approximate model for the natural evolution of a cell-cycle-synchronized population of human fibroblasts, based on data obtained by sampling the expression of 22,083 genes at several time points during the cell cycle. To arrive at a model of moderate complexity, we cluster gene expression based on division of the genome into topologically associating domains (TADs) and then model the dynamics of TAD expression levels. Based on this dynamical model and additional data, such as known TF binding sites and activity, we develop a methodology for identifying the top TF candidates for a specific cellular reprogramming task. Our data-guided methodology identifies a number of TFs previously validated for reprogramming and/or natural differentiation and predicts some potentially useful combinations of TFs. Our findings highlight the immense potential of dynamical models, mathematics, and data-guided methodologies for improving strategies for control over biological processes.},
}
@article {pmid29077530,
year = {2018},
author = {Hansen, AS and Cattoglio, C and Darzacq, X and Tjian, R},
title = {Recent evidence that TADs and chromatin loops are dynamic structures.},
journal = {Nucleus (Austin, Tex.)},
volume = {9},
number = {1},
pages = {20-32},
pmid = {29077530},
issn = {1949-1042},
support = {U01 EB021236/EB/NIBIB NIH HHS/United States ; U54 DK107980/DK/NIDDK NIH HHS/United States ; },
mesh = {Animals ; Chromatin/*chemistry/genetics/*metabolism ; *Chromatin Assembly and Disassembly ; Humans ; Models, Molecular ; },
abstract = {Mammalian genomes are folded into spatial domains, which regulate gene expression by modulating enhancer-promoter contacts. Here, we review recent studies on the structure and function of Topologically Associating Domains (TADs) and chromatin loops. We discuss how loop extrusion models can explain TAD formation and evidence that TADs are formed by the ring-shaped protein complex, cohesin, and that TAD boundaries are established by the DNA-binding protein, CTCF. We discuss our recent genomic, biochemical and single-molecule imaging studies on CTCF and cohesin, which suggest that TADs and chromatin loops are dynamic structures. We highlight complementary polymer simulation studies and Hi-C studies employing acute depletion of CTCF and cohesin, which also support such a dynamic model. We discuss the limitations of each approach and conclude that in aggregate the available evidence argues against stable loops and supports a model where TADs are dynamic structures that continually form and break throughout the cell cycle.},
}
@article {pmid28991264,
year = {2017},
author = {Tanizawa, H and Kim, KD and Iwasaki, O and Noma, KI},
title = {Architectural alterations of the fission yeast genome during the cell cycle.},
journal = {Nature structural &amp; molecular biology},
volume = {24},
number = {11},
pages = {965-976},
pmid = {28991264},
issn = {1545-9985},
support = {DP2 OD004348/OD/NIH HHS/United States ; P30 CA010815/CA/NCI NIH HHS/United States ; R01 GM124195/GM/NIGMS NIH HHS/United States ; },
mesh = {Adenosine Triphosphatases/metabolism ; Cell Cycle Proteins/metabolism ; Chromosomal Proteins, Non-Histone/metabolism ; Chromosomes, Fungal/*metabolism/*ultrastructure ; DNA-Binding Proteins/metabolism ; Fungal Proteins/metabolism ; *Genome, Fungal ; *Mitosis ; Multiprotein Complexes/metabolism ; Schizosaccharomyces/*cytology/*physiology ; },
abstract = {Eukaryotic genomes are highly ordered through various mechanisms, including topologically associating domain (TAD) organization. We employed an in situ Hi-C approach to follow the 3D organization of the fission yeast genome during the cell cycle. We demonstrate that during mitosis, large domains of 300 kb-1 Mb are formed by condensin. This mitotic domain organization does not suddenly dissolve, but gradually diminishes until the next mitosis. By contrast, small domains of 30-40 kb that are formed by cohesin are relatively stable across the cell cycle. Condensin and cohesin mediate long- and short-range contacts, respectively, by bridging their binding sites, thereby forming the large and small domains. These domains are inversely regulated during the cell cycle but assemble independently. Our study describes the chromosomal oscillation between the formation and decay phases of the large and small domains, and we predict that the condensin-mediated domains serve as chromosomal compaction units.},
}
@article {pmid28977529,
year = {2017},
author = {Wang, XT and Cui, W and Peng, C},
title = {HiTAD: detecting the structural and functional hierarchies of topologically associating domains from chromatin interactions.},
journal = {Nucleic acids research},
volume = {45},
number = {19},
pages = {e163},
pmid = {28977529},
issn = {1362-4962},
mesh = {*Algorithms ; Animals ; Cell Line ; Chromatin/*genetics/*metabolism ; *Chromatin Assembly and Disassembly ; Computational Biology/*methods ; DNA/genetics/metabolism ; Genome/genetics ; Humans ; K562 Cells ; Reproducibility of Results ; },
abstract = {A current question in the high-order organization of chromatin is whether topologically associating domains (TADs) are distinct from other hierarchical chromatin domains. However, due to the unclear TAD definition in tradition, the structural and functional uniqueness of TAD is not well studied. In this work, we refined TAD definition by further constraining TADs to the optimal separation on global intra-chromosomal interactions. Inspired by this constraint, we developed a novel method, called HiTAD, to detect hierarchical TADs from Hi-C chromatin interactions. HiTAD performs well in domain sensitivity, replicate reproducibility and inter cell-type conservation. With a novel domain-based alignment proposed by us, we defined several types of hierarchical TAD changes which were not systematically studied previously, and subsequently used them to reveal that TADs and sub-TADs differed statistically in correlating chromosomal compartment, replication timing and gene transcription. Finally, our work also has the implication that the refinement of TAD definition could be achieved by only utilizing chromatin interactions, at least in part. HiTAD is freely available online.},
}
@article {pmid28977418,
year = {2017},
author = {Boya, R and Yadavalli, AD and Nikhat, S and Kurukuti, S and Palakodeti, D and Pongubala, JMR},
title = {Developmentally regulated higher-order chromatin interactions orchestrate B cell fate commitment.},
journal = {Nucleic acids research},
volume = {45},
number = {19},
pages = {11070-11087},
pmid = {28977418},
issn = {1362-4962},
mesh = {Animals ; B-Lymphocytes/cytology/metabolism ; Binding Sites/genetics ; Cell Differentiation/*genetics ; Cells, Cultured ; Chromatin/genetics/*metabolism ; Gene Expression Profiling/methods ; Mice, Knockout ; Precursor Cells, B-Lymphoid/cytology/*metabolism ; Protein Binding ; Regulatory Sequences, Nucleic Acid/genetics ; Trans-Activators/genetics/metabolism ; },
abstract = {Genome organization in 3D nuclear-space is important for regulation of gene expression. However, the alterations of chromatin architecture that impinge on the B cell-fate choice of multi-potent progenitors are still unclear. By integrating in situ Hi-C analyses with epigenetic landscapes and genome-wide expression profiles, we tracked the changes in genome architecture as the cells transit from a progenitor to a committed state. We identified the genomic loci that undergo developmental switch between A and B compartments during B-cell fate determination. Furthermore, although, topologically associating domains (TADs) are stable, a significant number of TADs display structural alterations that are associated with changes in cis-regulatory interaction landscape. Finally, we demonstrate the potential roles for Ebf1 and its downstream factor, Pax5, in chromatin reorganization and transcription regulation. Collectively, our studies provide a general paradigm of the dynamic relationship between chromatin reorganization and lineage-specific gene expression pattern that dictates cell-fate determination.},
}
@article {pmid28961756,
year = {2018},
author = {Seaman, L and Rajapakse, I},
title = {4D nucleome Analysis Toolbox: analysis of Hi-C data with abnormal karyotype and time series capabilities.},
journal = {Bioinformatics (Oxford, England)},
volume = {34},
number = {1},
pages = {104-106},
doi = {10.1093/bioinformatics/btx484},
pmid = {28961756},
issn = {1367-4811},
mesh = {*Abnormal Karyotype ; *Chromosomes, Human ; Gene Expression Profiling/*methods ; Gene Expression Regulation ; Genomics/*methods ; Humans ; Sequence Analysis, RNA/methods ; *Software ; },
abstract = {MOTIVATION: The availability of powerful analysis tools will further understanding of genome organization and its relationship to phenotype in dynamical settings.<br><br>RESULTS: The 4D Nucleome Analysis Toolbox (NAT) is a user-friendly and powerful MATLAB toolbox for time series analysis of genome-wide chromosome conformation capture (Hi-C) data and gene expression (RNA-seq). NAT can load and normalize data, define topologically associating domains, analyse translocations, produce visualization, and study time course data. We provide examples that include time series data sets and karyotypically abnormal cell lines demonstrating the flexibility of NAT.<br><br>https://github.com/laseaman/4D_Nucleome_Analysis_Toolbox.<br><br>CONTACT: indikar@umich.edu.},
}
@article {pmid28931413,
year = {2017},
author = {Van Bortle, K and Phanstiel, DH and Snyder, MP},
title = {Topological organization and dynamic regulation of human tRNA genes during macrophage differentiation.},
journal = {Genome biology},
volume = {18},
number = {1},
pages = {180},
pmid = {28931413},
issn = {1474-760X},
support = {F32 DK107112/DK/NIDDK NIH HHS/United States ; K99 HG008662/HG/NHGRI NIH HHS/United States ; R00 HG008662/HG/NHGRI NIH HHS/United States ; },
mesh = {*Cell Differentiation ; Cell Line ; Gene Expression Regulation, Developmental ; Humans ; Macrophages/*cytology/metabolism ; Promoter Regions, Genetic ; RNA, Transfer/*genetics ; Repressor Proteins/metabolism ; Transcriptional Activation ; },
abstract = {BACKGROUND: The human genome is hierarchically organized into local and long-range structures that help shape cell-type-specific transcription patterns. Transfer RNA (tRNA) genes (tDNAs), which are transcribed by RNA polymerase III (RNAPIII) and encode RNA molecules responsible for translation, are dispersed throughout the genome and, in many cases, linearly organized into genomic clusters with other tDNAs. Whether the location and three-dimensional organization of tDNAs contribute to the activity of these genes has remained difficult to address, due in part to unique challenges related to tRNA sequencing. We therefore devised integrated tDNA expression profiling, a method that combines RNAPIII mapping with biotin-capture of nascent tRNAs. We apply this method to the study of dynamic tRNA gene regulation during macrophage development and further integrate these data with high-resolution maps of 3D chromatin structure.<br><br>RESULTS: Integrated tDNA expression profiling reveals domain-level and loop-based organization of tRNA gene transcription during cellular differentiation. tRNA genes connected by DNA loops, which are proximal to CTCF binding sites and expressed at elevated levels compared to non-loop tDNAs, change coordinately with tDNAs and protein-coding genes at distal ends of interactions mapped by in situ Hi-C. We find that downregulated tRNA genes are specifically marked by enhanced promoter-proximal binding of MAF1, a transcriptional repressor of RNAPIII activity, altogether revealing multiple levels of tDNA regulation during cellular differentiation.<br><br>CONCLUSIONS: We present evidence of both local and coordinated long-range regulation of human tDNA expression, suggesting the location and organization of tRNA genes contribute to dynamic tDNA activity during macrophage development.},
}
@article {pmid28912419,
year = {2017},
author = {Yu, W and He, B and Tan, K},
title = {Identifying topologically associating domains and subdomains by Gaussian Mixture model And Proportion test.},
journal = {Nature communications},
volume = {8},
number = {1},
pages = {535},
pmid = {28912419},
issn = {2041-1723},
support = {U01 CA226187/CA/NCI NIH HHS/United States ; R01 HG006130/HG/NHGRI NIH HHS/United States ; R01 GM108716/GM/NIGMS NIH HHS/United States ; R01 GM104369/GM/NIGMS NIH HHS/United States ; R01 AA024486/AA/NIAAA NIH HHS/United States ; },
mesh = {Algorithms ; Cell Line, Tumor ; Chromatin/*chemistry/genetics/metabolism ; Gene Expression ; Genome ; Humans ; Models, Genetic ; Mutation ; Neoplasms/*genetics/metabolism ; },
abstract = {The spatial organization of the genome plays a critical role in regulating gene expression. Recent chromatin interaction mapping studies have revealed that topologically associating domains and subdomains are fundamental building blocks of the three-dimensional genome. Identifying such hierarchical structures is a critical step toward understanding the three-dimensional structure-function relationship of the genome. Existing computational algorithms lack statistical assessment of domain predictions and are computationally inefficient for high-resolution Hi-C data. We introduce the Gaussian Mixture model And Proportion test (GMAP) algorithm to address the above-mentioned challenges. Using simulated and experimental Hi-C data, we show that domains identified by GMAP are more consistent with multiple lines of supporting evidence than three state-of-the-art methods. Application of GMAP to normal and cancer cells reveals several unique features of subdomain boundary as compared to domain boundary, including its higher dynamics across cell types and enrichment for somatic mutations in cancer.Spatial organization of the genome plays a crucial role in regulating gene expression. Here the authors introduce GMAP, the Gaussian Mixture model And Proportion test, to identify topologically associating domains and subdomains in Hi-C data.},
}
@article {pmid28910577,
year = {2018},
author = {Shah, FR and Bhat, YA and Wani, AH},
title = {Subnuclear distribution of proteins: Links with genome architecture.},
journal = {Nucleus (Austin, Tex.)},
volume = {9},
number = {1},
pages = {42-55},
pmid = {28910577},
issn = {1949-1042},
mesh = {Animals ; Cell Nucleus/*genetics/*metabolism ; Humans ; Nuclear Proteins/*metabolism ; Nucleosomes/metabolism ; },
abstract = {Metazoan genomes have a hierarchal 3-dimensional (3D) organization scaling from nucleosomes, loops, topologically associating domains (TADs), compartments, to chromosome territories. The 3D organization of genome has been linked with development, differentiation and disease. However, the principles governing the 3D chromatin architecture are just beginning to get unraveled. The nucleus has very high concentration of proteins and these proteins are either diffusely distributed throughout the nucleus, or aggregated in the form of foci/bodies/clusters/speckles or in combination of both. Several evidences suggest that the distribution of proteins within the nuclear space is linked to the organization and function of genome. Here, we describe advances made in understanding the relationship between subnuclear distribution of proteins and genome architecture.},
}
@article {pmid28902867,
year = {2017},
author = {Soler-Oliva, ME and Guerrero-Martínez, JA and Bachetti, V and Reyes, JC},
title = {Analysis of the relationship between coexpression domains and chromatin 3D organization.},
journal = {PLoS computational biology},
volume = {13},
number = {9},
pages = {e1005708},
pmid = {28902867},
issn = {1553-7358},
mesh = {Breast/chemistry/metabolism ; Breast Neoplasms/genetics/metabolism ; Chromatin/chemistry/genetics/*metabolism/*ultrastructure ; Chromatin Assembly and Disassembly ; Cluster Analysis ; Computational Biology ; Female ; Gene Expression Profiling ; Gene Expression Regulation/*genetics ; Gene Regulatory Networks/*genetics ; Genome/genetics ; Humans ; },
abstract = {Gene order is not random in eukaryotic chromosomes, and co-regulated genes tend to be clustered. The mechanisms that determine co-regulation of large regions of the genome and its connection with chromatin three-dimensional (3D) organization are still unclear however. Here we have adapted a recently described method for identifying chromatin topologically associating domains (TADs) to identify coexpression domains (which we term "CODs"). Using human normal breast and breast cancer RNA-seq data, we have identified approximately 500 CODs. CODs in the normal and breast cancer genomes share similar characteristics but differ in their gene composition. COD genes have a greater tendency to be coexpressed with genes that reside in other CODs than with non-COD genes. Such inter-COD coexpression is maintained over large chromosomal distances in the normal genome but is partially lost in the cancer genome. Analyzing the relationship between CODs and chromatin 3D organization using Hi-C contact data, we find that CODs do not correspond to TADs. In fact, intra-TAD gene coexpression is the same as random for most chromosomes. However, the contact profile is similar between gene pairs that reside either in the same COD or in coexpressed CODs. These data indicate that co-regulated genes in the genome present similar patterns of contacts irrespective of the frequency of physical chromatin contacts between them.},
}
@article {pmid28874668,
year = {2017},
author = {Harmston, N and Ing-Simmons, E and Tan, G and Perry, M and Merkenschlager, M and Lenhard, B},
title = {Topologically associating domains are ancient features that coincide with Metazoan clusters of extreme noncoding conservation.},
journal = {Nature communications},
volume = {8},
number = {1},
pages = {441},
pmid = {28874668},
issn = {2041-1723},
support = {MC_U120027516/MRC_/Medical Research Council/United Kingdom ; MC_UP_1102/1/MRC_/Medical Research Council/United Kingdom ; P55504_WCMA//Wellcome Trust/United Kingdom ; },
mesh = {Animals ; Conserved Sequence/*genetics ; DNA, Intergenic/*genetics ; Genes, Regulator ; Genome ; Genome Size ; Humans ; },
abstract = {Developmental genes in metazoan genomes are surrounded by dense clusters of conserved noncoding elements (CNEs). CNEs exhibit unexplained extreme levels of sequence conservation, with many acting as developmental long-range enhancers. Clusters of CNEs define the span of regulatory inputs for many important developmental regulators and have been described previously as genomic regulatory blocks (GRBs). Their function and distribution around important regulatory genes raises the question of how they relate to 3D conformation of these loci. Here, we show that clusters of CNEs strongly coincide with topological organisation, predicting the boundaries of hundreds of topologically associating domains (TADs) in human and Drosophila. The set of TADs that are associated with high levels of noncoding conservation exhibit distinct properties compared to TADs devoid of extreme noncoding conservation. The close correspondence between extreme noncoding conservation and TADs suggests that these TADs are ancient, revealing a regulatory architecture conserved over hundreds of millions of years.Metazoan genomes contain many clusters of conserved noncoding elements. Here, the authors provide evidence that these clusters coincide with distinct topologically associating domains in humans and Drosophila, revealing a conserved regulatory genomic architecture.},
}
@article {pmid28867287,
year = {2017},
author = {Brejc, K and Bian, Q and Uzawa, S and Wheeler, BS and Anderson, EC and King, DS and Kranzusch, PJ and Preston, CG and Meyer, BJ},
title = {Dynamic Control of X Chromosome Conformation and Repression by a Histone H4K20 Demethylase.},
journal = {Cell},
volume = {171},
number = {1},
pages = {85-102.e23},
pmid = {28867287},
issn = {1097-4172},
support = {F32 GM100647/GM/NIGMS NIH HHS/United States ; R01 GM030702/GM/NIGMS NIH HHS/United States ; S10 OD018174/OD/NIH HHS/United States ; },
mesh = {Amino Acid Sequence ; Animals ; Caenorhabditis elegans/metabolism ; Caenorhabditis elegans Proteins/*chemistry/genetics/*metabolism ; Carrier Proteins/*chemistry/genetics/*metabolism ; Dosage Compensation, Genetic ; Embryo, Nonmammalian/metabolism ; *Gene Expression Regulation ; Jumonji Domain-Containing Histone Demethylases/chemistry/metabolism ; Models, Molecular ; Mutation ; Piperidines/metabolism ; Sequence Alignment ; Thiophenes/metabolism ; X Chromosome/*chemistry ; },
abstract = {Chromatin modification and higher-order chromosome structure play key roles in gene regulation, but their functional interplay in controlling gene expression is elusive. We have discovered the machinery and mechanism underlying the dynamic enrichment of histone modification H4K20me1 on hermaphrodite X chromosomes during C. elegans dosage compensation and demonstrated H4K20me1's pivotal role in regulating higher-order chromosome structure and X-chromosome-wide gene expression. The structure and the activity of the dosage compensation complex (DCC) subunit DPY-21 define a Jumonji demethylase subfamily that converts H4K20me2 to H4K20me1 in worms and mammals. Selective inactivation of demethylase activity eliminates H4K20me1 enrichment in somatic cells, elevates X-linked gene expression, reduces X chromosome compaction, and disrupts X chromosome conformation by diminishing the formation of topologically associating domains (TADs). Unexpectedly, DPY-21 also associates with autosomes of germ cells in a DCC-independent manner to enrich H4K20me1 and trigger chromosome compaction. Our findings demonstrate the direct link between chromatin modification and higher-order chromosome structure in long-range regulation of gene expression.},
}
@article {pmid28863138,
year = {2017},
author = {Poterlowicz, K and Yarker, JL and Malashchuk, I and Lajoie, BR and Mardaryev, AN and Gdula, MR and Sharov, AA and Kohwi-Shigematsu, T and Botchkarev, VA and Fessing, MY},
title = {5C analysis of the Epidermal Differentiation Complex locus reveals distinct chromatin interaction networks between gene-rich and gene-poor TADs in skin epithelial cells.},
journal = {PLoS genetics},
volume = {13},
number = {9},
pages = {e1006966},
pmid = {28863138},
issn = {1553-7404},
support = {MR/M010015/1/MRC_/Medical Research Council/United Kingdom ; R01 AR064580/AR/NIAMS NIH HHS/United States ; MR/N009630/1/MRC_/Medical Research Council/United Kingdom ; R37 CA039681/CA/NCI NIH HHS/United States ; R01 AR071727/AR/NIAMS NIH HHS/United States ; },
mesh = {Animals ; CCCTC-Binding Factor ; Cell Cycle Proteins ; Cell Differentiation/*genetics ; Chromatin/*genetics ; Chromatin Assembly and Disassembly/genetics ; DNA Helicases/*genetics ; DNA-Binding Proteins/genetics ; Enhancer Elements, Genetic ; Epidermis/metabolism ; Epigenesis, Genetic ; Genome ; Keratinocytes ; Mice ; Nuclear Proteins/*genetics ; Phosphoproteins/*genetics ; Promoter Regions, Genetic ; Repressor Proteins/*genetics ; Skin/metabolism ; Transcription Factors/*genetics ; },
abstract = {Mammalian genomes contain several dozens of large (>0.5 Mbp) lineage-specific gene loci harbouring functionally related genes. However, spatial chromatin folding, organization of the enhancer-promoter networks and their relevance to Topologically Associating Domains (TADs) in these loci remain poorly understood. TADs are principle units of the genome folding and represents the DNA regions within which DNA interacts more frequently and less frequently across the TAD boundary. Here, we used Chromatin Conformation Capture Carbon Copy (5C) technology to characterize spatial chromatin interaction network in the 3.1 Mb Epidermal Differentiation Complex (EDC) locus harbouring 61 functionally related genes that show lineage-specific activation during terminal keratinocyte differentiation in the epidermis. 5C data validated by 3D-FISH demonstrate that the EDC locus is organized into several TADs showing distinct lineage-specific chromatin interaction networks based on their transcription activity and the gene-rich or gene-poor status. Correlation of the 5C results with genome-wide studies for enhancer-specific histone modifications (H3K4me1 and H3K27ac) revealed that the majority of spatial chromatin interactions that involves the gene-rich TADs at the EDC locus in keratinocytes include both intra- and inter-TAD interaction networks, connecting gene promoters and enhancers. Compared to thymocytes in which the EDC locus is mostly transcriptionally inactive, these interactions were found to be keratinocyte-specific. In keratinocytes, the promoter-enhancer anchoring regions in the gene-rich transcriptionally active TADs are enriched for the binding of chromatin architectural proteins CTCF, Rad21 and chromatin remodeler Brg1. In contrast to gene-rich TADs, gene-poor TADs show preferential spatial contacts with each other, do not contain active enhancers and show decreased binding of CTCF, Rad21 and Brg1 in keratinocytes. Thus, spatial interactions between gene promoters and enhancers at the multi-TAD EDC locus in skin epithelial cells are cell type-specific and involve extensive contacts within TADs as well as between different gene-rich TADs, forming the framework for lineage-specific transcription.},
}
@article {pmid28826674,
year = {2017},
author = {Rowley, MJ and Nichols, MH and Lyu, X and Ando-Kuri, M and Rivera, ISM and Hermetz, K and Wang, P and Ruan, Y and Corces, VG},
title = {Evolutionarily Conserved Principles Predict 3D Chromatin Organization.},
journal = {Molecular cell},
volume = {67},
number = {5},
pages = {837-852.e7},
pmid = {28826674},
issn = {1097-4164},
support = {R01 GM035463/GM/NIGMS NIH HHS/United States ; F32 GM113570/GM/NIGMS NIH HHS/United States ; P30 CA034196/CA/NCI NIH HHS/United States ; U54 DK107967/DK/NIDDK NIH HHS/United States ; R25 HG007631/HG/NHGRI NIH HHS/United States ; R01 CA186714/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Arabidopsis/genetics/metabolism ; Arabidopsis Proteins/chemistry/genetics/metabolism ; Caenorhabditis elegans/genetics/metabolism ; Caenorhabditis elegans Proteins/chemistry/genetics/metabolism ; Chromatin/chemistry/genetics/*metabolism ; *Chromatin Assembly and Disassembly ; Chromosomal Proteins, Non-Histone/chemistry/genetics/*metabolism ; Computer Simulation ; DNA/chemistry/genetics/*metabolism ; DNA, Plant/chemistry/genetics/metabolism ; Drosophila Proteins/chemistry/genetics/*metabolism ; Drosophila melanogaster/genetics/*metabolism ; Histones/chemistry/genetics/*metabolism ; Humans ; Models, Biological ; Nucleic Acid Conformation ; Protein Conformation ; Structure-Activity Relationship ; Transcription, Genetic ; },
abstract = {Topologically associating domains (TADs), CTCF loop domains, and A/B compartments have been identified as important structural and functional components of 3D chromatin organization, yet the relationship between these features is not well understood. Using high-resolution Hi-C and HiChIP, we show that Drosophila chromatin is organized into domains we term compartmental domains that correspond precisely with A/B compartments at high resolution. We find that transcriptional state is a major predictor of Hi-C contact maps in several eukaryotes tested, including C. elegans and A. thaliana. Architectural proteins insulate compartmental domains by reducing interaction frequencies between neighboring regions in Drosophila, but CTCF loops do not play a distinct role in this organism. In mammals, compartmental domains exist alongside CTCF loop domains to form topological domains. The results suggest that compartmental domains are responsible for domain structure in all eukaryotes, with CTCF playing an important role in domain formation in mammals.},
}
@article {pmid28802249,
year = {2017},
author = {Rosa-Garrido, M and Chapski, DJ and Schmitt, AD and Kimball, TH and Karbassi, E and Monte, E and Balderas, E and Pellegrini, M and Shih, TT and Soehalim, E and Liem, D and Ping, P and Galjart, NJ and Ren, S and Wang, Y and Ren, B and Vondriska, TM},
title = {High-Resolution Mapping of Chromatin Conformation in Cardiac Myocytes Reveals Structural Remodeling of the Epigenome in Heart Failure.},
journal = {Circulation},
volume = {136},
number = {17},
pages = {1613-1625},
pmid = {28802249},
issn = {1524-4539},
support = {R01 HL122737/HL/NHLBI NIH HHS/United States ; R01 HL115238/HL/NHLBI NIH HHS/United States ; P50 CA211015/CA/NCI NIH HHS/United States ; T32 HG000044/HG/NHGRI NIH HHS/United States ; R01 HL114437/HL/NHLBI NIH HHS/United States ; R01 HL105699/HL/NHLBI NIH HHS/United States ; R01 HL129639/HL/NHLBI NIH HHS/United States ; R01 HL087132/HL/NHLBI NIH HHS/United States ; },
mesh = {Animals ; Cardiomegaly/genetics/*metabolism/pathology ; Chromatin/genetics/*metabolism/pathology ; *Chromatin Assembly and Disassembly ; *Epigenesis, Genetic ; Genome-Wide Association Study ; Heart Failure/genetics/*metabolism/pathology ; Mice ; Mice, Knockout ; Myocytes, Cardiac/*metabolism/pathology ; },
abstract = {BACKGROUND: Cardiovascular disease is associated with epigenomic changes in the heart; however, the endogenous structure of cardiac myocyte chromatin has never been determined.<br><br>METHODS: To investigate the mechanisms of epigenomic function in the heart, genome-wide chromatin conformation capture (Hi-C) and DNA sequencing were performed in adult cardiac myocytes following development of pressure overload-induced hypertrophy. Mice with cardiac-specific deletion of CTCF (a ubiquitous chromatin structural protein) were generated to explore the role of this protein in chromatin structure and cardiac phenotype. Transcriptome analyses by RNA-seq were conducted as a functional readout of the epigenomic structural changes.<br><br>RESULTS: Depletion of CTCF was sufficient to induce heart failure in mice, and human patients with heart failure receiving mechanical unloading via left ventricular assist devices show increased CTCF abundance. Chromatin structural analyses revealed interactions within the cardiac myocyte genome at 5-kb resolution, enabling examination of intra- and interchromosomal events, and providing a resource for future cardiac epigenomic investigations. Pressure overload or CTCF depletion selectively altered boundary strength between topologically associating domains and A/B compartmentalization, measurements of genome accessibility. Heart failure involved decreased stability of chromatin interactions around disease-causing genes. In addition, pressure overload or CTCF depletion remodeled long-range interactions of cardiac enhancers, resulting in a significant decrease in local chromatin interactions around these functional elements.<br><br>CONCLUSIONS: These findings provide a high-resolution chromatin architecture resource for cardiac epigenomic investigations and demonstrate that global structural remodeling of chromatin underpins heart failure. The newly identified principles of endogenous chromatin structure have key implications for epigenetic therapy.},
}
@article {pmid28792605,
year = {2017},
author = {Ulianov, SV and Tachibana-Konwalski, K and Razin, SV},
title = {Single-cell Hi-C bridges microscopy and genome-wide sequencing approaches to study 3D chromatin organization.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {39},
number = {10},
pages = {},
doi = {10.1002/bies.201700104},
pmid = {28792605},
issn = {1521-1878},
mesh = {Chromatin/*metabolism ; Chromatin Assembly and Disassembly/genetics/physiology ; Chromosome Mapping ; Microscopy/*methods ; },
abstract = {Recent years have witnessed an explosion of the single-cell biochemical toolbox including chromosome conformation capture (3C)-based methods that provide novel insights into chromatin spatial organization in individual cells. The observations made with these techniques revealed that topologically associating domains emerge from cell population averages and do not exist as static structures in individual cells. Stochastic nature of the genome folding is likely to be biologically relevant and may reflect the ability of chromatin fibers to adopt a number of alternative configurations, some of which could be transiently stabilized and serve regulatory purposes. Single-cell Hi-C approaches provide an opportunity to analyze chromatin folding in rare cell types such as stem cells, tumor progenitors, oocytes, and totipotent cells, contributing to a deeper understanding of basic mechanisms in development and disease. Here, we review key findings of single-cell Hi-C and discuss possible biological reasons and consequences of the inferred dynamic chromatin spatial organization.},
}
@article {pmid28792001,
year = {2017},
author = {Way, GP and Youngstrom, DW and Hankenson, KD and Greene, CS and Grant, SF},
title = {Implicating candidate genes at GWAS signals by leveraging topologically associating domains.},
journal = {European journal of human genetics : EJHG},
volume = {25},
number = {11},
pages = {1286-1289},
pmid = {28792001},
issn = {1476-5438},
support = {F32 DE026346/DE/NIDCR NIH HHS/United States ; P30 ES013508/ES/NIEHS NIH HHS/United States ; T32 HG000046/HG/NHGRI NIH HHS/United States ; },
mesh = {Acid Phosphatase/genetics ; Bone Density/genetics ; Cell Line ; GTPase-Activating Proteins/genetics ; Genetic Loci ; Genome-Wide Association Study/*methods ; Humans ; Regulatory Sequences, Nucleic Acid/genetics ; },
abstract = {Genome-wide association studies (GWAS) have contributed significantly to the understanding of complex disease genetics. However, GWAS only report association signals and do not necessarily identify culprit genes. As most signals occur in non-coding regions of the genome, it is often challenging to assign genomic variants to the underlying causal mechanism(s). Topologically associating domains (TADs) are primarily cell-type-independent genomic regions that define interactome boundaries and can aid in the designation of limits within which an association most likely impacts gene function. We describe and validate a computational method that uses the genic content of TADs to prioritize candidate genes. Our method, called 'TAD_Pathways', performs a Gene Ontology (GO) analysis over genes that reside within TAD boundaries corresponding to GWAS signals for a given trait or disease. Applying our pipeline to the bone mineral density (BMD) GWAS catalog, we identify 'Skeletal System Development' (Benjamini-Hochberg adjusted P=1.02x10[-5]) as the top-ranked pathway. In many cases, our method implicated a gene other than the nearest gene. Our molecular experiments describe a novel example: ACP2, implicated near the canonical 'ARHGAP1' locus. We found ACP2 to be an important regulator of osteoblast metabolism, whereas ARHGAP1 was not supported. Our results via BMD, for example, demonstrate how basic principles of three-dimensional genome organization can define biologically informed association windows.},
}
@article {pmid28784160,
year = {2017},
author = {Fabre, PJ and Leleu, M and Mormann, BH and Lopez-Delisle, L and Noordermeer, D and Beccari, L and Duboule, D},
title = {Large scale genomic reorganization of topological domains at the HoxD locus.},
journal = {Genome biology},
volume = {18},
number = {1},
pages = {149},
pmid = {28784160},
issn = {1474-760X},
mesh = {Animals ; Chromatin Immunoprecipitation ; Enhancer Elements, Genetic ; Gene Rearrangement ; *Genes, Homeobox ; *Genetic Loci ; Genomic Islands ; *Genomics/methods ; High-Throughput Nucleotide Sequencing ; In Situ Hybridization, Fluorescence ; Mice ; Multigene Family ; Regulatory Sequences, Nucleic Acid ; Transcription, Genetic ; },
abstract = {BACKGROUND: The transcriptional activation of HoxD genes during mammalian limb development involves dynamic interactions with two topologically associating domains (TADs) flanking the HoxD cluster. In particular, the activation of the most posterior HoxD genes in developing digits is controlled by regulatory elements located in the centromeric TAD (C-DOM) through long-range contacts.<br><br>RESULTS: To assess the structure-function relationships underlying such interactions, we measured compaction levels and TAD discreteness using a combination of chromosome conformation capture (4C-seq) and DNA FISH. We assessed the robustness of the TAD architecture by using a series of genomic deletions and inversions that impact the integrity of this chromatin domain and that remodel long-range contacts. We report multi-partite associations between HoxD genes and up to three enhancers. We find that the loss of native chromatin topology leads to the remodeling of TAD structure following distinct parameters.<br><br>CONCLUSIONS: Our results reveal that the recomposition of TAD architectures after large genomic re-arrangements is dependent on a boundary-selection mechanism in which CTCF mediates the gating of long-range contacts in combination with genomic distance and sequence specificity. Accordingly, the building of a recomposed TAD at this locus depends on distinct functional and constitutive parameters.},
}
@article {pmid28783961,
year = {2017},
author = {Yu, M and Ren, B},
title = {The Three-Dimensional Organization of Mammalian Genomes.},
journal = {Annual review of cell and developmental biology},
volume = {33},
number = {},
pages = {265-289},
pmid = {28783961},
issn = {1530-8995},
support = {U01 DK105541/DK/NIDDK NIH HHS/United States ; R01 ES024984/ES/NIEHS NIH HHS/United States ; UM1 HL128773/HL/NHLBI NIH HHS/United States ; U54 DK107977/DK/NIDDK NIH HHS/United States ; R01 HG008135/HG/NHGRI NIH HHS/United States ; P50 GM085764/GM/NIGMS NIH HHS/United States ; U54 HG006997/HG/NHGRI NIH HHS/United States ; },
mesh = {Animals ; Disease/genetics ; Gene Expression Regulation ; *Genome ; Humans ; Mammals/*genetics ; Neoplasms/genetics ; },
abstract = {Animal development depends on not only the linear genome sequence that embeds millions of cis-regulatory elements, but also the three-dimensional (3D) chromatin architecture that orchestrates the interplay between cis-regulatory elements and their target genes. Compared to our knowledge of the cis-regulatory sequences, the understanding of the 3D genome organization in human and other eukaryotes is still limited. Recent advances in technologies to map the 3D genome architecture have greatly accelerated the pace of discovery. Here, we review emerging concepts of chromatin organization in mammalian cells, discuss the dynamics of chromatin conformation during development, and highlight important roles for chromatin organization in cancer and other human diseases.},
}
@article {pmid28742097,
year = {2017},
author = {Yan, KK and Lou, S and Gerstein, M},
title = {MrTADFinder: A network modularity based approach to identify topologically associating domains in multiple resolutions.},
journal = {PLoS computational biology},
volume = {13},
number = {7},
pages = {e1005647},
pmid = {28742097},
issn = {1553-7358},
support = {U24 HG009446/HG/NHGRI NIH HHS/United States ; U41 HG007000/HG/NHGRI NIH HHS/United States ; },
mesh = {Algorithms ; Cell Line ; Cell Nucleus/chemistry/genetics ; *Chromatin/chemistry/genetics/ultrastructure ; *Chromosomes/chemistry/genetics/ultrastructure ; Computational Biology/*methods ; Genome/genetics/physiology ; Humans ; *Models, Genetic ; Protein Binding ; Transcription Factors/metabolism ; },
abstract = {Genome-wide proximity ligation based assays such as Hi-C have revealed that eukaryotic genomes are organized into structural units called topologically associating domains (TADs). From a visual examination of the chromosomal contact map, however, it is clear that the organization of the domains is not simple or obvious. Instead, TADs exhibit various length scales and, in many cases, a nested arrangement. Here, by exploiting the resemblance between TADs in a chromosomal contact map and densely connected modules in a network, we formulate TAD identification as a network optimization problem and propose an algorithm, MrTADFinder, to identify TADs from intra-chromosomal contact maps. MrTADFinder is based on the network-science concept of modularity. A key component of it is deriving an appropriate background model for contacts in a random chain, by numerically solving a set of matrix equations. The background model preserves the observed coverage of each genomic bin as well as the distance dependence of the contact frequency for any pair of bins exhibited by the empirical map. Also, by introducing a tunable resolution parameter, MrTADFinder provides a self-consistent approach for identifying TADs at different length scales, hence the acronym "Mr" standing for Multiple Resolutions. We then apply MrTADFinder to various Hi-C datasets. The identified domain boundaries are marked by characteristic signatures in chromatin marks and transcription factors (TF) that are consistent with earlier work. Moreover, by calling TADs at different length scales, we observe that boundary signatures change with resolution, with different chromatin features having different characteristic length scales. Furthermore, we report an enrichment of HOT (high-occupancy target) regions near TAD boundaries and investigate the role of different TFs in determining boundaries at various resolutions. To further explore the interplay between TADs and epigenetic marks, as tumor mutational burden is known to be coupled to chromatin structure, we examine how somatic mutations are distributed across boundaries and find a clear stepwise pattern. Overall, MrTADFinder provides a novel computational framework to explore the multi-scale structures in Hi-C contact maps.},
}
@article {pmid28703188,
year = {2017},
author = {Du, Z and Zheng, H and Huang, B and Ma, R and Wu, J and Zhang, X and He, J and Xiang, Y and Wang, Q and Li, Y and Ma, J and Zhang, X and Zhang, K and Wang, Y and Zhang, MQ and Gao, J and Dixon, JR and Wang, X and Zeng, J and Xie, W},
title = {Allelic reprogramming of 3D chromatin architecture during early mammalian development.},
journal = {Nature},
volume = {547},
number = {7662},
pages = {232-235},
pmid = {28703188},
issn = {1476-4687},
mesh = {*Alleles ; Animals ; Blastocyst/metabolism ; Chromatin/*chemistry/*genetics/metabolism ; Chromatin Assembly and Disassembly/*genetics ; Chromosomes, Mammalian/*chemistry/*genetics/metabolism ; Embryonic Development/*genetics ; Female ; Fertilization ; Gene Expression Regulation, Developmental ; Male ; Mice ; Transcription, Genetic ; Zygote/metabolism ; },
abstract = {In mammals, chromatin organization undergoes drastic reprogramming after fertilization. However, the three-dimensional structure of chromatin and its reprogramming in preimplantation development remain poorly understood. Here, by developing a low-input Hi-C (genome-wide chromosome conformation capture) approach, we examined the reprogramming of chromatin organization during early development in mice. We found that oocytes in metaphase II show homogeneous chromatin folding that lacks detectable topologically associating domains (TADs) and chromatin compartments. Strikingly, chromatin shows greatly diminished higher-order structure after fertilization. Unexpectedly, the subsequent establishment of chromatin organization is a prolonged process that extends through preimplantation development, as characterized by slow consolidation of TADs and segregation of chromatin compartments. The two sets of parental chromosomes are spatially separated from each other and display distinct compartmentalization in zygotes. Such allele separation and allelic compartmentalization can be found as late as the 8-cell stage. Finally, we show that chromatin compaction in preimplantation embryos can partially proceed in the absence of zygotic transcription and is a multi-level hierarchical process. Taken together, our data suggest that chromatin may exist in a markedly relaxed state after fertilization, followed by progressive maturation of higher-order chromatin architecture during early development.},
}
@article {pmid28693562,
year = {2017},
author = {Ulianov, SV and Galitsyna, AA and Flyamer, IM and Golov, AK and Khrameeva, EE and Imakaev, MV and Abdennur, NA and Gelfand, MS and Gavrilov, AA and Razin, SV},
title = {Activation of the alpha-globin gene expression correlates with dramatic upregulation of nearby non-globin genes and changes in local and large-scale chromatin spatial structure.},
journal = {Epigenetics &amp; chromatin},
volume = {10},
number = {1},
pages = {35},
pmid = {28693562},
issn = {1756-8935},
mesh = {Animals ; Avian Proteins/*genetics/metabolism ; CCCTC-Binding Factor/metabolism ; Cell Line ; Chickens ; Chromatin/*genetics/metabolism ; Erythroid Cells/cytology/metabolism ; Erythropoiesis ; Genes, Essential ; Protein Binding ; *Transcriptional Activation ; *Up-Regulation ; alpha-Globins/*genetics/metabolism ; },
abstract = {BACKGROUND: In homeotherms, the alpha-globin gene clusters are located within permanently open genome regions enriched in housekeeping genes. Terminal erythroid differentiation results in dramatic upregulation of alpha-globin genes making their expression comparable to the rRNA transcriptional output. Little is known about the influence of the erythroid-specific alpha-globin gene transcription outburst on adjacent, widely expressed genes and large-scale chromatin organization. Here, we have analyzed the total transcription output, the overall chromatin contact profile, and CTCF binding within the 2.7 Mb segment of chicken chromosome 14 harboring the alpha-globin gene cluster in cultured lymphoid cells and cultured erythroid cells before and after induction of terminal erythroid differentiation.<br><br>RESULTS: We found that, similarly to mammalian genome, the chicken genomes is organized in TADs and compartments. Full activation of the alpha-globin gene transcription in differentiated erythroid cells is correlated with upregulation of several adjacent housekeeping genes and the emergence of abundant intergenic transcription. An extended chromosome region encompassing the alpha-globin cluster becomes significantly decompacted in differentiated erythroid cells, and depleted in CTCF binding and CTCF-anchored chromatin loops, while the sub-TAD harboring alpha-globin gene cluster and the upstream major regulatory element (MRE) becomes highly enriched with chromatin interactions as compared to lymphoid and proliferating erythroid cells. The alpha-globin gene domain and the neighboring loci reside within the A-like chromatin compartment in both lymphoid and erythroid cells and become further segregated from the upstream gene desert upon terminal erythroid differentiation.<br><br>CONCLUSIONS: Our findings demonstrate that the effects of tissue-specific transcription activation are not restricted to the host genomic locus but affect the overall chromatin structure and transcriptional output of the encompassing topologically associating domain.},
}
@article {pmid28615069,
year = {2017},
author = {Vicente-García, C and Villarejo-Balcells, B and Irastorza-Azcárate, I and Naranjo, S and Acemel, RD and Tena, JJ and Rigby, PWJ and Devos, DP and Gómez-Skarmeta, JL and Carvajal, JJ},
title = {Regulatory landscape fusion in rhabdomyosarcoma through interactions between the PAX3 promoter and FOXO1 regulatory elements.},
journal = {Genome biology},
volume = {18},
number = {1},
pages = {106},
pmid = {28615069},
issn = {1474-760X},
mesh = {Forkhead Box Protein O1/*genetics ; Gene Expression Regulation, Neoplastic ; Genome, Human ; Humans ; Oncogene Proteins, Fusion/genetics ; PAX3 Transcription Factor/*genetics ; Promoter Regions, Genetic ; Protein Domains/genetics ; Protein Interaction Maps/*genetics ; Regulatory Sequences, Nucleic Acid/genetics ; Rhabdomyosarcoma, Alveolar/*genetics/pathology ; Translocation, Genetic/genetics ; },
abstract = {BACKGROUND: The organisation of vertebrate genomes into topologically associating domains (TADs) is believed to facilitate the regulation of the genes located within them. A remaining question is whether TAD organisation is achieved through the interactions of the regulatory elements within them or if these interactions are favoured by the pre-existence of TADs. If the latter is true, the fusion of two independent TADs should result in the rewiring of the transcriptional landscape and the generation of ectopic contacts.<br><br>RESULTS: We show that interactions within the PAX3 and FOXO1 domains are restricted to their respective TADs in normal conditions, while in a patient-derived alveolar rhabdomyosarcoma cell line, harbouring the diagnostic t(2;13)(q35;q14) translocation that brings together the PAX3 and FOXO1 genes, the PAX3 promoter interacts ectopically with FOXO1 sequences. Using a combination of 4C-seq datasets, we have modelled the three-dimensional organisation of the fused landscape in alveolar rhabdomyosarcoma.<br><br>CONCLUSIONS: The chromosomal translocation that leads to alveolar rhabdomyosarcoma development generates a novel TAD that is likely to favour ectopic PAX3:FOXO1 oncogene activation in non-PAX3 territories. Rhabdomyosarcomas may therefore arise from cells which do not normally express PAX3. The borders of this novel TAD correspond to the original 5'- and 3'- borders of the PAX3 and FOXO1 TADs, respectively, suggesting that TAD organisation precedes the formation of regulatory long-range interactions. Our results demonstrate that, upon translocation, novel regulatory landscapes are formed allowing new intra-TAD interactions between the original loci involved.},
}
@article {pmid28604721,
year = {2017},
author = {Forcato, M and Nicoletti, C and Pal, K and Livi, CM and Ferrari, F and Bicciato, S},
title = {Comparison of computational methods for Hi-C data analysis.},
journal = {Nature methods},
volume = {14},
number = {7},
pages = {679-685},
pmid = {28604721},
issn = {1548-7105},
support = {670126/ERC_/European Research Council/International ; },
mesh = {Animals ; Chromatin/chemistry ; Chromosome Mapping/*methods ; Chromosomes/*chemistry/genetics ; Computational Biology/*methods ; Computer Simulation ; Genome ; Genome-Wide Association Study/*methods ; },
abstract = {Hi-C is a genome-wide sequencing technique used to investigate 3D chromatin conformation inside the nucleus. Computational methods are required to analyze Hi-C data and identify chromatin interactions and topologically associating domains (TADs) from genome-wide contact probability maps. We quantitatively compared the performance of 13 algorithms in their analyses of Hi-C data from six landmark studies and simulations. This comparison revealed differences in the performance of methods for chromatin interaction identification, but more comparable results for TAD detection between algorithms.},
}
@article {pmid28593374,
year = {2017},
author = {Sawyer, IA and Dundr, M},
title = {Chromatin loops and causality loops: the influence of RNA upon spatial nuclear architecture.},
journal = {Chromosoma},
volume = {126},
number = {5},
pages = {541-557},
pmid = {28593374},
issn = {1432-0886},
support = {R01 GM090156/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Cell Nucleus/*metabolism ; Chromatin/*metabolism ; DNA/metabolism ; Epigenesis, Genetic ; *Gene Expression Regulation ; Humans ; RNA, Long Noncoding/*metabolism ; Spatial Analysis ; },
abstract = {An intrinsic and essential trait exhibited by cells is the properly coordinated and integrated regulation of an astoundingly large number of simultaneous molecular decisions and reactions to maintain biochemical homeostasis. This is especially true inside the cell nucleus, where the recognition of DNA and RNA by a vast range of nucleic acid-interacting proteins organizes gene expression patterns. However, this dynamic system is not regulated by simple "on" or "off" signals. Instead, transcription factor and RNA polymerase recruitment to DNA are influenced by the local chromatin and epigenetic environment, a gene's relative position within the nucleus and the action of noncoding RNAs. In addition, major phase-separated structural features of the nucleus, such as nucleoli and paraspeckles, assemble in direct response to specific transcriptional activities and, in turn, influence global genomic function. Currently, the interpretation of these data is trapped in a causality dilemma reminiscent of the "chicken and the egg" paradox as it is unclear whether changes in nuclear architecture promote RNA function or vice versa. Here, we review recent advances that suggest a complex and interdependent interaction network between gene expression, chromatin topology, and noncoding RNA function. We also discuss the functional links between these essential nuclear processes from the nanoscale (gene looping) to the macroscale (sub-nuclear gene positioning and nuclear body function) and briefly highlight some of the challenges that researchers may encounter when studying these phenomena.},
}
@article {pmid28562241,
year = {2017},
author = {Albritton, SE and Kranz, AL and Winterkorn, LH and Street, LA and Ercan, S},
title = {Cooperation between a hierarchical set of recruitment sites targets the X chromosome for dosage compensation.},
journal = {eLife},
volume = {6},
number = {},
pages = {},
pmid = {28562241},
issn = {2050-084X},
support = {R01 GM107293/GM/NIGMS NIH HHS/United States ; P40 OD010440/OD/NIH HHS/United States ; },
mesh = {Animals ; Caenorhabditis elegans/*genetics ; Chromatin/metabolism ; *Dosage Compensation, Genetic ; Syndecan-2/metabolism ; X Chromosome/*metabolism ; },
abstract = {In many organisms, it remains unclear how X chromosomes are specified for dosage compensation, since DNA sequence motifs shown to be important for dosage compensation complex (DCC) recruitment are themselves not X-specific. Here, we addressed this problem in C. elegans. We found that the DCC recruiter, SDC-2, is required to maintain open chromatin at a small number of primary DCC recruitment sites, whose sequence and genomic context are X-specific. Along the X, primary recruitment sites are interspersed with secondary sites, whose function is X-dependent. A secondary site can ectopically recruit the DCC when additional recruitment sites are inserted either in tandem or at a distance (>30 kb). Deletion of a recruitment site on the X results in reduced DCC binding across several megabases surrounded by topologically associating domain (TAD) boundaries. Our work elucidates that hierarchy and long-distance cooperativity between gene-regulatory elements target a single chromosome for regulation.},
}
@article {pmid28549169,
year = {2017},
author = {Stolzenburg, LR and Yang, R and Kerschner, JL and Fossum, S and Xu, M and Hoffmann, A and Lamar, KM and Ghosh, S and Wachtel, S and Leir, SH and Harris, A},
title = {Regulatory dynamics of 11p13 suggest a role for EHF in modifying CF lung disease severity.},
journal = {Nucleic acids research},
volume = {45},
number = {15},
pages = {8773-8784},
pmid = {28549169},
issn = {1362-4962},
support = {F31 HL126458/HL/NHLBI NIH HHS/United States ; P30 DK065988/DK/NIDDK NIH HHS/United States ; R01 HL117843/HL/NHLBI NIH HHS/United States ; },
mesh = {Caco-2 Cells ; Cells, Cultured ; Chromatin/metabolism ; Chromosomes, Human, Pair 11/*genetics ; Cystic Fibrosis/*genetics/*pathology ; Enhancer Elements, Genetic ; *Gene Expression Regulation ; Genetic Loci ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; K562 Cells ; Polymorphism, Single Nucleotide ; Severity of Illness Index ; Transcription Factors/genetics/*physiology ; },
abstract = {Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF), but are not good predictors of lung phenotype. Genome-wide association studies (GWAS) previously identified additional genomic sites associated with CF lung disease severity. One of these, at chromosome 11p13, is an intergenic region between Ets homologous factor (EHF) and Apaf-1 interacting protein (APIP). Our goal was to determine the functional significance of this region, which being intergenic is probably regulatory. To identify cis-acting elements, we used DNase-seq and H3K4me1 and H3K27Ac ChIP-seq to map open and active chromatin respectively, in lung epithelial cells. Two elements showed strong enhancer activity for the promoters of EHF and the 5' adjacent gene E47 like ETS transcription factor 5 (ELF5) in reporter gene assays. No enhancers of the APIP promoter were found. Circular chromosome conformation capture (4C-seq) identified direct physical interactions of elements within 11p13. This confirmed the enhancer-promoter associations, identified additional interacting elements and defined topologically associating domain (TAD) boundaries, enriched for CCCTC-binding factor (CTCF). No strong interactions were observed with the APIP promoter, which lies outside the main TAD encompassing the GWAS signal. These results focus attention on the role of EHF in modifying CF lung disease severity.},
}
@article {pmid28525758,
year = {2017},
author = {Nora, EP and Goloborodko, A and Valton, AL and Gibcus, JH and Uebersohn, A and Abdennur, N and Dekker, J and Mirny, LA and Bruneau, BG},
title = {Targeted Degradation of CTCF Decouples Local Insulation of Chromosome Domains from Genomic Compartmentalization.},
journal = {Cell},
volume = {169},
number = {5},
pages = {930-944.e22},
pmid = {28525758},
issn = {1097-4172},
support = {U01 HL098179/HL/NHLBI NIH HHS/United States ; R01 GM112720/GM/NIGMS NIH HHS/United States ; R01 GM114190/GM/NIGMS NIH HHS/United States ; U01 HL131003/HL/NHLBI NIH HHS/United States ; R01 AI117839/AI/NIAID NIH HHS/United States ; U54 HG007010/HG/NHGRI NIH HHS/United States ; R01 HG003143/HG/NHGRI NIH HHS/United States ; U01 HG007910/HG/NHGRI NIH HHS/United States ; UM1 HL098179/HL/NHLBI NIH HHS/United States ; U54 DK107980/DK/NIDDK NIH HHS/United States ; P30 AI027763/AI/NIAID NIH HHS/United States ; U01 DA040588/DA/NIDA NIH HHS/United States ; U54 CA193419/CA/NCI NIH HHS/United States ; /HHMI_/Howard Hughes Medical Institute/United States ; },
mesh = {Animals ; CCCTC-Binding Factor ; Cell Cycle ; Chromatin/metabolism ; Chromosomes, Mammalian/*chemistry/genetics/metabolism ; Embryonic Stem Cells/metabolism ; Gene Expression Regulation ; Indoleacetic Acids/pharmacology ; Mice ; Repressor Proteins/metabolism ; Transcription, Genetic ; },
abstract = {The molecular mechanisms underlying folding of mammalian chromosomes remain poorly understood. The transcription factor CTCF is a candidate regulator of chromosomal structure. Using the auxin-inducible degron system in mouse embryonic stem cells, we show that CTCF is absolutely and dose-dependently required for looping between CTCF target sites and insulation of topologically associating domains (TADs). Restoring CTCF reinstates proper architecture on altered chromosomes, indicating a powerful instructive function for CTCF in chromatin folding. CTCF remains essential for TAD organization in non-dividing cells. Surprisingly, active and inactive genome compartments remain properly segregated upon CTCF depletion, revealing that compartmentalization of mammalian chromosomes emerges independently of proper insulation of TADs. Furthermore, our data support that CTCF mediates transcriptional insulator function through enhancer blocking but not as a direct barrier to heterochromatin spreading. Beyond defining the functions of CTCF in chromosome folding, these results provide new fundamental insights into the rules governing mammalian genome organization.},
}
@article {pmid28513628,
year = {2017},
author = {Carty, M and Zamparo, L and Sahin, M and González, A and Pelossof, R and Elemento, O and Leslie, CS},
title = {An integrated model for detecting significant chromatin interactions from high-resolution Hi-C data.},
journal = {Nature communications},
volume = {8},
number = {},
pages = {15454},
pmid = {28513628},
issn = {2041-1723},
support = {P30 CA008748/CA/NCI NIH HHS/United States ; U01 HG007893/HG/NHGRI NIH HHS/United States ; U01 HG009395/HG/NHGRI NIH HHS/United States ; },
mesh = {Animals ; Binding Sites/genetics ; Cell Line, Tumor ; Chromatin/genetics/*metabolism ; Chromosome Mapping/methods ; Chromosomes, Human, Pair 6/genetics/metabolism ; Computational Biology/*methods ; CpG Islands/genetics ; Datasets as Topic ; Genome/*genetics ; Genomics/*methods ; Histone Code/genetics ; Humans ; Mice ; *Models, Genetic ; Promoter Regions, Genetic/genetics ; Software ; },
abstract = {Here we present HiC-DC, a principled method to estimate the statistical significance (P values) of chromatin interactions from Hi-C experiments. HiC-DC uses hurdle negative binomial regression account for systematic sources of variation in Hi-C read counts-for example, distance-dependent random polymer ligation and GC content and mappability bias-and model zero inflation and overdispersion. Applied to high-resolution Hi-C data in a lymphoblastoid cell line, HiC-DC detects significant interactions at the sub-topologically associating domain level, identifying potential structural and regulatory interactions supported by CTCF binding sites, DNase accessibility, and/or active histone marks. CTCF-associated interactions are most strongly enriched in the middle genomic distance range (∼700 kb-1.5 Mb), while interactions involving actively marked DNase accessible elements are enriched both at short (<500 kb) and longer (>1.5 Mb) genomic distances. There is a striking enrichment of longer-range interactions connecting replication-dependent histone genes on chromosome 6, potentially representing the chromatin architecture at the histone locus body.},
}
@article {pmid28504305,
year = {2018},
author = {Fritz, AJ and Ghule, PN and Boyd, JR and Tye, CE and Page, NA and Hong, D and Shirley, DJ and Weinheimer, AS and Barutcu, AR and Gerrard, DL and Frietze, S and van Wijnen, AJ and Zaidi, SK and Imbalzano, AN and Lian, JB and Stein, JL and Stein, GS},
title = {Intranuclear and higher-order chromatin organization of the major histone gene cluster in breast cancer.},
journal = {Journal of cellular physiology},
volume = {233},
number = {2},
pages = {1278-1290},
pmid = {28504305},
issn = {1097-4652},
support = {U54 GM115516/GM/NIGMS NIH HHS/United States ; P30 GM118228/GM/NIGMS NIH HHS/United States ; P01 CA082834/CA/NCI NIH HHS/United States ; P20 RR021905/RR/NCRR NIH HHS/United States ; U01 CA196383/CA/NCI NIH HHS/United States ; R01 CA139322/CA/NCI NIH HHS/United States ; },
mesh = {Breast Neoplasms/*genetics/metabolism/pathology ; Cell Line, Tumor ; Cell Nucleus/metabolism/pathology ; Cell Nucleus Shape ; Cell Proliferation ; Chromatin/*genetics/metabolism ; *Chromatin Assembly and Disassembly ; *Chromosomes, Human, Pair 6 ; Computational Biology ; Databases, Genetic ; Disease Progression ; Female ; Gene Expression Regulation, Neoplastic ; Genetic Predisposition to Disease ; Histones/*genetics/metabolism ; Humans ; *Multigene Family ; Phenotype ; Protein Binding ; Protein Interaction Domains and Motifs ; Up-Regulation ; },
abstract = {Alterations in nuclear morphology are common in cancer progression. However, the degree to which gross morphological abnormalities translate into compromised higher-order chromatin organization is poorly understood. To explore the functional links between gene expression and chromatin structure in breast cancer, we performed RNA-seq gene expression analysis on the basal breast cancer progression model based on human MCF10A cells. Positional gene enrichment identified the major histone gene cluster at chromosome 6p22 as one of the most significantly upregulated (and not amplified) clusters of genes from the normal-like MCF10A to premalignant MCF10AT1 and metastatic MCF10CA1a cells. This cluster is subdivided into three sub-clusters of histone genes that are organized into hierarchical topologically associating domains (TADs). Interestingly, the sub-clusters of histone genes are located at TAD boundaries and interact more frequently with each other than the regions in-between them, suggesting that the histone sub-clusters form an active chromatin hub. The anchor sites of loops within this hub are occupied by CTCF, a known chromatin organizer. These histone genes are transcribed and processed at a specific sub-nuclear microenvironment termed the major histone locus body (HLB). While the overall chromatin structure of the major HLB is maintained across breast cancer progression, we detected alterations in its structure that may relate to gene expression. Importantly, breast tumor specimens also exhibit a coordinate pattern of upregulation across the major histone gene cluster. Our results provide a novel insight into the connection between the higher-order chromatin organization of the major HLB and its regulation during breast cancer progression.},
}
@article {pmid28487148,
year = {2017},
author = {Agarwal, H and Reisser, M and Wortmann, C and Gebhardt, JCM},
title = {Direct Observation of Cell-Cycle-Dependent Interactions between CTCF and Chromatin.},
journal = {Biophysical journal},
volume = {112},
number = {10},
pages = {2051-2055},
pmid = {28487148},
issn = {1542-0086},
mesh = {CCCTC-Binding Factor ; Cell Cycle/*physiology ; Cell Line ; Chromatin/*metabolism ; Humans ; Kinetics ; Molecular Imaging ; Protein Binding ; Repressor Proteins/*metabolism ; },
abstract = {The three-dimensional arrangement of chromatin encodes regulatory traits important for nuclear processes such as transcription and replication. Chromatin topology is in part mediated by the architectural protein CCCTC-binding factor (CTCF) that binds to the boundaries of topologically associating domains. Whereas sites of CTCF interactions are well characterized, little is known on how long CTCF binds to chromatin and how binding evolves during the cell cycle. We monitored CTCF-chromatin interactions by live cell single molecule tracking in different phases of the cell cycle. In G1-, S-, and G2-phases, a majority of CTCF molecules was bound transiently (∼0.2 s) to chromatin, whereas minor fractions were bound dynamically (∼4 s) or stably (>15 min). During mitosis, CTCF was mostly excluded from chromatin. Our data suggest that CTCF scans DNA in search for two different subsets of specific target sites and provide information on the timescales over which topologically associating domains might be restructured. During S-phase, dynamic and stable interactions decreased considerably compared to G1-phase, but were resumed in G2-phase, indicating that specific interactions need to be dissolved for replication to proceed.},
}
@article {pmid28475875,
year = {2017},
author = {Siersbæk, R and Madsen, JGS and Javierre, BM and Nielsen, R and Bagge, EK and Cairns, J and Wingett, SW and Traynor, S and Spivakov, M and Fraser, P and Mandrup, S},
title = {Dynamic Rewiring of Promoter-Anchored Chromatin Loops during Adipocyte Differentiation.},
journal = {Molecular cell},
volume = {66},
number = {3},
pages = {420-435.e5},
doi = {10.1016/j.molcel.2017.04.010},
pmid = {28475875},
issn = {1097-4164},
support = {MR/L007150/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {3T3-L1 Cells ; Adipocytes/*metabolism ; *Adipogenesis ; Animals ; Cell Cycle Proteins/genetics/metabolism ; Chromatin/chemistry/genetics/*metabolism ; *Chromatin Assembly and Disassembly ; Chromatin Immunoprecipitation ; Chromosomal Proteins, Non-Histone/genetics/metabolism ; E1A-Associated p300 Protein/genetics/metabolism ; Enhancer Elements, Genetic ; Mediator Complex Subunit 1/genetics/metabolism ; Mice ; Nucleic Acid Conformation ; *Promoter Regions, Genetic ; RNA, Messenger/genetics/metabolism ; Sequence Analysis, RNA ; Time Factors ; Transcription, Genetic ; Transcriptional Activation ; },
abstract = {Interactions between transcriptional promoters and their distal regulatory elements play an important role in transcriptional regulation; however, the extent to which these interactions are subject to rapid modulations in response to signals is unknown. Here, we use promoter capture Hi-C to demonstrate a rapid reorganization of promoter-anchored chromatin loops within 4 hr after inducing differentiation of 3T3-L1 preadipocytes. The establishment of new promoter-enhancer loops is tightly coupled to activation of poised (histone H3 lysine 4 mono- and dimethylated) enhancers, as evidenced by the acquisition of histone H3 lysine 27 acetylation and the binding of MED1, SMC1, and P300 proteins to these regions, as well as to activation of target genes. Intriguingly, formation of loops connecting activated enhancers and promoters is also associated with extensive recruitment of corepressors such as NCoR and HDACs, indicating that this class of coregulators may play a previously unrecognized role during enhancer activation.},
}
@article {pmid28435001,
year = {2017},
author = {Belaghzal, H and Dekker, J and Gibcus, JH},
title = {Hi-C 2.0: An optimized Hi-C procedure for high-resolution genome-wide mapping of chromosome conformation.},
journal = {Methods (San Diego, Calif.)},
volume = {123},
number = {},
pages = {56-65},
pmid = {28435001},
issn = {1095-9130},
support = {R01 GM112720/GM/NIGMS NIH HHS/United States ; R01 HG003143/HG/NHGRI NIH HHS/United States ; U01 HG007910/HG/NHGRI NIH HHS/United States ; U54 DK107980/DK/NIDDK NIH HHS/United States ; R01 AI117839/AI/NIAID NIH HHS/United States ; U01 DA040588/DA/NIDA NIH HHS/United States ; U54 HG007010/HG/NHGRI NIH HHS/United States ; U54 CA193419/CA/NCI NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; },
mesh = {Base Sequence ; Biotin/chemistry ; Cell Line ; Chromosome Mapping/*methods ; Chromosomes/*chemistry/ultrastructure ; Cross-Linking Reagents/chemistry ; DNA/*chemistry ; Deoxyribonucleases, Type II Site-Specific/chemistry ; Formaldehyde/chemistry ; *Genome, Human ; High-Throughput Nucleotide Sequencing ; Humans ; Staining and Labeling/*methods ; },
abstract = {Chromosome conformation capture-based methods such as Hi-C have become mainstream techniques for the study of the 3D organization of genomes. These methods convert chromatin interactions reflecting topological chromatin structures into digital information (counts of pair-wise interactions). Here, we describe an updated protocol for Hi-C (Hi-C 2.0) that integrates recent improvements into a single protocol for efficient and high-resolution capture of chromatin interactions. This protocol combines chromatin digestion and frequently cutting enzymes to obtain kilobase (kb) resolution. It also includes steps to reduce random ligation and the generation of uninformative molecules, such as unligated ends, to improve the amount of valid intra-chromosomal read pairs. This protocol allows for obtaining information on conformational structures such as compartment and topologically associating domains, as well as high-resolution conformational features such as DNA loops.},
}
@article {pmid28420341,
year = {2017},
author = {Nikumbh, S and Pfeifer, N},
title = {Genetic sequence-based prediction of long-range chromatin interactions suggests a potential role of short tandem repeat sequences in genome organization.},
journal = {BMC bioinformatics},
volume = {18},
number = {1},
pages = {218},
pmid = {28420341},
issn = {1471-2105},
mesh = {Chromatin/*genetics ; Genome/*genetics ; Humans ; Microsatellite Repeats/*genetics ; Promoter Regions, Genetic/*genetics ; Regulatory Sequences, Nucleic Acid ; },
abstract = {BACKGROUND: Knowing the three-dimensional (3D) structure of the chromatin is important for obtaining a complete picture of the regulatory landscape. Changes in the 3D structure have been implicated in diseases. While there exist approaches that attempt to predict the long-range chromatin interactions, they focus only on interactions between specific genomic regions - the promoters and enhancers, neglecting other possibilities, for instance, the so-called structural interactions involving intervening chromatin.<br><br>RESULTS: We present a method that can be trained on 5C data using the genetic sequence of the candidate loci to predict potential genome-wide interaction partners of a particular locus of interest. We have built locus-specific support vector machine (SVM)-based predictors using the oligomer distance histograms (ODH) representation. The method shows good performance with a mean test AUC (area under the receiver operating characteristic (ROC) curve) of 0.7 or higher for various regions across cell lines GM12878, K562 and HeLa-S3. In cases where any locus did not have sufficient candidate interaction partners for model training, we employed multitask learning to share knowledge between models of different loci. In this scenario, across the three cell lines, the method attained an average performance increase of 0.09 in the AUC. Performance evaluation of the models trained on 5C data regarding prediction on an independent high-resolution Hi-C dataset (which is a rather hard problem) shows 0.56 AUC, on average. Additionally, we have developed new, intuitive visualization methods that enable interpretation of sequence signals that contributed towards prediction of locus-specific interaction partners. The analysis of these sequence signals suggests a potential general role of short tandem repeat sequences in genome organization.<br><br>CONCLUSIONS: We demonstrated how our approach can 1) provide insights into sequence features of locus-specific interaction partners, and 2) also identify their cell-line specificity. That our models deem short tandem repeat sequences as discriminative for prediction of potential interaction partners, suggests that they could play a larger role in genome organization. Thus, our approach can (a) be beneficial to broadly understand, at the sequence-level, chromatin interactions and higher-order structures like (meta-) topologically associating domains (TADs); (b) study regions omitted from existing prediction approaches using various information sources (e.g., epigenetic information); and},
}
@article {pmid28408976,
year = {2017},
author = {Kaiser, VB and Semple, CA},
title = {When TADs go bad: chromatin structure and nuclear organisation in human disease.},
journal = {F1000Research},
volume = {6},
number = {},
pages = {},
pmid = {28408976},
issn = {2046-1402},
support = {MC_UU_12008/2/MRC_/Medical Research Council/United Kingdom ; },
abstract = {Chromatin in the interphase nucleus is organised as a hierarchical series of structural domains, including self-interacting domains called topologically associating domains (TADs). This arrangement is thought to bring enhancers into closer physical proximity with their target genes, which often are located hundreds of kilobases away in linear genomic distance. TADs are demarcated by boundary regions bound by architectural proteins, such as CTCF and cohesin, although much remains to be discovered about the structure and function of these domains. Recent studies of TAD boundaries disrupted in engineered mouse models show that boundary mutations can recapitulate human developmental disorders as a result of aberrant promoter-enhancer interactions in the affected TADs. Similar boundary disruptions in certain cancers can result in oncogene overexpression, and CTCF binding sites at boundaries appear to be hyper-mutated across cancers. Further insights into chromatin organisation, in parallel with accumulating whole genome sequence data for disease cohorts, are likely to yield additional valuable insights into the roles of noncoding sequence variation in human disease.},
}
@article {pmid28399667,
year = {2017},
author = {Chatterjee, S and Ahituv, N},
title = {Gene Regulatory Elements, Major Drivers of Human Disease.},
journal = {Annual review of genomics and human genetics},
volume = {18},
number = {},
pages = {45-63},
doi = {10.1146/annurev-genom-091416-035537},
pmid = {28399667},
issn = {1545-293X},
support = {R01 CA197139/CA/NCI NIH HHS/United States ; UM1 HG009408/HG/NHGRI NIH HHS/United States ; R01 MH109907/MH/NIMH NIH HHS/United States ; P01 HD084387/HD/NICHD NIH HHS/United States ; },
mesh = {CRISPR-Cas Systems ; *Enhancer Elements, Genetic ; *Gene Regulatory Networks ; High-Throughput Nucleotide Sequencing/methods ; Humans ; *Promoter Regions, Genetic ; Sequence Analysis, DNA/methods ; },
abstract = {Gene expression changes, the driving forces for cellular diversity in multicellular organisms, are regulated by a diverse set of gene regulatory elements that direct transcription in specific cells. Mutations in these elements, ranging from chromosomal aberrations to single-nucleotide polymorphisms, are a major cause of human disease. However, we currently have a very limited understanding of how regulatory element genotypes lead to specific phenotypes. In this review, we discuss the various methods of regulatory element identification, the different types of mutations they harbor, and their impact on human disease. We highlight how these variations can affect transcription of multiple genes in gene regulatory networks. In addition, we describe how novel technologies, such as massively parallel reporter assays and CRISPR/Cas9 genome editing, are beginning to provide a better understanding of the functional roles that these elements have and how their alteration can lead to specific phenotypes.},
}
@article {pmid28388407,
year = {2017},
author = {Hug, CB and Grimaldi, AG and Kruse, K and Vaquerizas, JM},
title = {Chromatin Architecture Emerges during Zygotic Genome Activation Independent of Transcription.},
journal = {Cell},
volume = {169},
number = {2},
pages = {216-228.e19},
doi = {10.1016/j.cell.2017.03.024},
pmid = {28388407},
issn = {1097-4172},
mesh = {Animals ; Chromatin/*metabolism ; Drosophila Proteins/metabolism ; Drosophila melanogaster/*embryology/*genetics ; Embryo, Nonmammalian/metabolism ; Genes, Essential ; *Genome, Insect ; Nuclear Proteins ; RNA Polymerase II/metabolism ; Time Factors ; Transcription Factors/metabolism ; Transcription, Genetic ; *Transcriptional Activation ; Zygote/*metabolism ; },
abstract = {Chromatin architecture is fundamental in regulating gene expression. To investigate when spatial genome organization is first established during development, we examined chromatin conformation during Drosophila embryogenesis and observed the emergence of chromatin architecture within a tight time window that coincides with the onset of transcription activation in the zygote. Prior to zygotic genome activation, the genome is mostly unstructured. Early expressed genes serve as nucleation sites for topologically associating domain (TAD) boundaries. Activation of gene expression coincides with the establishment of TADs throughout the genome and co-localization of housekeeping gene clusters, which remain stable in subsequent stages of development. However, the appearance of TAD boundaries is independent of transcription and requires the transcription factor Zelda for locus-specific TAD boundary insulation. These results offer insight into when spatial organization of the genome emerges and identify a key factor that helps trigger this architecture.},
}
@article {pmid28359583,
year = {2017},
author = {Fanucchi, S and Mhlanga, MM},
title = {Enhancer-Derived lncRNAs Regulate Genome Architecture: Fact or Fiction?.},
journal = {Trends in genetics : TIG},
volume = {33},
number = {6},
pages = {375-377},
doi = {10.1016/j.tig.2017.03.004},
pmid = {28359583},
issn = {0168-9525},
mesh = {Chromosomes/*genetics ; *Enhancer Elements, Genetic ; Epigenesis, Genetic ; Genome, Human ; Genome-Wide Association Study ; Humans ; Promoter Regions, Genetic ; RNA, Long Noncoding/*genetics ; Regulatory Sequences, Nucleic Acid/genetics ; },
abstract = {How does the non-coding portion of the genome contribute to the regulation of genome architecture? A recent paper by Tan et al. focuses on the relationship between cis-acting complex-trait-associated lincRNAs and the formation of chromosomal contacts in topologically associating domains (TADs).},
}
@article {pmid28355537,
year = {2017},
author = {Brackley, CA and Liebchen, B and Michieletto, D and Mouvet, F and Cook, PR and Marenduzzo, D},
title = {Ephemeral Protein Binding to DNA Shapes Stable Nuclear Bodies and Chromatin Domains.},
journal = {Biophysical journal},
volume = {112},
number = {6},
pages = {1085-1093},
pmid = {28355537},
issn = {1542-0086},
mesh = {Cell Nucleus/*metabolism ; Chromatin/*metabolism ; DNA/chemistry/*metabolism ; DNA-Binding Proteins/chemistry/*metabolism ; Microscopy, Fluorescence ; Models, Molecular ; Nucleic Acid Conformation ; Protein Binding ; Protein Conformation ; },
abstract = {Fluorescence microscopy reveals that the contents of many (membrane-free) nuclear bodies exchange rapidly with the soluble pool while the underlying structure persists; such observations await a satisfactory biophysical explanation. To shed light on this, we perform large-scale Brownian dynamics simulations of a chromatin fiber interacting with an ensemble of (multivalent) DNA-binding proteins able to switch between an "on" (binding) and an "off" (nonbinding) state. This system provides a model for any DNA-binding protein that can be posttranslationally modified to change its affinity for DNA (e.g., through phosphorylation). Protein switching is a nonequilibrium process, and it leads to the formation of clusters of self-limiting size, where individual proteins in a cluster exchange with the soluble pool with kinetics similar to those seen in photobleaching experiments. This behavior contrasts sharply with that exhibited by nonswitching proteins, which are permanently in the on-state; when these bind to DNA nonspecifically, they form clusters that grow indefinitely in size. To explain these findings, we propose a mean-field theory from which we obtain a scaling relation between the typical cluster size and the protein switching rate. Protein switching also reshapes intrachromatin contacts to give networks resembling those seen in topologically associating domains, as switching markedly favors local (short-range) contacts over distant ones. Our results point to posttranslational modification of chromatin-bridging proteins as a generic mechanism driving the self-assembly of highly dynamic, nonequilibrium, protein clusters with the properties of nuclear bodies.},
}
@article {pmid28355183,
year = {2017},
author = {Flyamer, IM and Gassler, J and Imakaev, M and Brandão, HB and Ulianov, SV and Abdennur, N and Razin, SV and Mirny, LA and Tachibana-Konwalski, K},
title = {Single-nucleus Hi-C reveals unique chromatin reorganization at oocyte-to-zygote transition.},
journal = {Nature},
volume = {544},
number = {7648},
pages = {110-114},
pmid = {28355183},
issn = {1476-4687},
support = {336460/ERC_/European Research Council/International ; R01 GM114190/GM/NIGMS NIH HHS/United States ; U54 DK107980/DK/NIDDK NIH HHS/United States ; },
mesh = {Animals ; Cell Nucleus/genetics/*metabolism ; Cell Transdifferentiation ; Cellular Reprogramming ; Chromatin/chemistry/genetics/*metabolism ; *Chromosome Positioning ; Female ; Haploidy ; Interphase ; Maternal Inheritance/genetics ; Mice ; Nucleic Acid Conformation ; Oocytes/*cytology/metabolism ; Paternal Inheritance/genetics ; Single-Cell Analysis/*methods ; Stochastic Processes ; Totipotent Stem Cells/cytology/metabolism ; Zygote/*cytology/metabolism ; },
abstract = {Chromatin is reprogrammed after fertilization to produce a totipotent zygote with the potential to generate a new organism. The maternal genome inherited from the oocyte and the paternal genome provided by sperm coexist as separate haploid nuclei in the zygote. How these two epigenetically distinct genomes are spatially organized is poorly understood. Existing chromosome conformation capture-based methods are not applicable to oocytes and zygotes owing to a paucity of material. To study three-dimensional chromatin organization in rare cell types, we developed a single-nucleus Hi-C (high-resolution chromosome conformation capture) protocol that provides greater than tenfold more contacts per cell than the previous method. Here we show that chromatin architecture is uniquely reorganized during the oocyte-to-zygote transition in mice and is distinct in paternal and maternal nuclei within single-cell zygotes. Features of genomic organization including compartments, topologically associating domains (TADs) and loops are present in individual oocytes when averaged over the genome, but the presence of each feature at a locus varies between cells. At the sub-megabase level, we observed stochastic clusters of contacts that can occur across TAD boundaries but average into TADs. Notably, we found that TADs and loops, but not compartments, are present in zygotic maternal chromatin, suggesting that these are generated by different mechanisms. Our results demonstrate that the global chromatin organization of zygote nuclei is fundamentally different from that of other interphase cells. An understanding of this zygotic chromatin 'ground state' could potentially provide insights into reprogramming cells to a state of totipotency.},
}
@article {pmid28348222,
year = {2017},
author = {Eser, U and Chandler-Brown, D and Ay, F and Straight, AF and Duan, Z and Noble, WS and Skotheim, JM},
title = {Form and function of topologically associating genomic domains in budding yeast.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {114},
number = {15},
pages = {E3061-E3070},
pmid = {28348222},
issn = {1091-6490},
support = {P50 GM107615/GM/NIGMS NIH HHS/United States ; R01 GM092925/GM/NIGMS NIH HHS/United States ; T32 GM007276/GM/NIGMS NIH HHS/United States ; U54 DK107979/DK/NIDDK NIH HHS/United States ; },
mesh = {Chromatin/*metabolism ; Chromatin Assembly and Disassembly ; Chromosomes, Fungal/genetics ; DNA Replication Timing ; *Genome, Fungal ; *Genomics ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Saccharomycetales/*genetics ; Structure-Activity Relationship ; },
abstract = {The genome of metazoan cells is organized into topologically associating domains (TADs) that have similar histone modifications, transcription level, and DNA replication timing. Although similar structures appear to be conserved in fission yeast, computational modeling and analysis of high-throughput chromosome conformation capture (Hi-C) data have been used to argue that the small, highly constrained budding yeast chromosomes could not have these structures. In contrast, herein we analyze Hi-C data for budding yeast and identify 200-kb scale TADs, whose boundaries are enriched for transcriptional activity. Furthermore, these boundaries separate regions of similarly timed replication origins connecting the long-known effect of genomic context on replication timing to genome architecture. To investigate the molecular basis of TAD formation, we performed Hi-C experiments on cells depleted for the Forkhead transcription factors, Fkh1 and Fkh2, previously associated with replication timing. Forkhead factors do not regulate TAD formation, but do promote longer-range genomic interactions and control interactions between origins near the centromere. Thus, our work defines spatial organization within the budding yeast nucleus, demonstrates the conserved role of genome architecture in regulating DNA replication, and identifies a molecular mechanism specifically regulating interactions between pericentric origins.},
}
@article {pmid28334818,
year = {2017},
author = {Sauerwald, N and Zhang, S and Kingsford, C and Bahar, I},
title = {Chromosomal dynamics predicted by an elastic network model explains genome-wide accessibility and long-range couplings.},
journal = {Nucleic acids research},
volume = {45},
number = {7},
pages = {3663-3673},
pmid = {28334818},
issn = {1362-4962},
support = {R01 HG007104/HG/NHGRI NIH HHS/United States ; P30 DA035778/DA/NIDA NIH HHS/United States ; P41 GM103712/GM/NIGMS NIH HHS/United States ; R01 GM099738/GM/NIGMS NIH HHS/United States ; U54 HG008540/HG/NHGRI NIH HHS/United States ; },
mesh = {Cell Line ; Chromatin/*chemistry ; Gene Expression ; Genetic Loci ; Genome ; Genomics ; Humans ; *Models, Genetic ; Sequence Analysis, DNA ; },
abstract = {Understanding the three-dimensional (3D) architecture of chromatin and its relation to gene expression and regulation is fundamental to understanding how the genome functions. Advances in Hi-C technology now permit us to study 3D genome organization, but we still lack an understanding of the structural dynamics of chromosomes. The dynamic couplings between regions separated by large genomic distances (>50 Mb) have yet to be characterized. We adapted a well-established protein-modeling framework, the Gaussian Network Model (GNM), to model chromatin dynamics using Hi-C data. We show that the GNM can identify spatial couplings at multiple scales: it can quantify the correlated fluctuations in the positions of gene loci, find large genomic compartments and smaller topologically-associating domains (TADs) that undergo en bloc movements, and identify dynamically coupled distal regions along the chromosomes. We show that the predictions of the GNM correlate well with genome-wide experimental measurements. We use the GNM to identify novel cross-correlated distal domains (CCDDs) representing pairs of regions distinguished by their long-range dynamic coupling and show that CCDDs are associated with increased gene co-expression. Together, these results show that GNM provides a mathematically well-founded unified framework for modeling chromatin dynamics and assessing the structural basis of genome-wide observations.},
}
@article {pmid28334773,
year = {2017},
author = {Dali, R and Blanchette, M},
title = {A critical assessment of topologically associating domain prediction tools.},
journal = {Nucleic acids research},
volume = {45},
number = {6},
pages = {2994-3005},
pmid = {28334773},
issn = {1362-4962},
mesh = {Algorithms ; Binding Sites ; CCCTC-Binding Factor ; Chromosomes/*chemistry ; *High-Throughput Nucleotide Sequencing ; Humans ; Repressor Proteins/metabolism ; *Sequence Analysis, DNA ; *Software ; },
abstract = {Topologically associating domains (TADs) have been proposed to be the basic unit of chromosome folding and have been shown to play key roles in genome organization and gene regulation. Several different tools are available for TAD prediction, but their properties have never been thoroughly assessed. In this manuscript, we compare the output of seven different TAD prediction tools on two published Hi-C data sets. TAD predictions varied greatly between tools in number, size distribution and other biological properties. Assessed against a manual annotation of TADs, individual TAD boundary predictions were found to be quite reliable, but their assembly into complete TAD structures was much less so. In addition, many tools were sensitive to sequencing depth and resolution of the interaction frequency matrix. This manuscript provides users and designers of TAD prediction tools with information that will help guide the choice of tools and the interpretation of their predictions.},
}
@article {pmid28315703,
year = {2017},
author = {Carlberg, C},
title = {Molecular endocrinology of vitamin D on the epigenome level.},
journal = {Molecular and cellular endocrinology},
volume = {453},
number = {},
pages = {14-21},
doi = {10.1016/j.mce.2017.03.016},
pmid = {28315703},
issn = {1872-8057},
mesh = {Chromatin/genetics/metabolism ; Endocrine System/*metabolism ; *Epigenesis, Genetic ; Gene Expression Regulation ; Genome-Wide Association Study ; Humans ; Ligands ; Receptors, Calcitriol/*genetics/*metabolism ; Transcription Factors/genetics/metabolism ; Vitamin D/*genetics/*metabolism ; },
abstract = {The molecular endocrinology of vitamin D is based on the facts that i) its metabolite 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) is the high affinity ligand of the nuclear receptor vitamin D receptor (VDR) and ii) the transcription factor VDR is the unique target of 1,25(OH)2D3 in the nucleus. Short-term alterations of the epigenome are primarily changes in the post-translational modification status of nucleosome-forming histone proteins, the consequences of which are i) a local increase or decrease in chromatin accessibility and ii) the activation or repression of gene transcription. Vitamin D has via VDR a direct effect on the expression of several hundred primary target genes implying numerous effects on the epigenome. Next-generation sequencing methods, such as ChIP-seq and FAIRE-seq, were applied to cellular model systems of vitamin D signaling, such as THP-1 human monocytes, and provided data for a chromatin model of vitamin D signaling. Key points of this model are that i) in the absence of ligand VDR binds to a limited number of loci within accessible chromatin, ii) a stimulation with ligand increases the number of DNA-bound VDR molecules, iii) VDR's access to genomic DNA is supported by pioneer factors, such as PU.1 in monocytes, iv) VDR binding leads to local opening of chromatin and v) the binding strength of topologically associating domain anchor forming CCCTC-binding factor sites upstream and downstream of prominent VDR binding sites is changing in response to ligand stimulation. This model provides the present basis of the molecular endocrinology of vitamin D and will be in future refined by the integration of vitamin D-sensitive chromatin markers and other genome-wide data, such as the 1,25(OH)2D3-sensitive binding of co-factors, chromatin modifying enzymes and chromatin remodeling proteins.},
}
@article {pmid28252665,
year = {2017},
author = {Yoshida, J and Akagi, K and Misawa, R and Kokubu, C and Takeda, J and Horie, K},
title = {Chromatin states shape insertion profiles of the piggyBac, Tol2 and Sleeping Beauty transposons and murine leukemia virus.},
journal = {Scientific reports},
volume = {7},
number = {},
pages = {43613},
pmid = {28252665},
issn = {2045-2322},
support = {R50 CA211533/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Chromatin/*genetics ; Chromatin Assembly and Disassembly ; *DNA Transposable Elements ; Gene Expression ; Gene Expression Regulation ; Gene Order ; Genetic Vectors/*genetics ; Genome ; Genomics/methods ; Histones/metabolism ; Leukemia Virus, Murine/*physiology ; Mice ; Models, Biological ; Mouse Embryonic Stem Cells/metabolism ; *Mutagenesis, Insertional ; Protein Binding ; Sequence Analysis, DNA ; Transcription Factors/metabolism ; Transcription Initiation Site ; *Virus Integration ; },
abstract = {DNA transposons and retroviruses are versatile tools in functional genomics and gene therapy. To facilitate their application, we conducted a genome-wide insertion site profiling of the piggyBac (PB), Tol2 and Sleeping Beauty (SB) transposons and the murine leukemia virus (MLV) in mouse embryonic stem cells (ESCs). PB and MLV preferred highly expressed genes, whereas Tol2 and SB preferred weakly expressed genes. However, correlations with DNase I hypersensitive sites were different for all vectors, indicating that chromatin accessibility is not the sole determinant. Therefore, we analysed various chromatin states. PB and MLV highly correlated with Cohesin, Mediator and ESC-specific transcription factors. Notably, CTCF sites were correlated with PB but not with MLV, suggesting MLV prefers smaller promoter-enhancer loops, whereas PB insertion encompasses larger chromatin loops termed topologically associating domains. Tol2 also correlated with Cohesin and CTCF. However, correlations with ESC-specific transcription factors were weaker, suggesting that Tol2 prefers transcriptionally weak chromatin loops. Consistently, Tol2 insertions were associated with bivalent histone modifications characteristic of silent and inducible loci. SB showed minimum preference to all chromatin states, suggesting the least adverse effect on adjacent genes. These results will be useful for vector selection for various applications.},
}
@article {pmid28167501,
year = {2017},
author = {Zhu, Y and Gong, K and Denholtz, M and Chandra, V and Kamps, MP and Alber, F and Murre, C},
title = {Comprehensive characterization of neutrophil genome topology.},
journal = {Genes &amp; development},
volume = {31},
number = {2},
pages = {141-153},
pmid = {28167501},
issn = {1549-5477},
support = {U54 DK107981/DK/NIDDK NIH HHS/United States ; P01 AI102853/AI/NIAID NIH HHS/United States ; R01 AI100880/AI/NIAID NIH HHS/United States ; P30 NS047101/NS/NINDS NIH HHS/United States ; U54 DK107977/DK/NIDDK NIH HHS/United States ; Z01 AI000880//Intramural NIH HHS/United States ; P30 CA023100/CA/NCI NIH HHS/United States ; },
mesh = {Cell Differentiation/*genetics ; Chromosomes/genetics/metabolism ; DNA, Ribosomal/genetics/metabolism ; Epigenesis, Genetic ; Gene Expression Regulation, Developmental/genetics ; Genome, Human/*genetics ; HEK293 Cells ; Humans ; Long Interspersed Nucleotide Elements/genetics ; Neutrophils/*cytology ; Receptors, Cytoplasmic and Nuclear/metabolism ; },
abstract = {Neutrophils are responsible for the first line of defense against invading pathogens. Their nuclei are uniquely structured as multiple lobes that establish a highly constrained nuclear environment. Here we found that neutrophil differentiation was not associated with large-scale changes in the number and sizes of topologically associating domains (TADs). However, neutrophil genomes were enriched for long-range genomic interactions that spanned multiple TADs. Population-based simulation of spherical and toroid genomes revealed declining radii of gyration for neutrophil chromosomes. We found that neutrophil genomes were highly enriched for heterochromatic genomic interactions across vast genomic distances, a process named supercontraction. Supercontraction involved genomic regions located in the heterochromatic compartment in both progenitors and neutrophils or genomic regions that switched from the euchromatic to the heterochromatic compartment during neutrophil differentiation. Supercontraction was accompanied by the repositioning of centromeres, pericentromeres, and long interspersed nuclear elements (LINEs) to the neutrophil nuclear lamina. We found that Lamin B receptor expression was required to attach centromeric and pericentromeric repeats but not LINE-1 elements to the lamina. Differentiating neutrophils also repositioned ribosomal DNA and mininucleoli to the lamina-a process that was closely associated with sharply reduced ribosomal RNA expression. We propose that large-scale chromatin reorganization involving supercontraction and recruitment of heterochromatin and nucleoli to the nuclear lamina facilitates the folding of the neutrophil genome into a confined geometry imposed by a multilobed nuclear architecture.},
}
@article {pmid28157505,
year = {2017},
author = {Kundu, S and Ji, F and Sunwoo, H and Jain, G and Lee, JT and Sadreyev, RI and Dekker, J and Kingston, RE},
title = {Polycomb Repressive Complex 1 Generates Discrete Compacted Domains that Change during Differentiation.},
journal = {Molecular cell},
volume = {65},
number = {3},
pages = {432-446.e5},
pmid = {28157505},
issn = {1097-4164},
support = {R01 GM043901/GM/NIGMS NIH HHS/United States ; P30 DK040561/DK/NIDDK NIH HHS/United States ; R01 HG003143/HG/NHGRI NIH HHS/United States ; R01 GM090278/GM/NIGMS NIH HHS/United States ; U54 DK107980/DK/NIDDK NIH HHS/United States ; },
mesh = {Animals ; Cell Differentiation ; Cells, Cultured ; Chromatin/chemistry/genetics/metabolism ; DNA/chemistry/genetics/*metabolism ; Embryonic Stem Cells/*cytology/metabolism ; Epigenesis, Genetic ; Gene Expression Regulation, Developmental ; Histones/metabolism ; Homeodomain Proteins/metabolism ; Humans ; Mice ; Neural Stem Cells/*cytology/metabolism ; Polycomb Repressive Complex 1/chemistry/*metabolism ; Protein Domains ; Ubiquitination ; },
abstract = {Master regulatory genes require stable silencing by the polycomb group (PcG) to prevent misexpression during differentiation and development. Some PcG proteins covalently modify histones, which contributes to heritable repression. The role for other effects on chromatin structure is less understood. We characterized the organization of PcG target genes in ESCs and neural progenitors using 5C and super-resolution microscopy. The genomic loci of repressed PcG targets formed discrete, small (20-140 Kb) domains of tight interaction that corresponded to locations bound by canonical polycomb repressive complex 1 (PRC1). These domains changed during differentiation as PRC1 binding changed. Their formation depended upon the Polyhomeotic component of canonical PRC1 and occurred independently of PRC1-catalyzed ubiquitylation. PRC1 domains differ from topologically associating domains in size and boundary characteristics. These domains have the potential to play a key role in transmitting epigenetic silencing of PcG targets by linking PRC1 to formation of a repressive higher-order structure.},
}
@article {pmid28154080,
year = {2017},
author = {Wang, X and Brandão, HB and Le, TB and Laub, MT and Rudner, DZ},
title = {Bacillus subtilis SMC complexes juxtapose chromosome arms as they travel from origin to terminus.},
journal = {Science (New York, N.Y.)},
volume = {355},
number = {6324},
pages = {524-527},
pmid = {28154080},
issn = {1095-9203},
support = {R01 GM073831/GM/NIGMS NIH HHS/United States ; R01 GM082899/GM/NIGMS NIH HHS/United States ; R01 GM086466/GM/NIGMS NIH HHS/United States ; },
mesh = {Adenosine Triphosphatases/*metabolism ; Bacillus subtilis/*genetics/*metabolism ; Bacterial Proteins/*metabolism ; Cell Cycle Proteins/*metabolism ; Chromosome Segregation ; Chromosomes, Bacterial/chemistry/*metabolism ; DNA, Bacterial/chemistry/metabolism ; DNA-Binding Proteins/*metabolism ; Multiprotein Complexes/*metabolism ; },
abstract = {Structural maintenance of chromosomes (SMC) complexes play critical roles in chromosome dynamics in virtually all organisms, but how they function remains poorly understood. In the bacterium Bacillus subtilis, SMC-condensin complexes are topologically loaded at centromeric sites adjacent to the replication origin. Here we provide evidence that these ring-shaped assemblies tether the left and right chromosome arms together while traveling from the origin to the terminus (>2 megabases) at rates >50 kilobases per minute. Condensin movement scales linearly with time, providing evidence for an active transport mechanism. These data support a model in which SMC complexes function by processively enlarging DNA loops. Loop formation followed by processive enlargement provides a mechanism by which condensin complexes compact and resolve sister chromatids in mitosis and by which cohesin generates topologically associating domains during interphase.},
}
@article {pmid28129029,
year = {2017},
author = {Chen, H and Seaman, L and Liu, S and Ried, T and Rajapakse, I},
title = {Chromosome conformation and gene expression patterns differ profoundly in human fibroblasts grown in spheroids versus monolayers.},
journal = {Nucleus (Austin, Tex.)},
volume = {8},
number = {4},
pages = {383-391},
pmid = {28129029},
issn = {1949-1042},
mesh = {*Cell Culture Techniques ; Chromosomes/*chemistry ; Fibroblasts/*chemistry/*metabolism ; Gene Expression Profiling ; *Gene Expression Regulation ; Humans ; Molecular Conformation ; Real-Time Polymerase Chain Reaction ; Spheroids, Cellular/physiology ; },
abstract = {Human cells derived for in vitro cultures are conventionally grown as adherent monolayers (2D) which do not resemble natural 3 dimensional (3D) tissue architecture. We examined genome structure with chromosome conformation capture (Hi-C) and gene expression with RNA-seq in fibroblasts derived from human foreskin grown in 2D and 3D conditions. Our combined analysis of Hi-C and RNA-seq data shows a large number of differentially expressed genes between 2D and 3D cells, and these changes are localized in genomic regions that displayed structural changes. We also find a trend of expression in a subset of skin-specific genes in fibroblast cells grown in 3D that resembles those in native tissue.},
}
@article {pmid28108933,
year = {2017},
author = {Zhan, Y and Giorgetti, L and Tiana, G},
title = {Modelling genome-wide topological associating domains in mouse embryonic stem cells.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {25},
number = {1},
pages = {5-14},
pmid = {28108933},
issn = {1573-6849},
mesh = {Animals ; Chromatin Assembly and Disassembly ; Chromosomes/chemistry/*ultrastructure ; *Genome ; Mice ; Models, Biological ; *Mouse Embryonic Stem Cells/ultrastructure ; Transcription, Genetic ; },
abstract = {Chromosome conformation capture (3C)-based techniques such as chromosome conformation capture carbon copy (5C) and Hi-C revealed that the folding of mammalian chromosomes is highly hierarchical. A fundamental structural unit in the hierarchy is represented by topologically associating domains (TADs), sub-megabase regions of the genome within which the chromatin fibre preferentially interacts. 3C-based methods provide the mean contact probabilities between chromosomal loci, averaged over a large number of cells, and do not give immediate access to the single-cell conformations of the chromatin fibre. However, coarse-grained polymer models based on 5C data can be used to extract the single-cell conformations of single TADs. Here, we extend this approach to analyse around 2500 TADs in murine embryonic stem cells based on high-resolution Hi-C data. This allowed to predict the cell-to-cell variability in single contacts within genome-wide TADs and correlations between them. Based on these results, we predict that TADs are more similar to ideal chains than to globules in terms of their physical size and three-dimensional shape distribution. Furthermore, we show that their physical size and the degree of structural anisotropy of single TADs are correlated with the level of transcriptional activity of the genes that it harbours. Finally, we show that a large number of multiplets of genomic loci co-localize more often than expected by random, and these loci are particularly enriched in promoters, enhancers and CTCF-bound sites. These results provide the first genome-wide structural reconstruction of TADs using polymeric models obeying the laws of thermodynamics and reveal important universal trends in the correlation between chromosome structure and transcription.},
}
@article {pmid28060840,
year = {2017},
author = {Jabbari, K and Bernardi, G},
title = {An Isochore Framework Underlies Chromatin Architecture.},
journal = {PloS one},
volume = {12},
number = {1},
pages = {e0168023},
pmid = {28060840},
issn = {1932-6203},
mesh = {Animals ; Base Composition ; *Chromatin ; Chromosomes, Mammalian ; Cluster Analysis ; Evolution, Molecular ; GC Rich Sequence ; Humans ; *Isochores ; Mice ; Synteny ; },
abstract = {A recent investigation showed the existence of correlations between the architectural features of mammalian interphase chromosomes and the compositional properties of isochores. This result prompted us to compare maps of the Topologically Associating Domains (TADs) and of the Lamina Associated Domains (LADs) with the corresponding isochore maps of mouse and human chromosomes. This approach revealed that: 1) TADs and LADs correspond to isochores, i.e., isochores are the genomic units that underlie chromatin domains; 2) the conservation of TADs and LADs in mammalian genomes is explained by the evolutionary conservation of isochores; 3) chromatin domains corresponding to GC-poor isochores (e.g., LADs) show not only self-interactions but also intrachromosomal interactions with other domains also corresponding to GC-poor isochores even if located far away; in contrast, chromatin domains corresponding to GC-rich isochores (e.g., TADs) show more localized chromosomal interactions, many of which are inter-chromosomal. In conclusion, this investigation establishes a link between DNA sequences and chromatin architecture, explains the evolutionary conservation of TADs and LADs and provides new information on the spatial distribution of GC-poor/gene-poor and GC-rich/gene-rich chromosomal regions in the interphase nucleus.},
}
@article {pmid28060558,
year = {2017},
author = {Barutcu, AR and Lian, JB and Stein, JL and Stein, GS and Imbalzano, AN},
title = {The connection between BRG1, CTCF and topoisomerases at TAD boundaries.},
journal = {Nucleus (Austin, Tex.)},
volume = {8},
number = {2},
pages = {150-155},
pmid = {28060558},
issn = {1949-1042},
support = {P01 CA082834/CA/NCI NIH HHS/United States ; R37 DE012528/DE/NIDCR NIH HHS/United States ; },
mesh = {Adenosine Triphosphatases/*metabolism ; Animals ; CCCTC-Binding Factor ; DNA Topoisomerases/*metabolism ; *Genomics ; Humans ; Nucleosomes/metabolism ; Repressor Proteins/*metabolism ; },
abstract = {The eukaryotic genome is partitioned into topologically associating domains (TADs). Despite recent advances characterizing TADs and TAD boundaries, the organization of these structures is an important dimension of genome architecture and function that is not well understood. Recently, we demonstrated that knockdown of BRG1, an ATPase driving the chromatin remodeling activity of mammalian SWI/SNF enzymes, globally alters long-range genomic interactions and results in a reduction of TAD boundary strength. We provided evidence suggesting that this effect may be due to BRG1 affecting nucleosome occupancy around CTCF sites present at TAD boundaries. In this review, we elaborate on our findings and speculate that BRG1 may contribute to the regulation of the structural and functional properties of chromatin at TAD boundaries by affecting the function or the recruitment of CTCF and DNA topoisomerase complexes.},
}
@article {pmid28057745,
year = {2017},
author = {Zhan, Y and Mariani, L and Barozzi, I and Schulz, EG and Blüthgen, N and Stadler, M and Tiana, G and Giorgetti, L},
title = {Reciprocal insulation analysis of Hi-C data shows that TADs represent a functionally but not structurally privileged scale in the hierarchical folding of chromosomes.},
journal = {Genome research},
volume = {27},
number = {3},
pages = {479-490},
pmid = {28057745},
issn = {1549-5469},
mesh = {*Algorithms ; Animals ; Cells, Cultured ; *Chromatin Assembly and Disassembly ; Chromosomes/*chemistry/genetics/metabolism ; Embryonic Stem Cells/metabolism ; Female ; Gene Expression Regulation, Developmental ; *Insulator Elements ; Mice ; Models, Theoretical ; Neural Stem Cells/metabolism ; },
abstract = {Understanding how regulatory sequences interact in the context of chromosomal architecture is a central challenge in biology. Chromosome conformation capture revealed that mammalian chromosomes possess a rich hierarchy of structural layers, from multi-megabase compartments to sub-megabase topologically associating domains (TADs) and sub-TAD contact domains. TADs appear to act as regulatory microenvironments by constraining and segregating regulatory interactions across discrete chromosomal regions. However, it is unclear whether other (or all) folding layers share similar properties, or rather TADs constitute a privileged folding scale with maximal impact on the organization of regulatory interactions. Here, we present a novel algorithm named CaTCH that identifies hierarchical trees of chromosomal domains in Hi-C maps, stratified through their reciprocal physical insulation, which is a single and biologically relevant parameter. By applying CaTCH to published Hi-C data sets, we show that previously reported folding layers appear at different insulation levels. We demonstrate that although no structurally privileged folding level exists, TADs emerge as a functionally privileged scale defined by maximal boundary enrichment in CTCF and maximal cell-type conservation. By measuring transcriptional output in embryonic stem cells and neural precursor cells, we show that the likelihood that genes in a domain are coregulated during differentiation is also maximized at the scale of TADs. Finally, we observe that regulatory sequences occur at genomic locations corresponding to optimized mutual interactions at the same scale. Our analysis suggests that the architectural functionality of TADs arises from the interplay between their ability to partition interactions and the specific genomic position of regulatory sequences.},
}
@article {pmid28035241,
year = {2016},
author = {Wachsmuth, M and Knoch, TA and Rippe, K},
title = {Dynamic properties of independent chromatin domains measured by correlation spectroscopy in living cells.},
journal = {Epigenetics &amp; chromatin},
volume = {9},
number = {},
pages = {57},
pmid = {28035241},
issn = {1756-8935},
abstract = {BACKGROUND: Genome organization into subchromosomal topologically associating domains (TADs) is linked to cell-type-specific gene expression programs. However, dynamic properties of such domains remain elusive, and it is unclear how domain plasticity modulates genomic accessibility for soluble factors.<br><br>RESULTS: Here, we combine and compare a high-resolution topology analysis of interacting chromatin loci with fluorescence correlation spectroscopy measurements of domain dynamics in single living cells. We identify topologically and dynamically independent chromatin domains of ~1&#xa0;Mb in size that are best described by a loop-cluster polymer model. Hydrodynamic relaxation times and gyration radii of domains are larger for open (161&#xa0;&#xb1;&#xa0;15&#xa0;ms, 297&#xa0;&#xb1;&#xa0;9&#xa0;nm) than for dense chromatin (88&#xa0;&#xb1;&#xa0;7&#xa0;ms, 243&#xa0;&#xb1;&#xa0;6&#xa0;nm) and increase globally upon chromatin hyperacetylation or ATP depletion.<br><br>CONCLUSIONS: Based on the domain structure and dynamics measurements, we propose a loop-cluster model for chromatin domains. It suggests that the regulation of chromatin accessibility for soluble factors displays a significantly stronger dependence on factor concentration than search processes within a static network.},
}
@article {pmid27974201,
year = {2016},
author = {Poulos, RC and Thoms, JAI and Guan, YF and Unnikrishnan, A and Pimanda, JE and Wong, JWH},
title = {Functional Mutations Form at CTCF-Cohesin Binding Sites in Melanoma Due to Uneven Nucleotide Excision Repair across the Motif.},
journal = {Cell reports},
volume = {17},
number = {11},
pages = {2865-2872},
doi = {10.1016/j.celrep.2016.11.055},
pmid = {27974201},
issn = {2211-1247},
mesh = {Binding Sites ; CCCTC-Binding Factor/*genetics/metabolism ; Cell Cycle Proteins/*genetics/metabolism ; Cell Line, Tumor ; Chromatin/genetics ; Chromosomal Proteins, Non-Histone/*genetics/metabolism ; DNA Repair/genetics ; Humans ; Melanoma/*genetics/pathology ; Mutation ; *Transcription, Genetic ; },
abstract = {CTCF binding sites are frequently mutated in cancer, but how these mutations accumulate and whether they broadly perturb CTCF binding are not well understood. Here, we report that skin cancers exhibit a highly specific asymmetric mutation pattern within CTCF motifs attributable to ultraviolet irradiation and differential nucleotide excision repair (NER). CTCF binding site mutations form independently of replication timing and are enriched at sites of CTCF/cohesin complex binding, suggesting a role for cohesin in stabilizing CTCF-DNA binding and impairing NER. Performing CTCF ChIP-seq in a melanoma cell line, we show CTCF binding site mutations to be functional by demonstrating allele-specific reduction of CTCF binding to mutant alleles. While topologically associating domains with mutated CTCF anchors in melanoma contain differentially expressed cancer-associated genes, CTCF motif mutations appear generally under neutral selection. However, the frequency and potential functional impact of such mutations in melanoma highlights the need to consider their impact on cellular phenotype in individual genomes.},
}
@article {pmid27940490,
year = {2016},
author = {Brant, L and Georgomanolis, T and Nikolic, M and Brackley, CA and Kolovos, P and van Ijcken, W and Grosveld, FG and Marenduzzo, D and Papantonis, A},
title = {Exploiting native forces to capture chromosome conformation in mammalian cell nuclei.},
journal = {Molecular systems biology},
volume = {12},
number = {12},
pages = {891},
pmid = {27940490},
issn = {1744-4292},
mesh = {Animals ; Cell Nucleus/*genetics ; Chromosomes, Human/*chemistry/*genetics ; High-Throughput Nucleotide Sequencing/methods ; Human Umbilical Vein Endothelial Cells ; Humans ; Interphase ; K562 Cells ; Mammals/genetics ; Models, Genetic ; Nucleic Acid Conformation ; Oligonucleotide Array Sequence Analysis ; Sequence Analysis, DNA/methods ; },
abstract = {Mammalian interphase chromosomes fold into a multitude of loops to fit the confines of cell nuclei, and looping is tightly linked to regulated function. Chromosome conformation capture (3C) technology has significantly advanced our understanding of this structure-to-function relationship. However, all 3C-based methods rely on chemical cross-linking to stabilize spatial interactions. This step remains a "black box" as regards the biases it may introduce, and some discrepancies between microscopy and 3C studies have now been reported. To address these concerns, we developed "i3C", a novel approach for capturing spatial interactions without a need for cross-linking. We apply i3C to intact nuclei of living cells and exploit native forces that stabilize chromatin folding. Using different cell types and loci, computational modeling, and a methylation-based orthogonal validation method, "TALE-iD", we show that native interactions resemble cross-linked ones, but display improved signal-to-noise ratios and are more focal on regulatory elements and CTCF sites, while strictly abiding to topologically associating domain restrictions.},
}
@article {pmid27936932,
year = {2017},
author = {Achinger-Kawecka, J and Clark, SJ},
title = {Disruption of the 3D cancer genome blueprint.},
journal = {Epigenomics},
volume = {9},
number = {1},
pages = {47-55},
doi = {10.2217/epi-2016-0111},
pmid = {27936932},
issn = {1750-192X},
mesh = {Animals ; CCCTC-Binding Factor ; Chromatin Assembly and Disassembly ; *Epigenesis, Genetic ; *Gene Expression Regulation, Neoplastic ; *Genome, Human ; Humans ; Neoplasms/*genetics ; Repressor Proteins/genetics/metabolism ; },
abstract = {Recent advances in chromosome conformation capture technologies are improving the current appreciation of how 3D genome architecture affects its function in different cell types and disease. Long-range chromatin interactions are organized into topologically associated domains, which are known to play a role in constraining gene expression patterns. However, in cancer cells there are alterations in the 3D genome structure, which impacts on gene regulation. Disruption of topologically associated domains architecture can result in alterations in chromatin interactions that bring new regulatory elements and genes together, leading to altered expression of oncogenes and tumor suppressor genes. Here, we discuss the impact of genetic and epigenetic changes in cancer and how this affects the spatial organization of chromatin. Understanding how disruptions to the 3D architecture contribute to the cancer genome will provide novel insights into the principles of epigenetic gene regulation in cancer and mechanisms responsible for cancer associated mutations and rearrangements.},
}
@article {pmid27899590,
year = {2017},
author = {Cubeñas-Potts, C and Rowley, MJ and Lyu, X and Li, G and Lei, EP and Corces, VG},
title = {Different enhancer classes in Drosophila bind distinct architectural proteins and mediate unique chromatin interactions and 3D architecture.},
journal = {Nucleic acids research},
volume = {45},
number = {4},
pages = {1714-1730},
pmid = {27899590},
issn = {1362-4962},
support = {F32 GM113570/GM/NIGMS NIH HHS/United States ; R01 GM035463/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Biomarkers ; Cell Line ; Chromatin/chemistry/*genetics/*metabolism ; Chromatin Immunoprecipitation ; Computational Biology/methods ; *DNA-Binding Proteins ; Drosophila/*genetics/*metabolism ; *Enhancer Elements, Genetic ; High-Throughput Nucleotide Sequencing ; Histones/metabolism ; Promoter Regions, Genetic ; Protein Binding ; },
abstract = {Eukaryotic gene expression is regulated by enhancer-promoter interactions but the molecular mechanisms that govern specificity have remained elusive. Genome-wide studies utilizing STARR-seq identified two enhancer classes in Drosophila that interact with different core promoters: housekeeping enhancers (hkCP) and developmental enhancers (dCP). We hypothesized that the two enhancer classes are occupied by distinct architectural proteins, affecting their enhancer-promoter contacts. By evaluating ChIP-seq occupancy of architectural proteins, typical enhancer-associated proteins, and histone modifications, we determine that both enhancer classes are enriched for RNA Polymerase II, CBP, and architectural proteins but there are also distinctions. hkCP enhancers contain H3K4me3 and exclusively bind Cap-H2, Chromator, DREF and Z4, whereas dCP enhancers contain H3K4me1 and are more enriched for Rad21 and Fs(1)h-L. Additionally, we map the interactions of each enhancer class utilizing a Hi-C dataset with <1 kb resolution. Results suggest that hkCP enhancers are more likely to form multi-TSS interaction networks and be associated with topologically associating domain (TAD) borders, while dCP enhancers are more often bound to one or two TSSs and are enriched at chromatin loop anchors. The data support a model suggesting that the unique architectural protein occupancy within enhancers is one contributor to enhancer-promoter interaction specificity.},
}
@article {pmid27869826,
year = {2017},
author = {Weischenfeldt, J and Dubash, T and Drainas, AP and Mardin, BR and Chen, Y and Stütz, AM and Waszak, SM and Bosco, G and Halvorsen, AR and Raeder, B and Efthymiopoulos, T and Erkek, S and Siegl, C and Brenner, H and Brustugun, OT and Dieter, SM and Northcott, PA and Petersen, I and Pfister, SM and Schneider, M and Solberg, SK and Thunissen, E and Weichert, W and Zichner, T and Thomas, R and Peifer, M and Helland, A and Ball, CR and Jechlinger, M and Sotillo, R and Glimm, H and Korbel, JO},
title = {Pan-cancer analysis of somatic copy-number alterations implicates IRS4 and IGF2 in enhancer hijacking.},
journal = {Nature genetics},
volume = {49},
number = {1},
pages = {65-74},
pmid = {27869826},
issn = {1546-1718},
mesh = {DNA Copy Number Variations/*genetics ; Enhancer Elements, Genetic/*genetics ; *Gene Expression Regulation, Neoplastic ; Genetic Association Studies ; Genetic Predisposition to Disease ; Humans ; Insulin Receptor Substrate Proteins/*genetics ; Insulin-Like Growth Factor II/*genetics ; Neoplasms/*genetics ; Promoter Regions, Genetic ; },
abstract = {Extensive prior research focused on somatic copy-number alterations (SCNAs) affecting cancer genes, yet the extent to which recurrent SCNAs exert their influence through rearrangement of cis-regulatory elements (CREs) remains unclear. Here we present a framework for inferring cancer-related gene overexpression resulting from CRE reorganization (e.g., enhancer hijacking) by integrating SCNAs, gene expression data and information on topologically associating domains (TADs). Analysis of 7,416 cancer genomes uncovered several pan-cancer candidate genes, including IRS4, SMARCA1 and TERT. We demonstrate that IRS4 overexpression in lung cancer is associated with recurrent deletions in cis, and we present evidence supporting a tumor-promoting role. We additionally pursued cancer-type-specific analyses and uncovered IGF2 as a target for enhancer hijacking in colorectal cancer. Recurrent tandem duplications intersecting with a TAD boundary mediate de novo formation of a 3D contact domain comprising IGF2 and a lineage-specific super-enhancer, resulting in high-level gene activation. Our framework enables systematic inference of CRE rearrangements mediating dysregulation in cancer.},
}
@article {pmid27867070,
year = {2016},
author = {Symmons, O and Pan, L and Remeseiro, S and Aktas, T and Klein, F and Huber, W and Spitz, F},
title = {The Shh Topological Domain Facilitates the Action of Remote Enhancers by Reducing the Effects of Genomic Distances.},
journal = {Developmental cell},
volume = {39},
number = {5},
pages = {529-543},
pmid = {27867070},
issn = {1878-1551},
mesh = {Animals ; Congenital Abnormalities/embryology/genetics ; *Enhancer Elements, Genetic ; Gene Expression Regulation, Developmental ; Gene Regulatory Networks ; Hedgehog Proteins/*genetics ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Promoter Regions, Genetic ; },
abstract = {Gene expression often requires interaction between promoters and distant enhancers, which occur within the context of highly organized topologically associating domains (TADs). Using a series of engineered chromosomal rearrangements at the Shh locus, we carried out an extensive fine-scale characterization of the factors that govern the long-range regulatory interactions controlling Shh expression. We show that Shh enhancers act pervasively, yet not uniformly, throughout the TAD. Importantly, changing intra-TAD distances had no impact on Shh expression. In contrast, inversions disrupting the TAD altered global folding of the region and prevented regulatory contacts in a distance-dependent manner. Our data indicate that the Shh TAD promotes distance-independent contacts between distant regions that would otherwise interact only sporadically, enabling functional communication between them. In large genomes where genomic distances per se can limit regulatory interactions, this function of TADs could be as essential for gene expression as the formation of insulated neighborhoods.},
}
@article {pmid27851967,
year = {2016},
author = {Schmitt, AD and Hu, M and Jung, I and Xu, Z and Qiu, Y and Tan, CL and Li, Y and Lin, S and Lin, Y and Barr, CL and Ren, B},
title = {A Compendium of Chromatin Contact Maps Reveals Spatially Active Regions in the Human Genome.},
journal = {Cell reports},
volume = {17},
number = {8},
pages = {2042-2059},
pmid = {27851967},
issn = {2211-1247},
support = {R01 HG006292/HG/NHGRI NIH HHS/United States ; R01 ES024984/ES/NIEHS NIH HHS/United States ; U54 DK107977/DK/NIDDK NIH HHS/United States ; R01 HL129132/HL/NHLBI NIH HHS/United States ; T32 GM008666/GM/NIGMS NIH HHS/United States ; P50 GM085764/GM/NIGMS NIH HHS/United States ; },
mesh = {Adult ; Animals ; Cell Cycle Proteins/metabolism ; Cell Line ; Chromatin/*metabolism ; Chromosomal Proteins, Non-Histone/metabolism ; Conserved Sequence ; Disease/genetics ; Enhancer Elements, Genetic/genetics ; Gene Expression Regulation ; *Genome, Human ; Genome-Wide Association Study ; Humans ; Insulator Elements/genetics ; Mice ; Nucleic Acid Conformation ; Organ Specificity ; Polymorphism, Single Nucleotide/genetics ; },
abstract = {The three-dimensional configuration of DNA is integral to all nuclear processes in eukaryotes, yet our knowledge of the chromosome architecture is still limited. Genome-wide chromosome conformation capture studies have uncovered features of chromatin organization in cultured cells, but genome architecture in human tissues has yet to be explored. Here, we report the most comprehensive survey to date of chromatin organization in human tissues. Through integrative analysis of chromatin contact maps in 21 primary human tissues and cell types, we find topologically associating domains highly conserved in different tissues. We also discover genomic regions that exhibit unusually high levels of local chromatin interactions. These frequently interacting regions (FIREs) are enriched for super-enhancers and are near tissue-specifically expressed genes. They display strong tissue-specificity in local chromatin interactions. Additionally, FIRE formation is partially dependent on CTCF and the Cohesin complex. We further show that FIREs can help annotate the function of non-coding sequence variants.},
}
@article {pmid27841970,
year = {2016},
author = {Brackley, CA and Michieletto, D and Mouvet, F and Johnson, J and Kelly, S and Cook, PR and Marenduzzo, D},
title = {Simulating topological domains in human chromosomes with a fitting-free model.},
journal = {Nucleus (Austin, Tex.)},
volume = {7},
number = {5},
pages = {453-461},
pmid = {27841970},
issn = {1949-1042},
mesh = {Chromosomes, Human/*chemistry/metabolism ; Humans ; *Models, Molecular ; Molecular Conformation ; },
abstract = {We discuss a polymer model for the 3D organization of human chromosomes. A chromosome is represented by a string of beads, with each bead being "colored" according to 1D bioinformatic data (e.g., chromatin state, histone modification, GC content). Individual spheres (representing bi- and multi-valent transcription factors) can bind reversibly and selectively to beads with the appropriate color. During molecular dynamics simulations, the factors bind, and the string spontaneously folds into loops, rosettes, and topologically-associating domains (TADs). This organization occurs in the absence of any specified interactions between distant DNA segments, or between transcription factors. A comparison with Hi-C data shows that simulations predict the location of most boundaries between TADs correctly. The model is "fitting-free" in the sense that it does not use Hi-C data as an input; consequently, one of its strengths is that it can - in principle - be used to predict the 3D organization of any region of interest, or whole chromosome, in a given organism, or cell line, in the absence of existing Hi-C data. We discuss how this simple model might be refined to include more transcription factors and binding sites, and to correctly predict contacts between convergent CTCF binding sites.},
}
@article {pmid27764097,
year = {2016},
author = {Shinkai, S and Nozaki, T and Maeshima, K and Togashi, Y},
title = {Dynamic Nucleosome Movement Provides Structural Information of Topological Chromatin Domains in Living Human Cells.},
journal = {PLoS computational biology},
volume = {12},
number = {10},
pages = {e1005136},
pmid = {27764097},
issn = {1553-7358},
mesh = {Binding Sites ; Chromatin/*chemistry/*genetics/ultrastructure ; Chromatin Assembly and Disassembly/genetics ; Computer Simulation ; HeLa Cells ; Humans ; *Models, Chemical ; Models, Genetic ; Models, Molecular ; Molecular Conformation ; Molecular Imaging/*methods ; Motion ; Nucleosomes/*chemistry/*genetics/ultrastructure ; },
abstract = {The mammalian genome is organized into submegabase-sized chromatin domains (CDs) including topologically associating domains, which have been identified using chromosome conformation capture-based methods. Single-nucleosome imaging in living mammalian cells has revealed subdiffusively dynamic nucleosome movement. It is unclear how single nucleosomes within CDs fluctuate and how the CD structure reflects the nucleosome movement. Here, we present a polymer model wherein CDs are characterized by fractal dimensions and the nucleosome fibers fluctuate in a viscoelastic medium with memory. We analytically show that the mean-squared displacement (MSD) of nucleosome fluctuations within CDs is subdiffusive. The diffusion coefficient and the subdiffusive exponent depend on the structural information of CDs. This analytical result enabled us to extract information from the single-nucleosome imaging data for HeLa cells. Our observation that the MSD is lower at the nuclear periphery region than the interior region indicates that CDs in the heterochromatin-rich nuclear periphery region are more compact than those in the euchromatin-rich interior region with respect to the fractal dimensions as well as the size. Finally, we evaluated that the average size of CDs is in the range of 100-500 nm and that the relaxation time of nucleosome movement within CDs is a few seconds. Our results provide physical and dynamic insights into the genome architecture in living cells.},
}
@article {pmid27569350,
year = {2016},
author = {Neme, A and Seuter, S and Carlberg, C},
title = {Vitamin D-dependent chromatin association of CTCF in human monocytes.},
journal = {Biochimica et biophysica acta},
volume = {1859},
number = {11},
pages = {1380-1388},
doi = {10.1016/j.bbagrm.2016.08.008},
pmid = {27569350},
issn = {0006-3002},
mesh = {CCCTC-Binding Factor ; Cell Line ; Chromatin/*metabolism ; Gene Expression Regulation ; Humans ; Monocytes/*metabolism ; Receptors, Calcitriol/metabolism ; Repressor Proteins/genetics/*metabolism ; Vitamin D/*pharmacology ; },
abstract = {CCCTC-binding factor (CTCF) is a transcription factor being involved in 3D chromatin organization and displays a highly conserved genome-wide binding pattern. In this study, we report the cistrome of CTCF in THP-1 human monocytes and confirm that from the 40,078 CTCF binding sites nearly 85% are identical with those found in K562 monocytes. Quadruplicate chromatin immunoprecipitation sequencing (ChIP-seq) demonstrated that at 2130 loci the association strenght of CTCF with genomic DNA was significantly (p<0.05) modulated by stimulation with the natural vitamin D receptor (VDR) ligand 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3). Some 55% of these CTCF sites contribute to DNA looping and mark the anchors of 587 putative topologically associating domains (TADs) containing at least one VDR binding site and one 1,25(OH)2D3 target gene. These TADs can explain the regulatory scenarios of up to 70% of all 1,25(OH)2D3 target genes. A self-organizing map approach subdivided the vitamin D-sensitive CTCF sites into seven classes that can be distinguished by participation in DNA loop formation, binding to open chromatin, carrying binding motifs for CTCF or its relative BORIS, overlap with transcription start site (TSS) regions and binding of VDR. These variant molecular profiles suggest different mechanisms of the 1,25(OH)2D3-dependent action of CTCF. The co-location of VDR and 1,25(OH)2D3-dependent CTCF sites increases in the context of accessible chromatin and TSS regions but does not show any significant correlation with classical DNA binding mechanisms of CTCF. In conclusion, vitamin D-sensitive CTCF sites provide further mechanistic details to the epigenome-wide understanding of 1,25(OH)2D3-mediated gene regulation.},
}
@article {pmid27514584,
year = {2016},
author = {Barutcu, AR and Hong, D and Lajoie, BR and McCord, RP and van Wijnen, AJ and Lian, JB and Stein, JL and Dekker, J and Imbalzano, AN and Stein, GS},
title = {RUNX1 contributes to higher-order chromatin organization and gene regulation in breast cancer cells.},
journal = {Biochimica et biophysica acta},
volume = {1859},
number = {11},
pages = {1389-1397},
pmid = {27514584},
issn = {0006-3002},
support = {/HHMI_/Howard Hughes Medical Institute/United States ; P01 CA082834/CA/NCI NIH HHS/United States ; R01 HG003143/HG/NHGRI NIH HHS/United States ; },
mesh = {Breast Neoplasms/*genetics/pathology ; Chromatin/*metabolism ; Chromatin Immunoprecipitation ; Extracellular Matrix/metabolism ; Female ; *Gene Expression Regulation, Neoplastic ; Humans ; MCF-7 Cells ; },
abstract = {RUNX1 is a transcription factor functioning both as an oncogene and a tumor suppressor in breast cancer. RUNX1 alters chromatin structure in cooperation with chromatin modifier and remodeling enzymes. In this study, we examined the relationship between RUNX1-mediated transcription and genome organization. We characterized genome-wide RUNX1 localization and performed RNA-seq and Hi-C in RUNX1-depleted and control MCF-7 breast cancer cells. RNA-seq analysis showed that RUNX1 depletion led to up-regulation of genes associated with chromatin structure and down-regulation of genes related to extracellular matrix biology, as well as NEAT1 and MALAT1 lncRNAs. Our ChIP-Seq analysis supports a prominent role for RUNX1 in transcriptional activation. About 30% of all RUNX1 binding sites were intergenic, indicating diverse roles in promoter and enhancer regulation and suggesting additional functions for RUNX1. Hi-C analysis of RUNX1-depleted cells demonstrated that overall three-dimensional genome organization is largely intact, but indicated enhanced association of RUNX1 near Topologically Associating Domain (TAD) boundaries and alterations in long-range interactions. These results suggest an architectural role for RUNX1 in fine-tuning local interactions rather than in global organization. Our results provide novel insight into RUNX1-mediated perturbations of higher-order genome organization that are functionally linked with RUNX1-dependent compromised gene expression in breast cancer cells.},
}
@article {pmid27669308,
year = {2016},
author = {Chung, IM and Ketharnathan, S and Kim, SH and Thiruvengadam, M and Rani, MK and Rajakumar, G},
title = {Making Sense of the Tangle: Insights into Chromatin Folding and Gene Regulation.},
journal = {Genes},
volume = {7},
number = {10},
pages = {},
pmid = {27669308},
issn = {2073-4425},
abstract = {Proximity ligation assays such as circularized chromosome conformation capture and high-throughput chromosome capture assays have shed light on the structural organization of the interphase genome. Functional topologically associating domains (TADs) that constitute the building blocks of genomic organization are disrupted and reconstructed during the cell cycle. Epigenetic memory, as well as the sequence of chromosomes, regulate TAD reconstitution. Sub-TAD domains that are invariant across cell types have been identified, and contacts between these domains, rather than looping, are speculated to drive chromatin folding. Replication domains are established simultaneously with TADs during the cell cycle and the two correlate well in terms of characteristic features, such as lamin association and histone modifications. CCCTC-binding factor (CTCF) and cohesin cooperate across different cell types to regulate genes and genome organization. CTCF elements that demarcate TAD boundaries are commonly disrupted in cancer and promote oncogene activation. Chromatin looping facilitates interactions between distant promoters and enhancers, and the resulting enhanceosome complex promotes gene expression. Deciphering the chromatin tangle requires comprehensive integrative analyses of DNA- and protein-dependent factors that regulate genomic organization.},
}
@article {pmid27634932,
year = {2017},
author = {Ibn-Salem, J and Muro, EM and Andrade-Navarro, MA},
title = {Co-regulation of paralog genes in the three-dimensional chromatin architecture.},
journal = {Nucleic acids research},
volume = {45},
number = {1},
pages = {81-91},
pmid = {27634932},
issn = {1362-4962},
mesh = {Animals ; Biological Evolution ; Chromatin/*chemistry/metabolism ; Chromatin Assembly and Disassembly ; Cluster Analysis ; Computational Biology ; Dogs ; Enhancer Elements, Genetic ; *Gene Duplication ; *Gene Expression Regulation ; *Genome ; Humans ; Mice ; Promoter Regions, Genetic ; },
abstract = {Paralog genes arise from gene duplication events during evolution, which often lead to similar proteins that cooperate in common pathways and in protein complexes. Consequently, paralogs show correlation in gene expression whereby the mechanisms of co-regulation remain unclear. In eukaryotes, genes are regulated in part by distal enhancer elements through looping interactions with gene promoters. These looping interactions can be measured by genome-wide chromatin conformation capture (Hi-C) experiments, which revealed self-interacting regions called topologically associating domains (TADs). We hypothesize that paralogs share common regulatory mechanisms to enable coordinated expression according to TADs. To test this hypothesis, we integrated paralogy annotations with human gene expression data in diverse tissues, genome-wide enhancer-promoter associations and Hi-C experiments in human, mouse and dog genomes. We show that paralog gene pairs are enriched for co-localization in the same TAD, share more often common enhancer elements than expected and have increased contact frequencies over large genomic distances. Combined, our results indicate that paralogs share common regulatory mechanisms and cluster not only in the linear genome but also in the three-dimensional chromatin architecture. This enables concerted expression of paralogs over diverse cell-types and indicate evolutionary constraints in functional genome organization.},
}
@article {pmid27582050,
year = {2016},
author = {Uusküla-Reimand, L and Hou, H and Samavarchi-Tehrani, P and Rudan, MV and Liang, M and Medina-Rivera, A and Mohammed, H and Schmidt, D and Schwalie, P and Young, EJ and Reimand, J and Hadjur, S and Gingras, AC and Wilson, MD},
title = {Topoisomerase II beta interacts with cohesin and CTCF at topological domain borders.},
journal = {Genome biology},
volume = {17},
number = {1},
pages = {182},
pmid = {27582050},
issn = {1474-760X},
support = {//Wellcome Trust/United Kingdom ; //CIHR/Canada ; },
mesh = {Alleles ; Animals ; Binding Sites ; CCCTC-Binding Factor ; Cell Cycle Proteins/*genetics/metabolism ; Chromatin/genetics ; Chromatin Immunoprecipitation ; Chromosomal Proteins, Non-Histone/*genetics/metabolism ; Chromosomes ; DNA Topoisomerases, Type II/*genetics/metabolism ; DNA, Ribosomal/genetics ; DNA-Binding Proteins/*genetics/metabolism ; Genome ; Humans ; Mice ; Poly-ADP-Ribose Binding Proteins ; Promoter Regions, Genetic ; Protein Binding ; Protein Interaction Maps/*genetics ; Proteomics ; Repressor Proteins/*genetics/metabolism ; *Transcription, Genetic ; },
abstract = {BACKGROUND: Type II DNA topoisomerases (TOP2) regulate DNA topology by generating transient double stranded breaks during replication and transcription. Topoisomerase II beta (TOP2B) facilitates rapid gene expression and functions at the later stages of development and differentiation. To gain new insight into the genome biology of TOP2B, we used proteomics (BioID), chromatin immunoprecipitation, and high-throughput chromosome conformation capture (Hi-C) to identify novel proximal TOP2B protein interactions and characterize the genomic landscape of TOP2B binding at base pair resolution.<br><br>RESULTS: Our human TOP2B proximal protein interaction network included members of the cohesin complex and nucleolar proteins associated with rDNA biology. TOP2B associates with DNase I hypersensitivity sites, allele-specific transcription factor (TF) binding, and evolutionarily conserved TF binding sites on the mouse genome. Approximately half of all CTCF/cohesion-bound regions coincided with TOP2B binding. Base pair resolution ChIP-exo mapping of TOP2B, CTCF, and cohesin sites revealed a striking structural ordering of these proteins along the genome relative to the CTCF motif. These ordered TOP2B-CTCF-cohesin sites flank the boundaries of topologically associating domains (TADs) with TOP2B positioned externally and cohesin internally to the domain loop.<br><br>CONCLUSIONS: TOP2B is positioned to solve topological problems at diverse cis-regulatory elements and its occupancy is a highly ordered and prevalent feature of CTCF/cohesin binding sites that flank TADs.},
}
@article {pmid27539148,
year = {2016},
author = {Xia, Q and Chesi, A and Manduchi, E and Johnston, BT and Lu, S and Leonard, ME and Parlin, UW and Rappaport, EF and Huang, P and Wells, AD and Blobel, GA and Johnson, ME and Grant, SFA},
title = {The type 2 diabetes presumed causal variant within TCF7L2 resides in an element that controls the expression of ACSL5.},
journal = {Diabetologia},
volume = {59},
number = {11},
pages = {2360-2368},
pmid = {27539148},
issn = {1432-0428},
mesh = {Blotting, Western ; CRISPR-Associated Proteins/metabolism ; Cell Line ; Chromatin/genetics/metabolism ; Coenzyme A Ligases/*genetics/*metabolism ; Colon/metabolism ; Diabetes Mellitus, Type 2/*genetics/*metabolism ; HCT116 Cells ; Humans ; Polymerase Chain Reaction ; Polymorphism, Single Nucleotide/genetics ; RNA, Small Interfering ; Reverse Transcriptase Polymerase Chain Reaction ; Transcription Factor 7-Like 2 Protein/*genetics/*metabolism ; },
abstract = {AIMS/HYPOTHESIS: One of the most strongly associated type 2 diabetes loci reported to date resides within the TCF7L2 gene. Previous studies point to the T allele of rs7903146 in intron 3 as the causal variant at this locus. We aimed to identify the actual gene(s) under the influence of this variant.<br><br>METHODS: Using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 nuclease, we generated a 1.4&#xa0;kb deletion of the genomic region harbouring rs7903146 in the HCT116 cell line, followed by global gene expression analysis. We then carried out a combination of circularised chromosome conformation capture (4C) and Capture C in cell lines, HCT116 and NCM460 in order to ascertain which promoters of these perturbed genes made consistent physical contact with this genomic region.<br><br>RESULTS: We observed 99 genes with significant differential expression (false discovery rate [FDR] cut-off:10%) and an effect size of at least twofold. The subsequent promoter contact analyses revealed just one gene, ACSL5, which resides in the same topologically associating domain as TCF7L2. The generation of additional, smaller deletions (66&#xa0;bp and 104&#xa0;bp) comprising rs7903146 showed consistently reduced ACSL5 mRNA levels across all three deletions of up to 30-fold, with commensurate loss of acyl-CoA synthetase long-chain family member 5 (ACSL5) protein. Notably, the deletion of this single-nucleotide polymorphism region abolished significantly detectable chromatin contacts with the ACSL5 promoter. We went on to confirm that contacts between rs7903146 and the ACSL5 promoter regions were conserved in human colon tissue. ACSL5 encodes ACSL5, an enzyme with known roles in fatty acid metabolism.<br><br>CONCLUSIONS/INTERPRETATION: This 'variant to gene mapping' effort implicates the genomic location harbouring rs7903146 as a regulatory region for ACSL5.},
}
@article {pmid27503290,
year = {2016},
author = {Glinsky, GV},
title = {Mechanistically Distinct Pathways of Divergent Regulatory DNA Creation Contribute to Evolution of Human-Specific Genomic Regulatory Networks Driving Phenotypic Divergence of Homo sapiens.},
journal = {Genome biology and evolution},
volume = {8},
number = {9},
pages = {2774-2788},
pmid = {27503290},
issn = {1759-6653},
mesh = {Animals ; *Evolution, Molecular ; *Gene Regulatory Networks ; *Genome, Human ; Humans ; *Phenotype ; Prefrontal Cortex/metabolism ; Primates/genetics ; *Regulatory Sequences, Nucleic Acid ; },
abstract = {Thousands of candidate human-specific regulatory sequences (HSRS) have been identified, supporting the hypothesis that unique to human phenotypes result from human-specific alterations of genomic regulatory networks. Collectively, a compendium of multiple diverse families of HSRS that are functionally and structurally divergent from Great Apes could be defined as the backbone of human-specific genomic regulatory networks. Here, the conservation patterns analysis of 18,364 candidate HSRS was carried out requiring that 100% of bases must remap during the alignments of human, chimpanzee, and bonobo sequences. A total of 5,535 candidate HSRS were identified that are: (i) highly conserved in Great Apes; (ii) evolved by the exaptation of highly conserved ancestral DNA; (iii) defined by either the acceleration of mutation rates on the human lineage or the functional divergence from non-human primates. The exaptation of highly conserved ancestral DNA pathway seems mechanistically distinct from the evolution of regulatory DNA segments driven by the species-specific expansion of transposable elements. Genome-wide proximity placement analysis of HSRS revealed that a small fraction of topologically associating domains (TADs) contain more than half of HSRS from four distinct families. TADs that are enriched for HSRS and termed rapidly evolving in humans TADs (revTADs) comprise 0.8-10.3% of 3,127 TADs in the hESC genome. RevTADs manifest distinct correlation patterns between placements of human accelerated regions, human-specific transcription factor-binding sites, and recombination rates. There is a significant enrichment within revTAD boundaries of hESC-enhancers, primate-specific CTCF-binding sites, human-specific RNAPII-binding sites, hCONDELs, and H3K4me3 peaks with human-specific enrichment at TSS in prefrontal cortex neurons (P < 0.0001 in all instances). Present analysis supports the idea that phenotypic divergence of Homo sapiens is driven by the evolution of human-specific genomic regulatory networks via at least two mechanistically distinct pathways of creation of divergent sequences of regulatory DNA: (i) recombination-associated exaptation of the highly conserved ancestral regulatory DNA segments; (ii) human-specific insertions of transposable elements.},
}
@article {pmid27445307,
year = {2016},
author = {Wang, S and Su, JH and Beliveau, BJ and Bintu, B and Moffitt, JR and Wu, CT and Zhuang, X},
title = {Spatial organization of chromatin domains and compartments in single chromosomes.},
journal = {Science (New York, N.Y.)},
volume = {353},
number = {6299},
pages = {598-602},
pmid = {27445307},
issn = {1095-9203},
support = {DP1 GM106412/GM/NIGMS NIH HHS/United States ; R01 GM096450/GM/NIGMS NIH HHS/United States ; R01 GM105637/GM/NIGMS NIH HHS/United States ; //Howard Hughes Medical Institute/United States ; },
mesh = {Cell Line ; Chromatin/*chemistry ; Chromosomes, Human, Pair 20/chemistry ; Chromosomes, Human, Pair 22/chemistry ; Chromosomes, Human, X/*chemistry ; Gene Expression Regulation ; *Genome, Human ; Humans ; *Interphase ; Molecular Imaging/methods ; },
abstract = {The spatial organization of chromatin critically affects genome function. Recent chromosome-conformation-capture studies have revealed topologically associating domains (TADs) as a conserved feature of chromatin organization, but how TADs are spatially organized in individual chromosomes remains unknown. Here, we developed an imaging method for mapping the spatial positions of numerous genomic regions along individual chromosomes and traced the positions of TADs in human interphase autosomes and X chromosomes. We observed that chromosome folding deviates from the ideal fractal-globule model at large length scales and that TADs are largely organized into two compartments spatially arranged in a polarized manner in individual chromosomes. Active and inactive X chromosomes adopt different folding and compartmentalization configurations. These results suggest that the spatial organization of chromatin domains can change in response to regulation.},
}
@article {pmid27437574,
year = {2016},
author = {Giorgetti, L and Lajoie, BR and Carter, AC and Attia, M and Zhan, Y and Xu, J and Chen, CJ and Kaplan, N and Chang, HY and Heard, E and Dekker, J},
title = {Structural organization of the inactive X chromosome in the mouse.},
journal = {Nature},
volume = {535},
number = {7613},
pages = {575-579},
pmid = {27437574},
issn = {1476-4687},
support = {P50-HG007735/HG/NHGRI NIH HHS/United States ; R01 HG003143/HG/NHGRI NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; U54 DK107980/DK/NIDDK NIH HHS/United States ; P50 HG007735/HG/NHGRI NIH HHS/United States ; T32 AG047126/AG/NIA NIH HHS/United States ; },
mesh = {Alleles ; Animals ; Binding Sites ; CCCTC-Binding Factor ; Chromatin/chemistry/genetics/metabolism ; Chromosomes, Mammalian/chemistry/genetics/*metabolism ; Embryonic Stem Cells/metabolism ; Female ; Gene Silencing ; Male ; Mice ; Neural Stem Cells/metabolism ; Promoter Regions, Genetic/genetics ; RNA, Long Noncoding/genetics/metabolism ; Repressor Proteins/metabolism ; Sequence Analysis ; Transcription, Genetic ; X Chromosome/chemistry/genetics/*metabolism ; *X Chromosome Inactivation/genetics ; },
abstract = {X-chromosome inactivation (XCI) involves major reorganization of the X chromosome as it becomes silent and heterochromatic. During female mammalian development, XCI is triggered by upregulation of the non-coding Xist RNA from one of the two X chromosomes. Xist coats the chromosome in cis and induces silencing of almost all genes via its A-repeat region, although some genes (constitutive escapees) avoid silencing in most cell types, and others (facultative escapees) escape XCI only in specific contexts. A role for Xist in organizing the inactive X (Xi) chromosome has been proposed. Recent chromosome conformation capture approaches have revealed global loss of local structure on the Xi chromosome and formation of large mega-domains, separated by a region containing the DXZ4 macrosatellite. However, the molecular architecture of the Xi chromosome, in both the silent and expressed regions,remains unclear. Here we investigate the structure, chromatin accessibility and expression status of the mouse Xi chromosome in highly polymorphic clonal neural progenitors (NPCs) and embryonic stem cells. We demonstrate a crucial role for Xist and the DXZ4-containing boundary in shaping Xi chromosome structure using allele-specific genome-wide chromosome conformation capture (Hi-C) analysis, an assay for transposase-accessible chromatin with high throughput sequencing (ATAC-seq) and RNA sequencing. Deletion of the boundary disrupts mega-domain formation, and induction of Xist RNA initiates formation of the boundary and the loss of DNA accessibility. We also show that in NPCs, the Xi chromosome lacks active/inactive compartments and topologically associating domains (TADs), except around genes that escape XCI. Escapee gene clusters display TAD-like structures and retain DNA accessibility at promoter-proximal and CTCF-binding sites. Furthermore, altered patterns of facultative escape genes indifferent neural progenitor clones are associated with the presence of different TAD-like structures after XCI. These findings suggest a key role for transcription and CTCF in the formation of TADs in the context of the Xi chromosome in neural progenitors.},
}
@article {pmid27435934,
year = {2016},
author = {Barutcu, AR and Lajoie, BR and Fritz, AJ and McCord, RP and Nickerson, JA and van Wijnen, AJ and Lian, JB and Stein, JL and Dekker, J and Stein, GS and Imbalzano, AN},
title = {SMARCA4 regulates gene expression and higher-order chromatin structure in proliferating mammary epithelial cells.},
journal = {Genome research},
volume = {26},
number = {9},
pages = {1188-1201},
pmid = {27435934},
issn = {1549-5469},
support = {P01 CA082834/CA/NCI NIH HHS/United States ; R01 HG003143/HG/NHGRI NIH HHS/United States ; },
mesh = {Cell Line, Tumor ; Cell Proliferation/*genetics ; Chromatin/*genetics ; Chromatin Assembly and Disassembly ; DNA Helicases/*genetics ; Epithelial Cells/metabolism ; Gene Expression Regulation/genetics ; Humans ; Nuclear Proteins/*genetics ; Nucleosomes/genetics ; Transcription Factors/*genetics ; },
abstract = {The packaging of DNA into chromatin plays an important role in transcriptional regulation and nuclear processes. Brahma-related gene-1 SMARCA4 (also known as BRG1), the essential ATPase subunit of the mammalian SWI/SNF chromatin remodeling complex, uses the energy from ATP hydrolysis to disrupt nucleosomes at target regions. Although the transcriptional role of SMARCA4 at gene promoters is well-studied, less is known about its role in higher-order genome organization. SMARCA4 knockdown in human mammary epithelial MCF-10A cells resulted in 176 up-regulated genes, including many related to lipid and calcium metabolism, and 1292 down-regulated genes, some of which encode extracellular matrix (ECM) components that can exert mechanical forces and affect nuclear structure. ChIP-seq analysis of SMARCA4 localization and SMARCA4-bound super-enhancers demonstrated extensive binding at intergenic regions. Furthermore, Hi-C analysis showed extensive SMARCA4-mediated alterations in higher-order genome organization at multiple resolutions. First, SMARCA4 knockdown resulted in clustering of intra- and inter-subtelomeric regions, demonstrating a novel role for SMARCA4 in telomere organization. SMARCA4 binding was enriched at topologically associating domain (TAD) boundaries, and SMARCA4 knockdown resulted in weakening of TAD boundary strength. Taken together, these findings provide a dynamic view of SMARCA4-dependent changes in higher-order chromatin organization and gene expression, identifying SMARCA4 as a novel component of chromatin organization.},
}
@article {pmid27423862,
year = {2016},
author = {Kim, KD and Iwasaki, O and Noma, K},
title = {An IF-FISH Approach for Covisualization of Gene Loci and Nuclear Architecture in Fission Yeast.},
journal = {Methods in enzymology},
volume = {574},
number = {},
pages = {167-180},
pmid = {27423862},
issn = {1557-7988},
support = {DP2 OD004348/OD/NIH HHS/United States ; P30 CA010815/CA/NCI NIH HHS/United States ; },
mesh = {Centromere/genetics/ultrastructure ; *Chromosomes, Fungal/genetics/ultrastructure ; Fluorescent Antibody Technique/*methods ; *Genetic Loci ; Genome, Fungal ; In Situ Hybridization, Fluorescence/*methods ; Schizosaccharomyces/cytology/*genetics/*ultrastructure ; },
abstract = {Recent genomic studies have revealed that chromosomal structures are formed by a hierarchy of organizing processes ranging from gene associations, including interactions among enhancers and promoters, to topologically associating domain formations. Gene associations identified by these studies can be characterized by microscopic analyses. Fission yeast is a model organism, in which gene associations have been broadly mapped across the genome, although many of those associations have not been further examined by cell biological approaches. To address the technically challenging process of the visualization of associating gene loci in the fission yeast nuclei, we provide, in detail, an IF-FISH procedure that allows for covisualizing both gene loci and nuclear structural markers such as the nuclear membrane and nucleolus.},
}
@article {pmid27414788,
year = {2016},
author = {Ye, BY and Shen, WL and Wang, D and Li, P and Zhang, Z and Shi, ML and Zhang, Y and Zhang, FX and Zhao, ZH},
title = {[ZNF143 is involved in CTCF-mediated chromatin interactions by cooperation with cohesin and other partners].},
journal = {Molekuliarnaia biologiia},
volume = {50},
number = {3},
pages = {496-503},
doi = {10.7868/S0026898416030034},
pmid = {27414788},
issn = {0026-8984},
mesh = {Binding Sites ; CCCTC-Binding Factor ; Cell Cycle Proteins/genetics/*metabolism ; Chromatin/*chemistry/metabolism ; Chromatin Assembly and Disassembly ; Chromosomal Proteins, Non-Histone/genetics/*metabolism ; Databases, Genetic ; Gene Expression ; Humans ; K562 Cells ; Nucleotide Motifs ; Protein Binding ; Protein Interaction Mapping ; Repressor Proteins/genetics/*metabolism ; Trans-Activators/genetics/*metabolism ; },
abstract = {ZNF143 is a ubiquitously expressed transcription factor conserved in vertebrates and might regulate the expression of numerous genes. But its function in mediating chromatin interactions remains elusive. By integrated analysis of public datasets, we provided evidence that a majority of ZNF143 binding sites (BSs) were involved in CTCF-mediated chromatin interaction networks (CTCF-CINs) by overlapping with cohesin-BSs and CTCF-BSs. We further showed that only a very few CTCF-CINs were associated with ZNF143 alone, whereas those associated with ZNF143 and cohesin simultaneously were highly overlapped with constitutive, conserved CTCF-BSs and enriched at boundaries of chromatin topologically associating domains. These observations implicate that as an important partner of CTCF, ZNF143 helps it establish the conserved chromatin structure by cooperating with cohesin.},
}
@article {pmid27402708,
year = {2016},
author = {Williamson, I and Lettice, LA and Hill, RE and Bickmore, WA},
title = {Shh and ZRS enhancer colocalisation is specific to the zone of polarising activity.},
journal = {Development (Cambridge, England)},
volume = {143},
number = {16},
pages = {2994-3001},
pmid = {27402708},
issn = {1477-9129},
support = {MC_PC_U127527202/MRC_/Medical Research Council/United Kingdom ; MC_PC_U127584494/MRC_/Medical Research Council/United Kingdom ; MC_U127584494/MRC_/Medical Research Council/United Kingdom ; MR/K01563X/1/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Animals ; Chromosomes/genetics/metabolism ; Enhancer Elements, Genetic/*genetics ; Gene Expression Regulation, Developmental ; Hedgehog Proteins/genetics/*metabolism ; In Situ Hybridization, Fluorescence ; Limb Buds/metabolism ; Mice ; },
abstract = {Limb-specific Shh expression is regulated by the (∼1 Mb distant) ZRS enhancer. In the mouse, limb bud-restricted spatiotemporal Shh expression occurs from ∼E10 to E11.5 at the distal posterior margin and is essential for correct autopod formation. Here, we have analysed the higher-order chromatin conformation of Shh in expressing and non-expressing tissues, both by fluorescence in situ hybridisation (FISH) and by chromosome conformation capture (5C). Conventional and super-resolution light microscopy identified significantly elevated frequencies of Shh/ZRS colocalisation only in the Shh-expressing regions of the limb bud, in a conformation consistent with enhancer-promoter loop formation. However, in all tissues and at all developmental stages analysed, Shh-ZRS spatial distances were still consistently shorter than those to a neural enhancer located between Shh and ZRS in the genome. 5C identified a topologically associating domain (TAD) over the Shh/ZRS genomic region and enriched interactions between Shh and ZRS throughout E11.5 embryos. Shh/ZRS colocalisation, therefore, correlates with the spatiotemporal domain of limb bud-specific Shh expression, but close Shh and ZRS proximity in the nucleus occurs regardless of whether the gene or enhancer is active. We suggest that this constrained chromatin configuration optimises the opportunity for the active enhancer to locate and instigate the expression of Shh.},
}
@article {pmid27367409,
year = {2016},
author = {Zhang, B and Wolynes, PG},
title = {Shape Transitions and Chiral Symmetry Breaking in the Energy Landscape of the Mitotic Chromosome.},
journal = {Physical review letters},
volume = {116},
number = {24},
pages = {248101},
doi = {10.1103/PhysRevLett.116.248101},
pmid = {27367409},
issn = {1079-7114},
mesh = {*Chromosomes ; *Entropy ; *Liquid Crystals ; *Mitosis ; Probability ; Stereoisomerism ; },
abstract = {We derive an unbiased information theoretic energy landscape for chromosomes at metaphase using a maximum entropy approach that accurately reproduces the details of the experimentally measured pairwise contact probabilities between genomic loci. Dynamical simulations using this landscape lead to cylindrical, helically twisted structures reflecting liquid crystalline order. These structures are similar to those arising from a generic ideal homogenized chromosome energy landscape. The helical twist can be either right or left handed so chiral symmetry is broken spontaneously. The ideal chromosome landscape when augmented by interactions like those leading to topologically associating domain formation in the interphase chromosome reproduces these behaviors. The phase diagram of this landscape shows that the helical fiber order and the cylindrical shape persist at temperatures above the onset of chiral symmetry breaking, which is limited by the topologically associating domain interaction strength.},
}
@article {pmid27318199,
year = {2016},
author = {Kruse, K and Hug, CB and Hernández-Rodríguez, B and Vaquerizas, JM},
title = {TADtool: visual parameter identification for TAD-calling algorithms.},
journal = {Bioinformatics (Oxford, England)},
volume = {32},
number = {20},
pages = {3190-3192},
pmid = {27318199},
issn = {1367-4811},
mesh = {*Algorithms ; Animals ; *Genome ; Humans ; Software ; },
abstract = {UNLABELLED: Eukaryotic genomes are hierarchically organized into topologically associating domains (TADs). The computational identification of these domains and their associated properties critically depends on the choice of suitable parameters of TAD-calling algorithms. To reduce the element of trial-and-error in parameter selection, we have developed TADtool: an interactive plot to find robust TAD-calling parameters with immediate visual feedback. TADtool allows the direct export of TADs called with a chosen set of parameters for two of the most common TAD calling algorithms: directionality and insulation index. It can be used as an intuitive, standalone application or as a Python package for maximum flexibility.<br><br>TADtool is available as a Python package from GitHub (https://github.com/vaquerizaslab/tadtool) or can be installed directly via PyPI, the Python package index (tadtool).<br><br>CONTACT: kai.kruse@mpi-muenster.mpg.de, jmv@mpi-muenster.mpg.deSupplementary information: Supplementary data are available at Bioinformatics online.},
}
@article {pmid27307607,
year = {2016},
author = {Hu, X and Shi, CH and Yip, KY},
title = {A novel method for discovering local spatial clusters of genomic regions with functional relationships from DNA contact maps.},
journal = {Bioinformatics (Oxford, England)},
volume = {32},
number = {12},
pages = {i111-i120},
pmid = {27307607},
issn = {1367-4811},
mesh = {DNA ; Genome ; *Genomics ; Programming Languages ; Software ; },
abstract = {MOTIVATION: The three-dimensional structure of genomes makes it possible for genomic regions not adjacent in the primary sequence to be spatially proximal. These DNA contacts have been found to be related to various molecular activities. Previous methods for analyzing DNA contact maps obtained from Hi-C experiments have largely focused on studying individual interactions, forming spatial clusters composed of contiguous blocks of genomic locations, or classifying these clusters into general categories based on some global properties of the contact maps.<br><br>RESULTS: Here, we describe a novel computational method that can flexibly identify small clusters of spatially proximal genomic regions based on their local contact patterns. Using simulated data that highly resemble Hi-C data obtained from real genome structures, we demonstrate that our method identifies spatial clusters that are more compact than methods previously used for clustering genomic regions based on DNA contact maps. The clusters identified by our method enable us to confirm functionally related genomic regions previously reported to be spatially proximal in different species. We further show that each genomic region can be assigned a numeric affinity value that indicates its degree of participation in each local cluster, and these affinity values correlate quantitatively with DNase I hypersensitivity, gene expression, super enhancer activities and replication timing in a cell type specific manner. We also show that these cluster affinity values can precisely define boundaries of reported topologically associating domains, and further define local sub-domains within each domain.<br><br>The source code of BNMF and tutorials on how to use the software to extract local clusters from contact maps are available at http://yiplab.cse.cuhk.edu.hk/bnmf/<br><br>CONTACT: kevinyip@cse.cuhk.edu.hk<br><br>SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},
}
@article {pmid27300486,
year = {2016},
author = {Khoroshko, VA and Levitsky, VG and Zykova, TY and Antonenko, OV and Belyaeva, ES and Zhimulev, IF},
title = {Chromatin Heterogeneity and Distribution of Regulatory Elements in the Late-Replicating Intercalary Heterochromatin Domains of Drosophila melanogaster Chromosomes.},
journal = {PloS one},
volume = {11},
number = {6},
pages = {e0157147},
pmid = {27300486},
issn = {1932-6203},
mesh = {Animals ; Chromosomes, Insect/chemistry/*genetics ; DNA Replication Timing ; Drosophila melanogaster/chemistry/*genetics ; Gene Expression Regulation ; Heterochromatin/chemistry/*genetics ; Regulatory Sequences, Nucleic Acid ; },
abstract = {Late-replicating domains (intercalary heterochromatin) in the Drosophila genome display a number of features suggesting their organization is quite unique. Typically, they are quite large and encompass clusters of functionally unrelated tissue-specific genes. They correspond to the topologically associating domains and conserved microsynteny blocks. Our study aims at exploring further details of molecular organization of intercalary heterochromatin and has uncovered surprising heterogeneity of chromatin composition in these regions. Using the 4HMM model developed in our group earlier, intercalary heterochromatin regions were found to host chromatin fragments with a particular epigenetic profile. Aquamarine chromatin fragments (spanning 0.67% of late-replicating regions) are characterized as a class of sequences that appear heterogeneous in terms of their decompactization. These fragments are enriched with enhancer sequences and binding sites for insulator proteins. They likely mark the chromatin state that is related to the binding of cis-regulatory proteins. Malachite chromatin fragments (11% of late-replicating regions) appear to function as universal transitional regions between two contrasting chromatin states. Namely, they invariably delimit intercalary heterochromatin regions from the adjacent active chromatin of interbands. Malachite fragments also flank aquamarine fragments embedded in the repressed chromatin of late-replicating regions. Significant enrichment of insulator proteins CP190, SU(HW), and MOD2.2 was observed in malachite chromatin. Neither aquamarine nor malachite chromatin types appear to correlate with the positions of highly conserved non-coding elements (HCNE) that are typically replete in intercalary heterochromatin. Malachite chromatin found on the flanks of intercalary heterochromatin regions tends to replicate earlier than the malachite chromatin embedded in intercalary heterochromatin. In other words, there exists a gradient of replication progressing from the flanks of intercalary heterochromatin regions center-wise. The peculiar organization and features of replication in large late-replicating regions are discussed as possible factors shaping the evolutionary stability of intercalary heterochromatin.},
}
@article {pmid27259200,
year = {2016},
author = {Dixon, JR and Gorkin, DU and Ren, B},
title = {Chromatin Domains: The Unit of Chromosome Organization.},
journal = {Molecular cell},
volume = {62},
number = {5},
pages = {668-680},
pmid = {27259200},
issn = {1097-4164},
support = {R01 ES024984/ES/NIEHS NIH HHS/United States ; K12 GM068524/GM/NIGMS NIH HHS/United States ; U54 DK107977/DK/NIDDK NIH HHS/United States ; P50 GM085764/GM/NIGMS NIH HHS/United States ; U54 HG006997/HG/NHGRI NIH HHS/United States ; P30 CA014195/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cell Nucleus/*metabolism ; Chromatin/chemistry/genetics/*metabolism ; *Chromatin Assembly and Disassembly ; Chromosomes/chemistry/genetics/*metabolism ; Gene Expression Regulation ; *Genome ; Genomics/methods ; Humans ; *Interphase ; Nucleic Acid Conformation ; Protein Conformation ; Structure-Activity Relationship ; },
abstract = {How eukaryotic chromosomes fold inside the nucleus is an age-old question that remains unanswered today. Early biochemical and microscopic studies revealed the existence of chromatin domains and loops as a pervasive feature of interphase chromosomes, but the biological implications of such organizational features were obscure. Genome-wide analysis of pair-wise chromatin interactions using chromatin conformation capture (3C)-based techniques has shed new light on the organization of chromosomes in interphase nuclei. Particularly, the finding of cell-type invariant, evolutionarily conserved topologically associating domains (TADs) in a broad spectrum of cell types has provided a new molecular framework for the study of animal development and human diseases. Here, we review recent progress in characterization of such chromatin domains and delineation of mechanisms of their formation in animal cells.},
}
@article {pmid27257057,
year = {2016},
author = {Vasquez, PA and Hult, C and Adalsteinsson, D and Lawrimore, J and Forest, MG and Bloom, K},
title = {Entropy gives rise to topologically associating domains.},
journal = {Nucleic acids research},
volume = {44},
number = {12},
pages = {5540-5549},
pmid = {27257057},
issn = {1362-4962},
support = {R37 GM032238/GM/NIGMS NIH HHS/United States ; T32 GM007092/GM/NIGMS NIH HHS/United States ; T32 CA201159/CA/NCI NIH HHS/United States ; },
mesh = {Cell Nucleus/genetics ; Chromatin/*genetics ; Chromosomes/*genetics ; Entropy ; *Models, Genetic ; Saccharomyces cerevisiae/genetics ; },
abstract = {We investigate chromosome organization within the nucleus using polymer models whose formulation is closely guided by experiments in live yeast cells. We employ bead-spring chromosome models together with loop formation within the chains and the presence of nuclear bodies to quantify the extent to which these mechanisms shape the topological landscape in the interphase nucleus. By investigating the genome as a dynamical system, we show that domains of high chromosomal interactions can arise solely from the polymeric nature of the chromosome arms due to entropic interactions and nuclear confinement. In this view, the role of bio-chemical related processes is to modulate and extend the duration of the interacting domains.},
}
@article {pmid27249516,
year = {2016},
author = {Gavrilov, AA and Shevelyov, YY and Ulianov, SV and Khrameeva, EE and Kos, P and Chertovich, A and Razin, SV},
title = {Unraveling the mechanisms of chromatin fibril packaging.},
journal = {Nucleus (Austin, Tex.)},
volume = {7},
number = {3},
pages = {319-324},
pmid = {27249516},
issn = {1949-1042},
mesh = {Animals ; Chromatin/*chemistry/*metabolism ; Chromosomes, Insect/genetics ; Drosophila melanogaster/genetics ; Humans ; },
abstract = {Recent data indicate that eukaryotic chromosomes are organized into Topologically Associating Domains (TADs); however, the mechanisms underlying TAD formation remain obscure. Based on the results of Hi-C analysis performed on 4 Drosophila melanogaster cell lines, we have proposed that specific properties of nucleosomes in active and repressed chromatin play a key role in the formation of TADs. Our computer simulations showed that the ability of "inactive" nucleosomes to stick to each other and the lack of such ability in "active" nucleosomes is sufficient for spatial segregation of these types of chromatin, which is revealed in the Hi-C analysis as TAD/inter-TAD partitioning. However, some Drosophila and mammalian TADs contain both active and inactive chromatin, a fact that does not fit this model. Herein, we present additional arguments for the model by postulating that transcriptionally active chromatin is extruded on the surface of a TAD, and discuss the possible impact of this organization on the enhancer-promoter communication and on the segregation of TADs.},
}
@article {pmid27222515,
year = {2016},
author = {Ros, MA},
title = {HOX13 proteins: the molecular switcher in Hoxd bimodal regulation.},
journal = {Genes &amp; development},
volume = {30},
number = {10},
pages = {1135-1137},
pmid = {27222515},
issn = {1549-5477},
mesh = {Embryonic Development ; Extremities/*embryology ; *Gene Expression Regulation, Developmental ; Genes, Homeobox ; Homeodomain Proteins/genetics ; Transcription Factors/genetics ; },
abstract = {The striking correlation between the genomic arrangement of Hox genes and their temporal and spatial pattern of expression during embryonic development has been a source of fascination since its discovery. This correspondence has been used as a privileged example in the investigation of the connection between genomic architecture and function. In this issue of Genes &amp; Development, Beccari and colleagues (pp. 1172-1186) make a big step forward in understanding Hox gene regulation during limb development by showing the pivotal role of HOXA13 and HOXD13 proteins in the transition from a proximal to a distal type of Hoxd transcriptional regulation.},
}
@article {pmid27210764,
year = {2016},
author = {Fudenberg, G and Imakaev, M and Lu, C and Goloborodko, A and Abdennur, N and Mirny, LA},
title = {Formation of Chromosomal Domains by Loop Extrusion.},
journal = {Cell reports},
volume = {15},
number = {9},
pages = {2038-2049},
pmid = {27210764},
issn = {2211-1247},
support = {R01 GM114190/GM/NIGMS NIH HHS/United States ; R01 HG003143/HG/NHGRI NIH HHS/United States ; U54 DK107980/DK/NIDDK NIH HHS/United States ; },
mesh = {CCCTC-Binding Factor/metabolism ; Cell Cycle Proteins/metabolism ; Chromosomal Proteins, Non-Histone/metabolism ; Chromosomes/*chemistry ; Insulator Elements/genetics ; Models, Molecular ; *Nucleic Acid Conformation ; Sequence Deletion ; },
abstract = {Topologically associating domains (TADs) are fundamental structural and functional building blocks of human interphase chromosomes, yet the mechanisms of TAD formation remain unclear. Here, we propose that loop extrusion underlies TAD formation. In this process, cis-acting loop-extruding factors, likely cohesins, form progressively larger loops but stall at TAD boundaries due to interactions with boundary proteins, including CTCF. Using polymer simulations, we show that this model produces TADs and finer-scale features of Hi-C data. Each TAD emerges from multiple loops dynamically formed through extrusion, contrary to typical illustrations of single static loops. Loop extrusion both explains diverse experimental observations-including the preferential orientation of CTCF motifs, enrichments of architectural proteins at TAD boundaries, and boundary deletion experiments-and makes specific predictions for the depletion of CTCF versus cohesin. Finally, loop extrusion has potentially far-ranging consequences for processes such as enhancer-promoter interactions, orientation-specific chromosomal looping, and compaction of mitotic chromosomes.},
}
@article {pmid27198226,
year = {2016},
author = {Beccari, L and Yakushiji-Kaminatsui, N and Woltering, JM and Necsulea, A and Lonfat, N and Rodríguez-Carballo, E and Mascrez, B and Yamamoto, S and Kuroiwa, A and Duboule, D},
title = {A role for HOX13 proteins in the regulatory switch between TADs at the HoxD locus.},
journal = {Genes &amp; development},
volume = {30},
number = {10},
pages = {1172-1186},
pmid = {27198226},
issn = {1549-5477},
mesh = {Animals ; Body Patterning/*genetics ; Chick Embryo ; Enhancer Elements, Genetic/genetics ; Extremities/*embryology ; Gene Expression Regulation, Developmental/*genetics ; Genes, Homeobox/*genetics ; Homeodomain Proteins/genetics/*metabolism ; Limb Deformities, Congenital/genetics ; Mice ; Mice, Transgenic ; Mutation ; Protein Binding/genetics ; Protein Domains/*genetics ; },
abstract = {During vertebrate limb development, Hoxd genes are regulated following a bimodal strategy involving two topologically associating domains (TADs) located on either side of the gene cluster. These regulatory landscapes alternatively control different subsets of Hoxd targets, first into the arm and subsequently into the digits. We studied the transition between these two global regulations, a switch that correlates with the positioning of the wrist, which articulates these two main limb segments. We show that the HOX13 proteins themselves help switch off the telomeric TAD, likely through a global repressive mechanism. At the same time, they directly interact with distal enhancers to sustain the activity of the centromeric TAD, thus explaining both the sequential and exclusive operating processes of these two regulatory domains. We propose a model in which the activation of Hox13 gene expression in distal limb cells both interrupts the proximal Hox gene regulation and re-enforces the distal regulation. In the absence of HOX13 proteins, a proximal limb structure grows without any sign of wrist articulation, likely related to an ancestral fish-like condition.},
}
@article {pmid27115331,
year = {2016},
author = {Rivera-Mulia, JC and Gilbert, DM},
title = {Replication timing and transcriptional control: beyond cause and effect-part III.},
journal = {Current opinion in cell biology},
volume = {40},
number = {},
pages = {168-178},
pmid = {27115331},
issn = {1879-0410},
support = {P01 GM085354/GM/NIGMS NIH HHS/United States ; R01 GM083337/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Cell Cycle ; Cell Nucleus/genetics ; DNA Replication ; *DNA Replication Timing ; *Gene Expression Regulation ; Genome ; Humans ; *Transcription, Genetic ; },
abstract = {DNA replication is essential for faithful transmission of genetic information and is intimately tied to chromosome structure and function. Genome duplication occurs in a defined temporal order known as the replication-timing (RT) program, which is regulated during the cell cycle and development in discrete units referred to as replication domains (RDs). RDs correspond to topologically-associating domains (TADs) and are spatio-temporally compartmentalized in the nucleus. While improvements in experimental tools have begun to reveal glimpses of causality, they have also unveiled complex context-dependent relationships that challenge long recognized correlations of RT to chromatin organization and gene regulation. In particular, RDs/TADs that switch RT during development march to the beat of a different drummer.},
}
@article {pmid27111891,
year = {2016},
author = {Valton, AL and Dekker, J},
title = {TAD disruption as oncogenic driver.},
journal = {Current opinion in genetics &amp; development},
volume = {36},
number = {},
pages = {34-40},
pmid = {27111891},
issn = {1879-0380},
support = {R01 GM112720/GM/NIGMS NIH HHS/United States ; R01 HG003143/HG/NHGRI NIH HHS/United States ; U01 HG007910/HG/NHGRI NIH HHS/United States ; U54 DK107980/DK/NIDDK NIH HHS/United States ; R01 AI117839/AI/NIAID NIH HHS/United States ; U01 DA040588/DA/NIDA NIH HHS/United States ; U54 HG007010/HG/NHGRI NIH HHS/United States ; U54 CA193419/CA/NCI NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; },
mesh = {Carcinogenesis/*genetics ; Chromatin/genetics ; Gene Expression Regulation, Neoplastic/*genetics ; *Genome, Human ; Genomics ; Humans ; Oncogene Proteins, Fusion/*genetics ; Protein Domains/genetics ; },
abstract = {Topologically Associating Domains (TADs) are conserved during evolution and play roles in guiding and constraining long-range regulation of gene expression. Disruption of TAD boundaries results in aberrant gene expression by exposing genes to inappropriate regulatory elements. Recent studies have shown that TAD disruption is often found in cancer cells and contributes to oncogenesis through two mechanisms. One mechanism locally disrupts domains by deleting or mutating a TAD boundary leading to fusion of the two adjacent TADs. The other mechanism involves genomic rearrangements that break up TADs and creates new ones without directly affecting TAD boundaries. Understanding the mechanisms by which TADs form and control long-range chromatin interactions will therefore not only provide insights into the mechanism of gene regulation in general, but will also reveal how genomic rearrangements and mutations in cancer genomes can lead to misregulation of oncogenes and tumor suppressors.},
}
@article {pmid27111547,
year = {2016},
author = {Razin, SV and Gavrilov, AA and Vassetzky, YS and Ulianov, SV},
title = {Topologically-associating domains: gene warehouses adapted to serve transcriptional regulation.},
journal = {Transcription},
volume = {7},
number = {3},
pages = {84-90},
pmid = {27111547},
issn = {2154-1272},
mesh = {Chromosomes/*chemistry/genetics ; *Gene Expression Regulation ; Genome ; Nucleic Acid Conformation ; Regulatory Sequences, Nucleic Acid ; *Transcription, Genetic ; },
abstract = {Structural-functional domains have long been hypothesized to occur in eukaryotic chromosomes, but their existence still remains controversial. Here, we discuss the current state of studies of 3D genome folding and the relation of this folding to the functional organization of the genome.},
}
@article {pmid27098512,
year = {2016},
author = {Yu, S and Yang, F and Shen, WH},
title = {Genome maintenance in the context of 4D chromatin condensation.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {73},
number = {16},
pages = {3137-3150},
pmid = {27098512},
issn = {1420-9071},
support = {R01 GM100478/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Cell Cycle ; Chromatin/chemistry/*genetics/metabolism ; Chromatin Assembly and Disassembly ; Chromosome Segregation ; Epigenesis, Genetic ; *Genomic Instability ; Histone Code ; Histones/chemistry/genetics/metabolism ; Humans ; Neoplasms/genetics/metabolism ; },
abstract = {The eukaryotic genome is packaged in the three-dimensional nuclear space by forming loops, domains, and compartments in a hierarchical manner. However, when duplicated genomes prepare for segregation, mitotic cells eliminate topologically associating domains and abandon the compartmentalized structure. Alongside chromatin architecture reorganization during the transition from interphase to mitosis, cells halt most DNA-templated processes such as transcription and repair. The intrinsically condensed chromatin serves as a sophisticated signaling module subjected to selective relaxation for programmed genomic activities. To understand the elaborate genome-epigenome interplay during cell cycle progression, the steady three-dimensional genome requires a time scale to form a dynamic four-dimensional and a more comprehensive portrait. In this review, we will dissect the functions of critical chromatin architectural components in constructing and maintaining an orderly packaged chromatin environment. We will also highlight the importance of the spatially and temporally conscious orchestration of chromatin remodeling to ensure high-fidelity genetic transmission.},
}
@article {pmid27028634,
year = {2016},
author = {Tiana, G and Amitai, A and Pollex, T and Piolot, T and Holcman, D and Heard, E and Giorgetti, L},
title = {Structural Fluctuations of the Chromatin Fiber within Topologically Associating Domains.},
journal = {Biophysical journal},
volume = {110},
number = {6},
pages = {1234-1245},
pmid = {27028634},
issn = {1542-0086},
support = {250367/ERC_/European Research Council/International ; },
mesh = {Algorithms ; Animals ; Chromatin/*chemistry ; Cluster Analysis ; Genetic Loci ; Mice ; Nucleic Acid Conformation ; Probability ; },
abstract = {Experiments based on chromosome conformation capture have shown that mammalian genomes are partitioned into topologically associating domains (TADs), within which the chromatin fiber preferentially interacts. TADs may provide three-dimensional scaffolds allowing genes to contact their appropriate distal regulatory DNA sequences (e.g., enhancers) and thus to be properly regulated. Understanding the cell-to-cell and temporal variability of the chromatin fiber within TADs, and what determines them, is thus of great importance to better understand transcriptional regulation. We recently described an equilibrium polymer model that can accurately predict cell-to-cell variation of chromosome conformation within single TADs, from chromosome conformation capture-based data. Here we further analyze the conformational and energetic properties of our model. We show that the chromatin fiber within TADs can easily fluctuate between several conformational states, which are hierarchically organized and are not separated by important free energy barriers, and that this is facilitated by the fact that the chromatin fiber within TADs is close to the onset of the coil-globule transition. We further show that in this dynamic state the properties of the chromatin fiber, and its contact probabilities in particular, are determined in a nontrivial manner not only by site-specific interactions between strongly interacting loci along the fiber, but also by nonlocal correlations between pairs of contacts. Finally, we use live-cell experiments to measure the dynamics of the chromatin fiber in mouse embryonic stem cells, in combination with dynamical simulations, and predict that conformational changes within one TAD are likely to occur on timescales that are much shorter than the duration of one cell cycle. This suggests that genes and their regulatory elements may come together and disassociate several times during a cell cycle. These results have important implications for transcriptional regulation as they support the concept of highly dynamic interactions driven by a complex interplay between site-specific interactions and the intrinsic biophysical properties of the chromatin fiber.},
}
@article {pmid26970625,
year = {2016},
author = {Darbellay, F and Duboule, D},
title = {Topological Domains, Metagenes, and the Emergence of Pleiotropic Regulations at Hox Loci.},
journal = {Current topics in developmental biology},
volume = {116},
number = {},
pages = {299-314},
doi = {10.1016/bs.ctdb.2015.11.022},
pmid = {26970625},
issn = {1557-8933},
mesh = {Animals ; Biological Evolution ; Chromatin ; *Enhancer Elements, Genetic ; Gene Expression Regulation ; *Genes, Homeobox ; Genome ; Homeodomain Proteins/*chemistry/genetics ; Multigene Family ; Protein Domains ; Vertebrates ; },
abstract = {Hox gene clusters of jaw vertebrates display a tight genomic organization, which has no equivalent in any other bilateria genomes sequenced thus far. It was previously argued that such a topological consolidation toward a condensed, metagenic structure was due to the accumulation of long-range regulations flanking Hox loci, a phenomenon made possible by the successive genome duplications that occurred at the root of the vertebrate lineage, similar to gene neofunctionalization but applied to a coordinated multigenic system. Here, we propose that the emergence of such large vertebrate regulatory landscapes containing a range of global enhancers was greatly facilitated by the presence of topologically associating domains (TADs). These chromatin domains, mostly constitutive, may have been used as genomic niches where novel regulations could evolve due to both the preexistence of a structural backbone poised to integrate novel regulatory inputs, and a highly adaptive transcriptional readout. We propose a scenario for the coevolution of such TADs and the emergence of pleiotropy at ancestral vertebrate Hox loci.},
}
@article {pmid26960733,
year = {2016},
author = {Zhu, Y and Chen, Z and Zhang, K and Wang, M and Medovoy, D and Whitaker, JW and Ding, B and Li, N and Zheng, L and Wang, W},
title = {Constructing 3D interaction maps from 1D epigenomes.},
journal = {Nature communications},
volume = {7},
number = {},
pages = {10812},
pmid = {26960733},
issn = {2041-1723},
support = {U01 ES017166/ES/NIEHS NIH HHS/United States ; U01ES017166/ES/NIEHS NIH HHS/United States ; },
mesh = {Chromatin/*metabolism ; Chromosome Mapping ; *Epigenomics ; *Gene Expression Regulation ; *Gene Regulatory Networks ; *Genome, Human ; Humans ; Promoter Regions, Genetic ; Transcriptional Activation ; },
abstract = {The human genome is tightly packaged into chromatin whose functional output depends on both one-dimensional (1D) local chromatin states and three-dimensional (3D) genome organization. Currently, chromatin modifications and 3D genome organization are measured by distinct assays. An emerging question is whether it is possible to deduce 3D interactions by integrative analysis of 1D epigenomic data and associate 3D contacts to functionality of the interacting loci. Here we present EpiTensor, an algorithm to identify 3D spatial associations within topologically associating domains (TADs) from 1D maps of histone modifications, chromatin accessibility and RNA-seq. We demonstrate that active promoter-promoter, promoter-enhancer and enhancer-enhancer associations identified by EpiTensor are highly concordant with those detected by Hi-C, ChIA-PET and eQTL analyses at 200 bp resolution. Moreover, EpiTensor has identified a set of interaction hotspots, characterized by higher chromatin and transcriptional activity as well as enriched TF and ncRNA binding across diverse cell types, which may be critical for stabilizing the local 3D interactions.},
}
@article {pmid26906681,
year = {2016},
author = {Deschamps, J},
title = {Birth and upgrowth of the Hox topological domains during evolution.},
journal = {Nature genetics},
volume = {48},
number = {3},
pages = {227-228},
pmid = {26906681},
issn = {1546-1718},
mesh = {Animals ; Body Patterning/*genetics ; *Evolution, Molecular ; Homeodomain Proteins/*biosynthesis ; Lancelets/*genetics ; },
abstract = {The recently discovered chromatin compartments called topologically associating domains (TADs) are essential for the three-dimensional organization of regulatory interactions driving gene expression. A new study documents the emergence of a TAD flanking the amphioxus Hox cluster, prefiguring the vertebrate anterior Hox TAD and preceding the appearance of the concurring posterior Hox TAD.},
}
@article {pmid26876719,
year = {2016},
author = {Ramani, V and Shendure, J and Duan, Z},
title = {Understanding Spatial Genome Organization: Methods and Insights.},
journal = {Genomics, proteomics &amp; bioinformatics},
volume = {14},
number = {1},
pages = {7-20},
pmid = {26876719},
issn = {2210-3244},
support = {U54 DK107979/DK/NIDDK NIH HHS/United States ; 1U54DK107979/DK/NIDDK NIH HHS/United States ; },
mesh = {Chromatin/chemistry/metabolism ; Chromatin Immunoprecipitation ; DNA/chemistry/metabolism ; Gene Expression Regulation ; *Genome, Human ; Humans ; Microscopy, Electron ; Molecular Conformation ; Transcription Factors/chemistry/metabolism ; },
abstract = {The manner by which eukaryotic genomes are packaged into nuclei while maintaining crucial nuclear functions remains one of the fundamental mysteries in biology. Over the last ten years, we have witnessed rapid advances in both microscopic and nucleic acid-based approaches to map genome architecture, and the application of these approaches to the dissection of higher-order chromosomal structures has yielded much new information. It is becoming increasingly clear, for example, that interphase chromosomes form stable, multilevel hierarchical structures. Among them, self-associating domains like so-called topologically associating domains (TADs) appear to be building blocks for large-scale genomic organization. This review describes features of these broadly-defined hierarchical structures, insights into the mechanisms underlying their formation, our current understanding of how interactions in the nuclear space are linked to gene regulation, and important future directions for the field.},
}
@article {pmid26868017,
year = {2016},
author = {Sharmin, M and Bravo, HC and Hannenhalli, S},
title = {Distinct genomic and epigenomic features demarcate hypomethylated blocks in colon cancer.},
journal = {BMC cancer},
volume = {16},
number = {},
pages = {88},
pmid = {26868017},
issn = {1471-2407},
support = {R01 GM100335/GM/NIGMS NIH HHS/United States ; R01 HG005220/HG/NHGRI NIH HHS/United States ; NIH R01GM100335/GM/NIGMS NIH HHS/United States ; NIH R01HG005220/HG/NHGRI NIH HHS/United States ; },
mesh = {Cell Line, Tumor ; Chromatin/genetics ; Colonic Neoplasms/*genetics/pathology ; CpG Islands/genetics ; DNA Methylation/*genetics ; *Epigenomics ; *Genome, Human ; Histones/genetics ; Humans ; Promoter Regions, Genetic ; },
abstract = {BACKGROUND: Large mega base-pair genomic regions show robust alterations in DNA methylation levels in multiple cancers. A vast majority of these regions are hypomethylated in cancers. These regions are generally enriched for CpG islands, Lamin Associated Domains and Large organized chromatin lysine modification domains, and are associated with stochastic variability in gene expression. Given the size and consistency of hypomethylated blocks (HMB) across cancer types, we hypothesized that the immediate causes of methylation instability are likely to be encoded in the genomic region near HMB boundaries, in terms of specific genomic or epigenomic signatures. However, a detailed characterization of the HMB boundaries has not been reported.<br><br>METHOD: Here, we focused on ~13 k HMBs, encompassing approximately half of the genome, identified in colon cancer. We modeled the genomic features of HMB boundaries by Random Forest to identify their salient features, in terms of transcription factor (TF) binding motifs. Additionally we analyzed various epigenomic marks, and chromatin structural features of HMB boundaries relative to the non-HMB genomic regions.<br><br>RESULT: We found that the classical promoter epigenomic mark--H3K4me3, is highly enriched at HMB boundaries, as are CTCF bound sites. HMB boundaries harbor distinct combinations of TF motifs. Our Random Forest model based on TF motifs can accurately distinguish boundaries not only from regions inside and outside HMBs, but surprisingly, from active promoters as well. Interestingly, the distinguishing TFs and their interacting proteins are involved in chromatin modification. Finally, HMB boundaries significantly coincide with the boundaries of Topologically Associating Domains of the chromatin.<br><br>CONCLUSION: Our analyses suggest that the overall architecture of HMBs is guided by pre-existing chromatin architecture, and are associated with aberrant activity of promoter-like sequences at the boundary.},
}
@article {pmid26862051,
year = {2016},
author = {Lupiáñez, DG and Spielmann, M and Mundlos, S},
title = {Breaking TADs: How Alterations of Chromatin Domains Result in Disease.},
journal = {Trends in genetics : TIG},
volume = {32},
number = {4},
pages = {225-237},
doi = {10.1016/j.tig.2016.01.003},
pmid = {26862051},
issn = {0168-9525},
mesh = {Chromatin/*chemistry/genetics ; *Genetic Predisposition to Disease ; Humans ; },
abstract = {Spatial organization is an inherent property of the vertebrate genome to accommodate the roughly 2m of DNA in the nucleus of a cell. In this nonrandom organization, topologically associating domains (TADs) emerge as a fundamental structural unit that is thought to guide regulatory elements to their cognate promoters. In this review we summarize the most recent findings about TADs and the boundary regions separating them. We discuss how the disruption of these structures by genomic rearrangements can result in gene misexpression and disease.},
}
@article {pmid26852111,
year = {2016},
author = {Rowley, MJ and Corces, VG},
title = {The three-dimensional genome: principles and roles of long-distance interactions.},
journal = {Current opinion in cell biology},
volume = {40},
number = {},
pages = {8-14},
pmid = {26852111},
issn = {1879-0410},
support = {F32 GM113570/GM/NIGMS NIH HHS/United States ; R01 GM035463/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; CCCTC-Binding Factor ; Chromatin/metabolism ; Chromatin Assembly and Disassembly ; Eukaryota/classification/*genetics ; Gene Expression Regulation ; *Genome ; Humans ; Repressor Proteins/metabolism ; },
abstract = {The linear sequence of eukaryotic genomes is arranged in a specific manner within the three-dimensional nuclear space. Interactions between distant sites partition the genome into domains of highly associating chromatin. Interaction domains are found in many organisms, but their properties and the principles governing their establishment vary between different species. Topologically associating domains (TADs) extending over large genomic regions are found in mammals and Drosophila melanogaster, whereas other types of contact domains exist in lower eukaryotes. Here we review recent studies that explore the mechanisms by which long distance chromatin interactions determine the 3D organization of the genome and the relationship between this organization and the establishment of specific patterns of gene expression.},
}
@article {pmid26767994,
year = {2015},
author = {Fabre, PJ and Benke, A and Manley, S and Duboule, D},
title = {Visualizing the HoxD Gene Cluster at the Nanoscale Level.},
journal = {Cold Spring Harbor symposia on quantitative biology},
volume = {80},
number = {},
pages = {9-16},
doi = {10.1101/sqb.2015.80.027177},
pmid = {26767994},
issn = {1943-4456},
mesh = {Animals ; Chromatin/*metabolism ; Embryonic Stem Cells ; Extremities/embryology ; *Gene Expression Regulation, Developmental ; Genes, Homeobox/*genetics ; Microscopy ; *Multigene Family ; Optical Imaging ; },
abstract = {Transcription of HoxD cluster genes in limbs is coordinated by two topologically associating domains (TADs), neighboring the cluster and containing various enhancers. Here, we use a combination of microscopy approaches and chromosome conformation capture to assess the structural changes occurring in this global architecture in various functional states. We observed that despite their spatial juxtaposition, the TADs are consistently kept as distinct three-dimensional units. Hox genes located at their boundary can show significant spatial segregation over long distances, suggesting that physical elongation of the HoxD cluster occurs. The use of superresolution imaging (STORM [stochastic optical reconstruction microscopy]) revealed that the gene cluster can be in an either compact or elongated shape. The latter configuration is observed in transcriptionally active tissue and in embryonic stem cells, consistent with chromosome conformation capture results. Such morphological changes at HoxD in developing digits seem to be associated with its position at the boundary between two TADs and support the idea that chromatin dynamics is important in the establishment of transcriptional activity.},
}
@article {pmid26751768,
year = {2016},
author = {Petryk, N and Kahli, M and d'Aubenton-Carafa, Y and Jaszczyszyn, Y and Shen, Y and Silvain, M and Thermes, C and Chen, CL and Hyrien, O},
title = {Replication landscape of the human genome.},
journal = {Nature communications},
volume = {7},
number = {},
pages = {10208},
pmid = {26751768},
issn = {2041-1723},
mesh = {Binding Sites ; Chromatin/metabolism ; DNA ; *DNA Replication ; *Genome, Human ; Histones/metabolism ; Humans ; Origin Recognition Complex/*metabolism ; *Replication Origin ; Sequence Analysis, DNA ; Transcription, Genetic ; },
abstract = {Despite intense investigation, human replication origins and termini remain elusive. Existing data have shown strong discrepancies. Here we sequenced highly purified Okazaki fragments from two cell types and, for the first time, quantitated replication fork directionality and delineated initiation and termination zones genome-wide. Replication initiates stochastically, primarily within non-transcribed, broad (up to 150 kb) zones that often abut transcribed genes, and terminates dispersively between them. Replication fork progression is significantly co-oriented with the transcription. Initiation and termination zones are frequently contiguous, sometimes separated by regions of unidirectional replication. Initiation zones are enriched in open chromatin and enhancer marks, even when not flanked by genes, and often border 'topologically associating domains' (TADs). Initiation zones are enriched in origin recognition complex (ORC)-binding sites and better align to origins previously mapped using bubble-trap than λ-exonuclease. This novel panorama of replication reveals how chromatin and transcription modulate the initiation process to create cell-type-specific replication programs.},
}
@article {pmid26748519,
year = {2016},
author = {Smith, EM and Lajoie, BR and Jain, G and Dekker, J},
title = {Invariant TAD Boundaries Constrain Cell-Type-Specific Looping Interactions between Promoters and Distal Elements around the CFTR Locus.},
journal = {American journal of human genetics},
volume = {98},
number = {1},
pages = {185-201},
pmid = {26748519},
issn = {1537-6605},
support = {HG003143/HG/NHGRI NIH HHS/United States ; R01 HG003143/HG/NHGRI NIH HHS/United States ; //Howard Hughes Medical Institute/United States ; U54 HG007010/HG/NHGRI NIH HHS/United States ; HG007010/HG/NHGRI NIH HHS/United States ; },
mesh = {Cell Line ; Chromatin/metabolism ; Cystic Fibrosis Transmembrane Conductance Regulator/*genetics ; *Enhancer Elements, Genetic ; Humans ; *Promoter Regions, Genetic ; },
abstract = {Three-dimensional genome structure plays an important role in gene regulation. Globally, chromosomes are organized into active and inactive compartments while, at the gene level, looping interactions connect promoters to regulatory elements. Topologically associating domains (TADs), typically several hundred kilobases in size, form an intermediate level of organization. Major questions include how TADs are formed and how they are related to looping interactions between genes and regulatory elements. Here we performed a focused 5C analysis of a 2.8 Mb chromosome 7 region surrounding CFTR in a panel of cell types. We find that the same TAD boundaries are present in all cell types, indicating that TADs represent a universal chromosome architecture. Furthermore, we find that these TAD boundaries are present irrespective of the expression and looping of genes located between them. In contrast, looping interactions between promoters and regulatory elements are cell-type specific and occur mostly within TADs. This is exemplified by the CFTR promoter that in different cell types interacts with distinct sets of distal cell-type-specific regulatory elements that are all located within the same TAD. Finally, we find that long-range associations between loci located in different TADs are also detected, but these display much lower interaction frequencies than looping interactions within TADs. Interestingly, interactions between TADs are also highly cell-type-specific and often involve loci clustered around TAD boundaries. These data point to key roles of invariant TAD boundaries in constraining as well as mediating cell-type-specific long-range interactions and gene regulation.},
}
@article {pmid26700852,
year = {2015},
author = {Fraser, J and Ferrai, C and Chiariello, AM and Schueler, M and Rito, T and Laudanno, G and Barbieri, M and Moore, BL and Kraemer, DC and Aitken, S and Xie, SQ and Morris, KJ and Itoh, M and Kawaji, H and Jaeger, I and Hayashizaki, Y and Carninci, P and Forrest, AR and , and Semple, CA and Dostie, J and Pombo, A and Nicodemi, M},
title = {Hierarchical folding and reorganization of chromosomes are linked to transcriptional changes in cellular differentiation.},
journal = {Molecular systems biology},
volume = {11},
number = {12},
pages = {852},
pmid = {26700852},
issn = {1744-4292},
support = {BB/H008098/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom ; MC_U120061476/MRC_/Medical Research Council/United Kingdom ; MOP-86716//Canadian Institutes of Health Research/Canada ; CAP-120350//Canadian Institutes of Health Research/Canada ; },
mesh = {Animals ; Cell Differentiation ; Cells, Cultured ; Chromatin/*chemistry ; Chromatin Assembly and Disassembly ; Chromosomes/*chemistry ; Epigenesis, Genetic ; Gene Expression Regulation ; Mice ; Mouse Embryonic Stem Cells/*cytology ; Neurons/*cytology ; *Transcription, Genetic ; },
abstract = {Mammalian chromosomes fold into arrays of megabase-sized topologically associating domains (TADs), which are arranged into compartments spanning multiple megabases of genomic DNA. TADs have internal substructures that are often cell type specific, but their higher-order organization remains elusive. Here, we investigate TAD higher-order interactions with Hi-C through neuronal differentiation and show that they form a hierarchy of domains-within-domains (metaTADs) extending across genomic scales up to the range of entire chromosomes. We find that TAD interactions are well captured by tree-like, hierarchical structures irrespective of cell type. metaTAD tree structures correlate with genetic, epigenomic and expression features, and structural tree rearrangements during differentiation are linked to transcriptional state changes. Using polymer modelling, we demonstrate that hierarchical folding promotes efficient chromatin packaging without the loss of contact specificity, highlighting a role far beyond the simple need for packing efficiency.},
}
@article {pmid26700097,
year = {2015},
author = {Geeven, G and Zhu, Y and Kim, BJ and Bartholdy, BA and Yang, SM and Macfarlan, TS and Gifford, WD and Pfaff, SL and Verstegen, MJ and Pinto, H and Vermunt, MW and Creyghton, MP and Wijchers, PJ and Stamatoyannopoulos, JA and Skoultchi, AI and de Laat, W},
title = {Local compartment changes and regulatory landscape alterations in histone H1-depleted cells.},
journal = {Genome biology},
volume = {16},
number = {},
pages = {289},
pmid = {26700097},
issn = {1474-760X},
support = {CA079057/CA/NCI NIH HHS/United States ; R01 CA079057/CA/NCI NIH HHS/United States ; GM116143/GM/NIGMS NIH HHS/United States ; R01 GM116143/GM/NIGMS NIH HHS/United States ; R56 CA079057/CA/NCI NIH HHS/United States ; P30 CA013330/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cell Line ; Chromatin/genetics/metabolism ; *Chromatin Assembly and Disassembly ; *Epigenesis, Genetic ; Histones/genetics/*metabolism ; Mice ; },
abstract = {BACKGROUND: Linker histone H1 is a core chromatin component that binds to nucleosome core particles and the linker DNA between nucleosomes. It has been implicated in chromatin compaction and gene regulation and is anticipated to play a role in higher-order genome structure. Here we have used a combination of genome-wide approaches including DNA methylation, histone modification and DNase I hypersensitivity profiling as well as Hi-C to investigate the impact of reduced cellular levels of histone H1 in embryonic stem cells on chromatin folding and function.<br><br>RESULTS: We find that depletion of histone H1 changes the epigenetic signature of thousands of potential regulatory sites across the genome. Many of them show cooperative loss or gain of multiple chromatin marks. Epigenetic alterations cluster to gene-dense topologically associating domains (TADs) that already showed a high density of corresponding chromatin features. Genome organization at the three-dimensional level is largely intact, but we find changes in the structural segmentation of chromosomes specifically for the epigenetically most modified TADs.<br><br>CONCLUSIONS: Our data show that cells require normal histone H1 levels to expose their proper regulatory landscape. Reducing the levels of histone H1 results in massive epigenetic changes and altered topological organization particularly at the most active chromosomal domains. Changes in TAD configuration coincide with epigenetic landscape changes but not with transcriptional output changes, supporting the emerging concept that transcriptional control and nuclear positioning of TADs are not causally related but independently controlled by the locally associated trans-acting factors.},
}
@article {pmid26686465,
year = {2016},
author = {Ji, X and Dadon, DB and Powell, BE and Fan, ZP and Borges-Rivera, D and Shachar, S and Weintraub, AS and Hnisz, D and Pegoraro, G and Lee, TI and Misteli, T and Jaenisch, R and Young, RA},
title = {3D Chromosome Regulatory Landscape of Human Pluripotent Cells.},
journal = {Cell stem cell},
volume = {18},
number = {2},
pages = {262-275},
pmid = {26686465},
issn = {1875-9777},
support = {T32 GM007287/GM/NIGMS NIH HHS/United States ; R01 MH104610/MH/NIMH NIH HHS/United States ; R25 HG007631/HG/NHGRI NIH HHS/United States ; R01 NS088538/NS/NINDS NIH HHS/United States ; R37 HD045022/HD/NICHD NIH HHS/United States ; //Intramural NIH HHS/United States ; HD 045022/HD/NICHD NIH HHS/United States ; R01 HD045022/HD/NICHD NIH HHS/United States ; R01 HG002668/HG/NHGRI NIH HHS/United States ; HG002668/HG/NHGRI NIH HHS/United States ; },
mesh = {CCCTC-Binding Factor ; Cell Cycle Proteins/metabolism ; Cell Line ; Chromatin/metabolism ; Chromosomal Proteins, Non-Histone/metabolism ; Chromosomes, Human/*genetics ; DNA/chemistry/metabolism ; Disease/genetics ; Enhancer Elements, Genetic ; Gene Expression Regulation ; Human Embryonic Stem Cells/metabolism ; Humans ; Insulator Elements/genetics ; MicroRNAs/metabolism ; Nucleic Acid Conformation ; Pluripotent Stem Cells/*metabolism ; Repressor Proteins ; Transcription Factors/metabolism ; },
abstract = {In this study, we describe the 3D chromosome regulatory landscape of human naive and primed embryonic stem cells. To devise this map, we identified transcriptional enhancers and insulators in these cells and placed them within the context of cohesin-associated CTCF-CTCF loops using cohesin ChIA-PET data. The CTCF-CTCF loops we identified form a chromosomal framework of insulated neighborhoods, which in turn form topologically associating domains (TADs) that are largely preserved during the transition between the naive and primed states. Regulatory changes in enhancer-promoter interactions occur within insulated neighborhoods during cell state transition. The CTCF anchor regions we identified are conserved across species, influence gene expression, and are a frequent site of mutations in cancer cells, underscoring their functional importance in cellular regulation. These 3D regulatory maps of human pluripotent cells therefore provide a foundation for future interrogation of the relationships between chromosome structure and gene control in development and disease.},
}
@article {pmid26610607,
year = {2015},
author = {Nguyen, VT and Barozzi, I and Faronato, M and Lombardo, Y and Steel, JH and Patel, N and Darbre, P and Castellano, L and Győrffy, B and Woodley, L and Meira, A and Patten, DK and Vircillo, V and Periyasamy, M and Ali, S and Frige, G and Minucci, S and Coombes, RC and Magnani, L},
title = {Differential epigenetic reprogramming in response to specific endocrine therapies promotes cholesterol biosynthesis and cellular invasion.},
journal = {Nature communications},
volume = {6},
number = {},
pages = {10044},
pmid = {26610607},
issn = {2041-1723},
support = {/WT_/Wellcome Trust/United Kingdom ; 12011/CRUK_/Cancer Research UK/United Kingdom ; 103034/Z/13/Z/WT_/Wellcome Trust/United Kingdom ; },
mesh = {Animals ; Antineoplastic Agents, Hormonal/pharmacology/therapeutic use ; Aromatase Inhibitors/pharmacology/therapeutic use ; Biosynthetic Pathways/drug effects/genetics ; Blotting, Western ; Breast Neoplasms/drug therapy/*genetics/pathology ; Cholesterol/*biosynthesis ; Chromatin Immunoprecipitation ; Drug Resistance, Neoplasm/drug effects/*genetics ; Epigenesis, Genetic/*genetics ; Estrogen Receptor alpha/*metabolism ; Female ; Humans ; Hydroxycholesterols ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology ; Immunohistochemistry ; In Vitro Techniques ; MCF-7 Cells ; Mice ; Mice, SCID ; Neoplasm Invasiveness ; Neoplasm Transplantation ; Real-Time Polymerase Chain Reaction ; Up-Regulation ; },
abstract = {Endocrine therapies target the activation of the oestrogen receptor alpha (ERα) via distinct mechanisms, but it is not clear whether breast cancer cells can adapt to treatment using drug-specific mechanisms. Here we demonstrate that resistance emerges via drug-specific epigenetic reprogramming. Resistant cells display a spectrum of phenotypical changes with invasive phenotypes evolving in lines resistant to the aromatase inhibitor (AI). Orthogonal genomics analysis of reprogrammed regulatory regions identifies individual drug-induced epigenetic states involving large topologically associating domains (TADs) and the activation of super-enhancers. AI-resistant cells activate endogenous cholesterol biosynthesis (CB) through stable epigenetic activation in vitro and in vivo. Mechanistically, CB sparks the constitutive activation of oestrogen receptors alpha (ERα) in AI-resistant cells, partly via the biosynthesis of 27-hydroxycholesterol. By targeting CB using statins, ERα binding is reduced and cell invasion is prevented. Epigenomic-led stratification can predict resistance to AI in a subset of ERα-positive patients.},
}
@article {pmid26590169,
year = {2015},
author = {Dileep, V and Rivera-Mulia, JC and Sima, J and Gilbert, DM},
title = {Large-Scale Chromatin Structure-Function Relationships during the Cell Cycle and Development: Insights from Replication Timing.},
journal = {Cold Spring Harbor symposia on quantitative biology},
volume = {80},
number = {},
pages = {53-63},
doi = {10.1101/sqb.2015.80.027284},
pmid = {26590169},
issn = {1943-4456},
support = {P01 GM085354/GM/NIGMS NIH HHS/United States ; R01 GM083337/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; *Cell Cycle ; Chromatin/*metabolism ; Chromatin Assembly and Disassembly ; Chromosomes/*metabolism ; *DNA Replication ; Humans ; Structure-Activity Relationship ; },
abstract = {Chromosome architecture has received a lot of attention since the recent development of genome-scale methods to measure chromatin interactions (Hi-C), enabling the first sequence-based models of chromosome tertiary structure. A view has emerged of chromosomes as a string of structural units (topologically associating domains; TADs) whose boundaries persist through the cell cycle and development. TADs with similar chromatin states tend to aggregate, forming spatially segregated chromatin compartments. However, high-resolution Hi-C has revealed substructure within TADs (subTADs) that poses a challenge for models that attribute significance to structural units at any given scale. More than 20 years ago, the DNA replication field independently identified stable structural (and functional) units of chromosomes (replication foci) as well as spatially segregated chromatin compartments (early and late foci), but lacked the means to link these units to genomic map units. Genome-wide studies of replication timing (RT) have now merged these two disciplines by identifying individual units of replication regulation (replication domains; RDs) that correspond to TADs and are arranged in 3D to form spatiotemporally segregated subnuclear compartments. Furthermore, classifying RDs/TADs by their constitutive versus developmentally regulated RT has revealed distinct classes of chromatin organization, providing unexpected insight into the relationship between large-scale chromosome structure and function.},
}
@article {pmid26558551,
year = {2016},
author = {Remeseiro, S and Hörnblad, A and Spitz, F},
title = {Gene regulation during development in the light of topologically associating domains.},
journal = {Wiley interdisciplinary reviews. Developmental biology},
volume = {5},
number = {2},
pages = {169-185},
doi = {10.1002/wdev.218},
pmid = {26558551},
issn = {1759-7692},
mesh = {Animals ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Embryonic Development/*genetics ; Enhancer Elements, Genetic ; *Gene Expression Regulation, Developmental ; Promoter Regions, Genetic ; Protein Structure, Tertiary ; *Transcriptional Activation ; },
abstract = {During embryonic development, complex transcriptional programs govern the precision of gene expression. Many key developmental genes are regulated via cis-regulatory elements that are located far away in the linear genome. How sequences located hundreds of kilobases away from a promoter can influence its activity has been the subject of numerous speculations, which all underline the importance of the 3D-organization of the genome. The recent advent of chromosome conformation capture techniques has put into focus the subdivision of the genome into topologically associating domains (TADs). TADs may influence regulatory activities on multiple levels. The relative invariance of TAD limits across cell types suggests that they may form fixed structural domains that could facilitate and/or confine long-range regulatory interactions. However, most recent studies suggest that interactions within TADs are more variable and dynamic than initially described. Hence, different models are emerging regarding how TADs shape the complex 3D conformations, and thereafter influence the networks of cis-interactions that govern gene expression during development. For further resources related to this article, please visit the WIREs website.},
}
@article {pmid26544940,
year = {2015},
author = {Eagen, KP and Hartl, TA and Kornberg, RD},
title = {Stable Chromosome Condensation Revealed by Chromosome Conformation Capture.},
journal = {Cell},
volume = {163},
number = {4},
pages = {934-946},
pmid = {26544940},
issn = {1097-4172},
support = {T32 GM007365/GM/NIGMS NIH HHS/United States ; R01 GM036659/GM/NIGMS NIH HHS/United States ; U01AI090905/AI/NIAID NIH HHS/United States ; U01 AI090905/AI/NIAID NIH HHS/United States ; T32 GM008294/GM/NIGMS NIH HHS/United States ; R01 AI021144/AI/NIAID NIH HHS/United States ; R37 GM036659/GM/NIGMS NIH HHS/United States ; T32GM007365/GM/NIGMS NIH HHS/United States ; AI21144/AI/NIAID NIH HHS/United States ; GM36659/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Cell Nucleus/chemistry/genetics ; Chromosomal Puffs ; Diploidy ; Drosophila melanogaster/chemistry/cytology/*genetics/growth &amp; development ; Genetic Techniques ; Larva/chemistry ; Polytene Chromosomes/*chemistry ; },
abstract = {Chemical cross-linking and DNA sequencing have revealed regions of intra-chromosomal interaction, referred to as topologically associating domains (TADs), interspersed with regions of little or no interaction, in interphase nuclei. We find that TADs and the regions between them correspond with the bands and interbands of polytene chromosomes of Drosophila. We further establish the conservation of TADs between polytene and diploid cells of Drosophila. From direct measurements on light micrographs of polytene chromosomes, we then deduce the states of chromatin folding in the diploid cell nucleus. Two states of folding, fully extended fibers containing regulatory regions and promoters, and fibers condensed up to 10-fold containing coding regions of active genes, constitute the euchromatin of the nuclear interior. Chromatin fibers condensed up to 30-fold, containing coding regions of inactive genes, represent the heterochromatin of the nuclear periphery. A convergence of molecular analysis with direct observation thus reveals the architecture of interphase chromosomes.},
}
@article {pmid26518482,
year = {2016},
author = {Ulianov, SV and Khrameeva, EE and Gavrilov, AA and Flyamer, IM and Kos, P and Mikhaleva, EA and Penin, AA and Logacheva, MD and Imakaev, MV and Chertovich, A and Gelfand, MS and Shevelyov, YY and Razin, SV},
title = {Active chromatin and transcription play a key role in chromosome partitioning into topologically associating domains.},
journal = {Genome research},
volume = {26},
number = {1},
pages = {70-84},
pmid = {26518482},
issn = {1549-5469},
mesh = {Animals ; Cell Line ; Chromatin/*genetics ; Chromatin Assembly and Disassembly ; Chromosome Mapping ; Computer Simulation ; Drosophila melanogaster/*genetics ; *Genome, Insect ; Models, Molecular ; Nucleosomes/genetics/metabolism ; Polytene Chromosomes/genetics ; Sequence Analysis, RNA ; *Transcription, Genetic ; },
abstract = {Recent advances enabled by the Hi-C technique have unraveled many principles of chromosomal folding that were subsequently linked to disease and gene regulation. In particular, Hi-C revealed that chromosomes of animals are organized into topologically associating domains (TADs), evolutionary conserved compact chromatin domains that influence gene expression. Mechanisms that underlie partitioning of the genome into TADs remain poorly understood. To explore principles of TAD folding in Drosophila melanogaster, we performed Hi-C and poly(A)(+) RNA-seq in four cell lines of various origins (S2, Kc167, DmBG3-c2, and OSC). Contrary to previous studies, we find that regions between TADs (i.e., the inter-TADs and TAD boundaries) in Drosophila are only weakly enriched with the insulator protein dCTCF, while another insulator protein Su(Hw) is preferentially present within TADs. However, Drosophila inter-TADs harbor active chromatin and constitutively transcribed (housekeeping) genes. Accordingly, we find that binding of insulator proteins dCTCF and Su(Hw) predicts TAD boundaries much worse than active chromatin marks do. Interestingly, inter-TADs correspond to decompacted inter-bands of polytene chromosomes, whereas TADs mostly correspond to densely packed bands. Collectively, our results suggest that TADs are condensed chromatin domains depleted in active chromatin marks, separated by regions of active chromatin. We propose the mechanism of TAD self-assembly based on the ability of nucleosomes from inactive chromatin to aggregate, and lack of this ability in acetylated nucleosomal arrays. Finally, we test this hypothesis by polymer simulations and find that TAD partitioning may be explained by different modes of inter-nucleosomal interactions for active and inactive chromatin.},
}
@article {pmid26504220,
year = {2015},
author = {Fabre, PJ and Benke, A and Joye, E and Nguyen Huynh, TH and Manley, S and Duboule, D},
title = {Nanoscale spatial organization of the HoxD gene cluster in distinct transcriptional states.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {112},
number = {45},
pages = {13964-13969},
pmid = {26504220},
issn = {1091-6490},
mesh = {Animals ; Chromatin/genetics/*ultrastructure ; Chromatin Assembly and Disassembly/genetics/*physiology ; Extremities/*embryology ; Gene Expression Regulation, Developmental/*genetics ; Genes, Homeobox/*genetics ; Image Processing, Computer-Assisted ; In Situ Hybridization, Fluorescence ; Mice ; Multigene Family/*genetics ; Protein Structure, Tertiary ; Statistics, Nonparametric ; Transcriptional Activation/*genetics ; },
abstract = {Chromatin condensation plays an important role in the regulation of gene expression. Recently, it was shown that the transcriptional activation of Hoxd genes during vertebrate digit development involves modifications in 3D interactions within and around the HoxD gene cluster. This reorganization follows a global transition from one set of regulatory contacts to another, between two topologically associating domains (TADs) located on either side of the HoxD locus. Here, we use 3D DNA FISH to assess the spatial organization of chromatin at and around the HoxD gene cluster and report that although the two TADs are tightly associated, they appear as spatially distinct units. We measured the relative position of genes within the cluster and found that they segregate over long distances, suggesting that a physical elongation of the HoxD cluster can occur. We analyzed this possibility by super-resolution imaging (STORM) and found that tissues with distinct transcriptional activity exhibit differing degrees of elongation. We also observed that the morphological change of the HoxD cluster in developing digits is associated with its position at the boundary between the two TADs. Such variations in the fine-scale architecture of the gene cluster suggest causal links among its spatial configuration, transcriptional activation, and the flanking chromatin context.},
}
@article {pmid26431028,
year = {2015},
author = {Ramírez, F and Lingg, T and Toscano, S and Lam, KC and Georgiev, P and Chung, HR and Lajoie, BR and de Wit, E and Zhan, Y and de Laat, W and Dekker, J and Manke, T and Akhtar, A},
title = {High-Affinity Sites Form an Interaction Network to Facilitate Spreading of the MSL Complex across the X Chromosome in Drosophila.},
journal = {Molecular cell},
volume = {60},
number = {1},
pages = {146-162},
pmid = {26431028},
issn = {1097-4164},
support = {R01 HG003143/HG/NHGRI NIH HHS/United States ; //Howard Hughes Medical Institute/United States ; },
mesh = {Animals ; Binding Sites ; Cell Line ; Chromatin Assembly and Disassembly ; Cytogenetic Analysis ; DNA-Binding Proteins/*metabolism ; Dosage Compensation, Genetic ; Drosophila Proteins/genetics/*metabolism ; Drosophila melanogaster/*genetics/metabolism ; Female ; Male ; RNA-Binding Proteins/genetics/*metabolism ; Transcription Factors/genetics/*metabolism ; X Chromosome/genetics/*metabolism ; },
abstract = {Dosage compensation mechanisms provide a paradigm to study the contribution of chromosomal conformation toward targeting and spreading of epigenetic regulators over a specific chromosome. By using Hi-C and 4C analyses, we show that high-affinity sites (HAS), landing platforms of the male-specific lethal (MSL) complex, are enriched around topologically associating domain (TAD) boundaries on the X chromosome and harbor more long-range contacts in a sex-independent manner. Ectopically expressed roX1 and roX2 RNAs target HAS on the X chromosome in trans and, via spatial proximity, induce spreading of the MSL complex in cis, leading to increased expression of neighboring autosomal genes. We show that the MSL complex regulates nucleosome positioning at HAS, therefore acting locally rather than influencing the overall chromosomal architecture. We propose that the sex-independent, three-dimensional conformation of the X chromosome poises it for exploitation by the MSL complex, thereby facilitating spreading in males.},
}
@article {pmid26418477,
year = {2015},
author = {Cubeñas-Potts, C and Corces, VG},
title = {Topologically Associating Domains: An invariant framework or a dynamic scaffold?.},
journal = {Nucleus (Austin, Tex.)},
volume = {6},
number = {6},
pages = {430-434},
pmid = {26418477},
issn = {1949-1042},
support = {R01 GM035463/GM/NIGMS NIH HHS/United States ; R01GM035463/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Binding Sites ; CCCTC-Binding Factor ; Cell Differentiation ; Chromatin/chemistry/*metabolism ; Enhancer Elements, Genetic ; Epigenesis, Genetic ; *Genome ; Promoter Regions, Genetic ; Protein Binding ; Proteins/chemistry/*metabolism ; Repressor Proteins/chemistry/metabolism ; Stress, Physiological ; Temperature ; },
abstract = {Metazoan genomes are organized into regions of topologically associating domains (TADs). TADs are demarcated by border elements, which are enriched for active genes and high occupancy architectural protein binding sites. We recently demonstrated that 3D chromatin architecture is dynamic in response to heat shock, a physiological stress that downregulates transcription and causes a global redistribution of architectural proteins. We utilized a quantitative measure of border strength after heat shock, transcriptional inhibition, and architectural protein knockdown to demonstrate that changes in both transcription and architectural protein occupancy contribute to heat shock-induced TAD dynamics. Notably, architectural proteins appear to play a more important role in altering 3D chromatin architecture. Here, we discuss the implications of our findings on previous studies evaluating the dynamics of TAD structure during cellular differentiation. We propose that the subset of variable TADs observed after differentiation are representative of cell-type specific gene expression and are biologically significant.},
}
@article {pmid26348399,
year = {2015},
author = {Dekker, J and Heard, E},
title = {Structural and functional diversity of Topologically Associating Domains.},
journal = {FEBS letters},
volume = {589},
number = {20 Pt A},
pages = {2877-2884},
pmid = {26348399},
issn = {1873-3468},
support = {R01 HG003143/HG/NHGRI NIH HHS/United States ; },
mesh = {Animals ; Chromatin/genetics ; *Gene Expression Regulation ; Humans ; Nucleic Acid Conformation ; *Regulatory Sequences, Nucleic Acid ; },
abstract = {Recent studies have shown that chromosomes in a range of organisms are compartmentalized in different types of chromatin domains. In mammals, chromosomes form compartments that are composed of smaller Topologically Associating Domains (TADs). TADs are thought to represent functional domains of gene regulation but much is still unknown about the mechanisms of their formation and how they exert their regulatory effect on embedded genes. Further, similar domains have been detected in other organisms, including flies, worms, fungi and bacteria. Although in all these cases these domains appear similar as detected by 3C-based methods, their biology appears to be quite distinct with differences in the protein complexes involved in their formation and differences in their internal organization. Here we outline our current understanding of such domains in different organisms and their roles in gene regulation.},
}
@article {pmid26340055,
year = {2015},
author = {Higgins, GA and Allyn-Feuer, A and Athey, BD},
title = {Epigenomic mapping and effect sizes of noncoding variants associated with psychotropic drug response.},
journal = {Pharmacogenomics},
volume = {16},
number = {14},
pages = {1565-1583},
doi = {10.2217/pgs.15.105},
pmid = {26340055},
issn = {1744-8042},
support = {T32 GM0704490552/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Cycle Proteins/genetics ; Chromatin/genetics ; Chromosomal Proteins, Non-Histone/genetics ; Chromosome Mapping/*methods ; Computational Biology ; Computer Simulation ; DNA Methylation ; Deoxyribonuclease I/genetics ; Epigenomics/*methods ; Genetic Variation ; Genome-Wide Association Study ; Humans ; Polymorphism, Single Nucleotide ; Psychotropic Drugs/*pharmacology ; Transcription Factors/genetics ; White People ; },
abstract = {AIM: To provide insight into potential regulatory mechanisms of gene expression underlying addiction, analgesia, psychotropic drug response and adverse drug events, genome-wide association studies searching for variants associated with these phenotypes has been undertaken with limited success. We undertook analysis of these results with the aim of applying epigenetic knowledge to aid variant discovery and interpretation.<br><br>METHODS: We applied conditional imputation to results from 26 genome-wide association studies and three candidate gene-association studies. The analysis workflow included data from chromatin conformation capture, chromatin state annotation, DNase I hypersensitivity, hypomethylation, anatomical localization and biochronicity. We also made use of chromatin state data from the epigenome roadmap, transcription factor-binding data, spatial maps from published Hi-C datasets and 'guilt by association' methods.<br><br>RESULTS: We identified 31 pharmacoepigenomic SNPs from a total of 2024 variants in linkage disequilibrium with lead SNPs, of which only 6% were coding variants. Interrogation of chromatin state using our workflow and the epigenome roadmap showed agreement on 34 of 35 tissue assignments to regulatory elements including enhancers and promoters. Loop boundary domains were inferred by association with CTCF (CCCTC-binding factor) and cohesin, suggesting proximity to topologically associating domain boundaries and enhancer clusters. Spatial interactions between enhancer-promoter pairs detected both known and previously unknown mechanisms. Addiction and analgesia SNPs were common in relevant populations and exhibited large effect sizes, whereas a SNP located in the promoter of the SLC1A2 gene exhibited a moderate effect size for lithium response in bipolar disorder in patients of European ancestry. SNPs associated with drug-induced organ injury were rare but exhibited the largest effect sizes, consistent with the published literature.<br><br>CONCLUSION: This work demonstrates that an in silico bioinformatics-based approach using integrative analysis of a diversity of molecular and morphological data types can discover pharmacoepigenomic variants that are suitable candidates for further validation in cell lines, animal models and human clinical trials.},
}
@article {pmid26315910,
year = {2016},
author = {Weinreb, C and Raphael, BJ},
title = {Identification of hierarchical chromatin domains.},
journal = {Bioinformatics (Oxford, England)},
volume = {32},
number = {11},
pages = {1601-1609},
pmid = {26315910},
issn = {1367-4811},
support = {R01 HG005690/HG/NHGRI NIH HHS/United States ; },
mesh = {Cell Differentiation ; *Chromatin ; Gene Expression Regulation ; Genome ; },
abstract = {MOTIVATION: The three-dimensional structure of the genome is an important regulator of many cellular processes including differentiation and gene regulation. Recently, technologies such as Hi-C that combine proximity ligation with high-throughput sequencing have revealed domains of self-interacting chromatin, called topologically associating domains (TADs), in many organisms. Current methods for identifying TADs using Hi-C data assume that TADs are non-overlapping, despite evidence for a nested structure in which TADs and sub-TADs form a complex hierarchy.<br><br>RESULTS: We introduce a model for decomposition of contact frequencies into a hierarchy of nested TADs. This model is based on empirical distributions of contact frequencies within TADs, where positions that are far apart have a greater enrichment of contacts than positions that are close together. We find that the increase in contact enrichment with distance is stronger for the inner TAD than for the outer TAD in a TAD/sub-TAD pair. Using this model, we develop the TADtree algorithm for detecting hierarchies of nested TADs. TADtree compares favorably with previous methods, finding TADs with a greater enrichment of chromatin marks such as CTCF at their boundaries.<br><br>A python implementation of TADtree is available at http://compbio.cs.brown.edu/software/<br><br>CONTACT: braphael@cs.brown.edu<br><br>SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},
}
@article {pmid26271925,
year = {2015},
author = {Ea, V and Sexton, T and Gostan, T and Herviou, L and Baudement, MO and Zhang, Y and Berlivet, S and Le Lay-Taha, MN and Cathala, G and Lesne, A and Victor, JM and Fan, Y and Cavalli, G and Forné, T},
title = {Distinct polymer physics principles govern chromatin dynamics in mouse and Drosophila topological domains.},
journal = {BMC genomics},
volume = {16},
number = {1},
pages = {607},
pmid = {26271925},
issn = {1471-2164},
support = {R01 GM085261/GM/NIGMS NIH HHS/United States ; GM085261/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Chromatin/chemistry/genetics/*metabolism ; Chromatin Assembly and Disassembly ; DNA/*chemistry ; Drosophila melanogaster/*genetics ; Epigenesis, Genetic ; Liver/metabolism ; Mice ; *Models, Molecular ; *Models, Statistical ; Mouse Embryonic Stem Cells/cytology ; Nucleic Acid Conformation ; },
abstract = {BACKGROUND: In higher eukaryotes, the genome is partitioned into large "Topologically Associating Domains" (TADs) in which the chromatin displays favoured long-range contacts. While a crumpled/fractal globule organization has received experimental supports at higher-order levels, the organization principles that govern chromatin dynamics within these TADs remain unclear. Using simple polymer models, we previously showed that, in mouse liver cells, gene-rich domains tend to adopt a statistical helix shape when no significant locus-specific interaction takes place.<br><br>RESULTS: Here, we use data from diverse 3C-derived methods to explore chromatin dynamics within mouse and Drosophila TADs. In mouse Embryonic Stem Cells (mESC), that possess large TADs (median size of 840&#xa0;kb), we show that the statistical helix model, but not globule models, is relevant not only in gene-rich TADs, but also in gene-poor and gene-desert TADs. Interestingly, this statistical helix organization is considerably relaxed in mESC compared to liver cells, indicating that the impact of the constraints responsible for this organization is weaker in pluripotent cells. Finally, depletion of histone H1 in mESC alters local chromatin flexibility but not the statistical helix organization. In Drosophila, which possesses TADs of smaller sizes (median size of 70&#xa0;kb), we show that, while chromatin compaction and flexibility are finely tuned according to the epigenetic landscape, chromatin dynamics within TADs is generally compatible with an unconstrained polymer configuration.<br><br>CONCLUSIONS: Models issued from polymer physics can accurately describe the organization principles governing chromatin dynamics in both mouse and Drosophila TADs. However, constraints applied on this dynamics within mammalian TADs have a peculiar impact resulting in a statistical helix organization.},
}
@article {pmid26235224,
year = {2015},
author = {Marks, H and Kerstens, HH and Barakat, TS and Splinter, E and Dirks, RA and van Mierlo, G and Joshi, O and Wang, SY and Babak, T and Albers, CA and Kalkan, T and Smith, A and Jouneau, A and de Laat, W and Gribnau, J and Stunnenberg, HG},
title = {Dynamics of gene silencing during X inactivation using allele-specific RNA-seq.},
journal = {Genome biology},
volume = {16},
number = {1},
pages = {149},
pmid = {26235224},
issn = {1474-760X},
support = {G1001028/MRC_/Medical Research Council/United Kingdom ; G1100526/MRC_/Medical Research Council/United Kingdom ; MC_PC_12009/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Alleles ; Animals ; Chromatin/chemistry ; Embryoid Bodies/metabolism ; Embryonic Stem Cells/metabolism ; Female ; *Gene Silencing ; Humans ; Mice ; Neural Stem Cells/metabolism ; Sequence Analysis, RNA ; *X Chromosome Inactivation ; },
abstract = {BACKGROUND: During early embryonic development, one of the two X chromosomes in mammalian female cells is inactivated to compensate for a potential imbalance in transcript levels with male cells, which contain a single X chromosome. Here, we use mouse female embryonic stem cells (ESCs) with non-random X chromosome inactivation (XCI) and polymorphic X chromosomes to study the dynamics of gene silencing over the inactive X chromosome by high-resolution allele-specific RNA-seq.<br><br>RESULTS: Induction of XCI by differentiation of female ESCs shows that genes proximal to the X-inactivation center are silenced earlier than distal genes, while lowly expressed genes show faster XCI dynamics than highly expressed genes. The active X chromosome shows a minor but significant increase in gene activity during differentiation, resulting in complete dosage compensation in differentiated cell types. Genes escaping XCI show little or no silencing during early propagation of XCI. Allele-specific RNA-seq of neural progenitor cells generated from the female ESCs identifies three regions distal to the X-inactivation center that escape XCI. These regions, which stably escape during propagation and maintenance of XCI, coincide with topologically associating domains (TADs) as present in the female ESCs. Also, the previously characterized gene clusters escaping XCI in human fibroblasts correlate with TADs.<br><br>CONCLUSIONS: The gene silencing observed during XCI provides further insight in the establishment of the repressive complex formed by the inactive X chromosome. The association of escape regions with TADs, in mouse and human, suggests that TADs are the primary targets during propagation of XCI over the X chromosome.},
}
@article {pmid26220994,
year = {2015},
author = {Alekseyenko, AA and Walsh, EM and Wang, X and Grayson, AR and Hsi, PT and Kharchenko, PV and Kuroda, MI and French, CA},
title = {The oncogenic BRD4-NUT chromatin regulator drives aberrant transcription within large topological domains.},
journal = {Genes &amp; development},
volume = {29},
number = {14},
pages = {1507-1523},
pmid = {26220994},
issn = {1549-5477},
support = {T32 HL007627/HL/NHLBI NIH HHS/United States ; 2R01CA124633/CA/NCI NIH HHS/United States ; R01 CA124633/CA/NCI NIH HHS/United States ; GM101958/GM/NIGMS NIH HHS/United States ; R01 GM101958/GM/NIGMS NIH HHS/United States ; },
mesh = {Carcinoma, Squamous Cell/*physiopathology ; Cell Cycle Proteins ; Cell Line, Tumor ; Enhancer Elements, Genetic ; *Gene Expression Regulation, Neoplastic ; Humans ; Neoplasm Proteins ; Nuclear Proteins/genetics/*metabolism ; Oncogene Proteins/genetics/*metabolism ; Protein Structure, Tertiary ; Transcription Factors/genetics/*metabolism ; },
abstract = {NUT midline carcinoma (NMC), a subtype of squamous cell cancer, is one of the most aggressive human solid malignancies known. NMC is driven by the creation of a translocation oncoprotein, BRD4-NUT, which blocks differentiation and drives growth of NMC cells. BRD4-NUT forms distinctive nuclear foci in patient tumors, which we found correlate with ∼100 unprecedented, hyperacetylated expanses of chromatin that reach up to 2 Mb in size. These "megadomains" appear to be the result of aberrant, feed-forward loops of acetylation and binding of acetylated histones that drive transcription of underlying DNA in NMC patient cells and naïve cells induced to express BRD4-NUT. Megadomain locations are typically cell lineage-specific; however, the cMYC and TP63 regions are targeted in all NMCs tested and play functional roles in tumor growth. Megadomains appear to originate from select pre-existing enhancers that progressively broaden but are ultimately delimited by topologically associating domain (TAD) boundaries. Therefore, our findings establish a basis for understanding the powerful role played by large-scale chromatin organization in normal and aberrant lineage-specific gene transcription.},
}
@article {pmid26198462,
year = {2016},
author = {van Bemmel, JG and Mira-Bontenbal, H and Gribnau, J},
title = {Cis- and trans-regulation in X inactivation.},
journal = {Chromosoma},
volume = {125},
number = {1},
pages = {41-50},
pmid = {26198462},
issn = {1432-0886},
mesh = {Animals ; Cell Differentiation ; Embryonic Stem Cells/*metabolism/physiology ; Female ; Gene Expression Regulation, Developmental ; Gene Silencing ; Genes, X-Linked/genetics ; Humans ; *RNA, Long Noncoding ; *X Chromosome Inactivation ; },
abstract = {Female mammalian cells compensate dosage of X-linked gene expression through the inactivation of one of their two X chromosomes. X chromosome inactivation (XCI) in eutherians is dependent on the non-coding RNA Xist that is up-regulated from the future inactive X chromosome, coating it and recruiting factors involved in silencing and altering its chromatin state. Xist lies within the X-inactivation center (Xic), a region on the X that is required for XCI, and is regulated in cis by elements on the X chromosome and in trans by diffusible factors. In this review, we summarize the latest results in cis- and trans-regulation of the Xic. We discuss how the organization of the Xic in topologically associating domains is important for XCI (cis-regulation) and how proteins in the pluripotent state and upon development or differentiation of embryonic stem cells control proper inactivation of one X chromosome (trans-regulation).},
}
@article {pmid26184319,
year = {2015},
author = {Del Prete, S and Mikulski, P and Schubert, D and Gaudin, V},
title = {One, Two, Three: Polycomb Proteins Hit All Dimensions of Gene Regulation.},
journal = {Genes},
volume = {6},
number = {3},
pages = {520-542},
pmid = {26184319},
issn = {2073-4425},
abstract = {Polycomb group (PcG) proteins contribute to the formation and maintenance of a specific repressive chromatin state that prevents the expression of genes in a particular space and time. Polycomb repressive complexes (PRCs) consist of several PcG proteins with specific regulatory or catalytic properties. PRCs are recruited to thousands of target genes, and various recruitment factors, including DNA-binding proteins and non-coding RNAs, are involved in the targeting. PcG proteins contribute to a multitude of biological processes by altering chromatin features at different scales. PcG proteins mediate both biochemical modifications of histone tails and biophysical modifications (e.g., chromatin fiber compaction and three-dimensional (3D) chromatin conformation). Here, we review the role of PcG proteins in nuclear architecture, describing their impact on the structure of the chromatin fiber, on chromatin interactions, and on the spatial organization of the genome in nuclei. Although little is known about the role of plant PcG proteins in nuclear organization, much is known in the animal field, and we highlight similarities and differences in the roles of PcG proteins in 3D gene regulation in plants and animals.},
}
@article {pmid26150425,
year = {2015},
author = {Wang, XT and Dong, PF and Zhang, HY and Peng, C},
title = {Structural heterogeneity and functional diversity of topologically associating domains in mammalian genomes.},
journal = {Nucleic acids research},
volume = {43},
number = {15},
pages = {7237-7246},
pmid = {26150425},
issn = {1362-4962},
mesh = {Animals ; Base Sequence ; Cell Line ; Chromatin/*chemistry ; DNA/chemistry ; Epigenesis, Genetic ; *Genome ; Genome, Human ; Humans ; Mice ; Transcription, Genetic ; },
abstract = {Recent chromosome conformation capture (3C) derived techniques have revealed that topologically associating domain (TAD) is a pervasive element in chromatin three-dimensional (3D) organization. However, there is currently no parameter to quantitatively measure the structural characteristics of TADs, thus obscuring our understanding on the structural and functional differences among TADs. Based on our finding that there exist intrinsic chromatin interaction patterns in TADs, we define a theoretical parameter, called aggregation preference (AP), to characterize TAD structures by capturing the interaction aggregation degree. Applying this defined parameter to 11 Hi-C data sets generated by both traditional and in situ Hi-C experimental pipelines, our analyses reveal that heterogeneous structures exist among TADs, and this structural heterogeneity is significantly correlated to DNA sequences, epigenomic signals and gene expressions. Although TADs can be stable in genomic positions across cell lines, structural comparisons show that a considerable number of stable TADs undergo significantly structural rearrangements during cell changes. Moreover, the structural change of TAD is tightly associated with its transcription remodeling. Altogether, the theoretical parameter defined in this work provides a quantitative method to link structural characteristics and biological functions of TADs, and this linkage implies that chromatin interaction pattern has the potential to mark transcription activity in TADs.},
}
@article {pmid26119342,
year = {2015},
author = {Hsieh, TH and Weiner, A and Lajoie, B and Dekker, J and Friedman, N and Rando, OJ},
title = {Mapping Nucleosome Resolution Chromosome Folding in Yeast by Micro-C.},
journal = {Cell},
volume = {162},
number = {1},
pages = {108-119},
pmid = {26119342},
issn = {1097-4172},
support = {HG003143/HG/NHGRI NIH HHS/United States ; //Howard Hughes Medical Institute/United States ; 340712/ERC_/European Research Council/International ; R01 GM079205/GM/NIGMS NIH HHS/United States ; R01 HG003143/HG/NHGRI NIH HHS/United States ; GM079205/GM/NIGMS NIH HHS/United States ; },
mesh = {Biochemistry/*methods ; Chromosomes, Fungal/*chemistry ; Nucleosomes/*chemistry ; Saccharomyces cerevisiae/*chemistry/genetics ; },
abstract = {We describe a Hi-C-based method, Micro-C, in which micrococcal nuclease is used instead of restriction enzymes to fragment chromatin, enabling nucleosome resolution chromosome folding maps. Analysis of Micro-C maps for budding yeast reveals abundant self-associating domains similar to those reported in other species, but not previously observed in yeast. These structures, far shorter than topologically associating domains in mammals, typically encompass one to five genes in yeast. Strong boundaries between self-associating domains occur at promoters of highly transcribed genes and regions of rapid histone turnover that are typically bound by the RSC chromatin-remodeling complex. Investigation of chromosome folding in mutants confirms roles for RSC, "gene looping" factor Ssu72, Mediator, H3K56 acetyltransferase Rtt109, and the N-terminal tail of H4 in folding of the yeast genome. This approach provides detailed structural maps of a eukaryotic genome, and our findings provide insights into the machinery underlying chromosome compaction.},
}
@article {pmid26030525,
year = {2015},
author = {Crane, E and Bian, Q and McCord, RP and Lajoie, BR and Wheeler, BS and Ralston, EJ and Uzawa, S and Dekker, J and Meyer, BJ},
title = {Condensin-driven remodelling of X chromosome topology during dosage compensation.},
journal = {Nature},
volume = {523},
number = {7559},
pages = {240-244},
pmid = {26030525},
issn = {1476-4687},
support = {R01 GM030702/GM/NIGMS NIH HHS/United States ; F32 GM100617/GM/NIGMS NIH HHS/United States ; R01 HG003143/HG/NHGRI NIH HHS/United States ; F32 GM100647/GM/NIGMS NIH HHS/United States ; S10RR029668/RR/NCRR NIH HHS/United States ; S10 RR029668/RR/NCRR NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; },
mesh = {Adenosine Triphosphatases/*metabolism ; Animals ; Caenorhabditis elegans/*genetics/*metabolism ; Caenorhabditis elegans Proteins/genetics/*metabolism ; DNA-Binding Proteins/*metabolism ; Dosage Compensation, Genetic/genetics/*physiology ; Female ; Gene Expression Regulation ; In Situ Hybridization, Fluorescence ; Male ; Multiprotein Complexes/*metabolism ; Protein Binding ; Sequence Analysis, RNA ; X Chromosome/genetics/*metabolism ; },
abstract = {The three-dimensional organization of a genome plays a critical role in regulating gene expression, yet little is known about the machinery and mechanisms that determine higher-order chromosome structure. Here we perform genome-wide chromosome conformation capture analysis, fluorescent in situ hybridization (FISH), and RNA-seq to obtain comprehensive three-dimensional (3D) maps of the Caenorhabditis elegans genome and to dissect X chromosome dosage compensation, which balances gene expression between XX hermaphrodites and XO males. The dosage compensation complex (DCC), a condensin complex, binds to both hermaphrodite X chromosomes via sequence-specific recruitment elements on X (rex sites) to reduce chromosome-wide gene expression by half. Most DCC condensin subunits also act in other condensin complexes to control the compaction and resolution of all mitotic and meiotic chromosomes. By comparing chromosome structure in wild-type and DCC-defective embryos, we show that the DCC remodels hermaphrodite X chromosomes into a sex-specific spatial conformation distinct from autosomes. Dosage-compensated X chromosomes consist of self-interacting domains (∼1 Mb) resembling mammalian topologically associating domains (TADs). TADs on X chromosomes have stronger boundaries and more regular spacing than on autosomes. Many TAD boundaries on X chromosomes coincide with the highest-affinity rex sites and become diminished or lost in DCC-defective mutants, thereby converting the topology of X to a conformation resembling autosomes. rex sites engage in DCC-dependent long-range interactions, with the most frequent interactions occurring between rex sites at DCC-dependent TAD boundaries. These results imply that the DCC reshapes the topology of X chromosomes by forming new TAD boundaries and reinforcing weak boundaries through interactions between its highest-affinity binding sites. As this model predicts, deletion of an endogenous rex site at a DCC-dependent TAD boundary using CRISPR/Cas9 greatly diminished the boundary. Thus, the DCC imposes a distinct higher-order structure onto X chromosomes while regulating gene expression chromosome-wide.},
}
@article {pmid26028501,
year = {2015},
author = {Cremer, T and Cremer, M and Hübner, B and Strickfaden, H and Smeets, D and Popken, J and Sterr, M and Markaki, Y and Rippe, K and Cremer, C},
title = {The 4D nucleome: Evidence for a dynamic nuclear landscape based on co-aligned active and inactive nuclear compartments.},
journal = {FEBS letters},
volume = {589},
number = {20 Pt A},
pages = {2931-2943},
doi = {10.1016/j.febslet.2015.05.037},
pmid = {26028501},
issn = {1873-3468},
mesh = {Animals ; Cell Nucleus/physiology/*ultrastructure ; Chromatin/*physiology/ultrastructure ; DNA Repair ; Gene Expression Regulation ; Humans ; Transcription, Genetic ; },
abstract = {Recent methodological advancements in microscopy and DNA sequencing-based methods provide unprecedented new insights into the spatio-temporal relationships between chromatin and nuclear machineries. We discuss a model of the underlying functional nuclear organization derived mostly from electron and super-resolved fluorescence microscopy studies. It is based on two spatially co-aligned, active and inactive nuclear compartments (ANC and INC). The INC comprises the compact, transcriptionally inactive core of chromatin domain clusters (CDCs). The ANC is formed by the transcriptionally active periphery of CDCs, called the perichromatin region (PR), and the interchromatin compartment (IC). The IC is connected to nuclear pores and serves nuclear import and export functions. The ANC is the major site of RNA synthesis. It is highly enriched in epigenetic marks for transcriptionally competent chromatin and RNA Polymerase II. Marks for silent chromatin are enriched in the INC. Multi-scale cross-correlation spectroscopy suggests that nuclear architecture resembles a random obstacle network for diffusing proteins. An increased dwell time of proteins and protein complexes within the ANC may help to limit genome scanning by factors or factor complexes to DNA exposed within the ANC.},
}
@article {pmid26013771,
year = {2015},
author = {Moore, BL and Aitken, S and Semple, CA},
title = {Integrative modeling reveals the principles of multi-scale chromatin boundary formation in human nuclear organization.},
journal = {Genome biology},
volume = {16},
number = {1},
pages = {110},
pmid = {26013771},
issn = {1474-760X},
support = {//Medical Research Council/United Kingdom ; },
mesh = {CCCTC-Binding Factor ; Cell Line ; Chromatin/*genetics ; DNA Replication Timing ; DNA-Binding Proteins/genetics ; Databases, Genetic ; Epigenesis, Genetic ; Genetic Loci ; Humans ; K562 Cells ; *Models, Molecular ; Multigene Family ; Repressor Proteins/genetics/metabolism ; },
abstract = {BACKGROUND: Interphase chromosomes adopt a hierarchical structure, and recent data have characterized their chromatin organization at very different scales, from sub-genic regions associated with DNA-binding proteins at the order of tens or hundreds of bases, through larger regions with active or repressed chromatin states, up to multi-megabase-scale domains associated with nuclear positioning, replication timing and other qualities. However, we have lacked detailed, quantitative models to understand the interactions between these different strata.<br><br>RESULTS: Here we collate large collections of matched locus-level chromatin features and Hi-C interaction data, representing higher-order organization, across three human cell types. We use quantitative modeling approaches to assess whether locus-level features are sufficient to explain higher-order structure, and identify the most influential underlying features. We identify structurally variable domains between cell types and examine the underlying features to discover a general association with cell-type-specific enhancer activity. We also identify the most prominent features marking the boundaries of two types of higher-order domains at different scales: topologically associating domains and nuclear compartments. We find parallel enrichments of particular chromatin features for both types, including features associated with active promoters and the architectural proteins CTCF and YY1.<br><br>CONCLUSIONS: We show that integrative modeling of large chromatin dataset collections using random forests can generate useful insights into chromosome structure. The models produced recapitulate known biological features of the cell types involved, allow exploration of the antecedents of higher-order structures and generate testable hypotheses for further experimental studies.},
}
@article {pmid26013116,
year = {2015},
author = {Shen, W and Wang, D and Ye, B and Shi, M and Zhang, Y and Zhao, Z},
title = {A possible role of Drosophila CTCF in mitotic bookmarking and maintaining chromatin domains during the cell cycle.},
journal = {Biological research},
volume = {48},
number = {1},
pages = {27},
pmid = {26013116},
issn = {0717-6287},
mesh = {Animals ; Base Sequence ; Binding Sites ; CCCTC-Binding Factor ; Cell Cycle/physiology ; Chromatin/*physiology ; Chromatin Assembly and Disassembly/physiology ; Computational Biology ; Conserved Sequence ; Datasets as Topic ; Drosophila Proteins/*physiology ; Drosophila melanogaster/*chemistry ; Genome, Insect/*genetics ; Interphase/physiology ; Mitosis/*physiology ; Molecular Sequence Annotation ; Repressor Proteins/*physiology ; Synteny ; },
abstract = {BACKGROUND: The CCCTC-binding factor (CTCF) is a highly conserved insulator protein that plays various roles in many cellular processes. CTCF is one of the main architecture proteins in higher eukaryotes, and in combination with other architecture proteins and regulators, also shapes the three-dimensional organization of a genome. Experiments show CTCF partially remains associated with chromatin during mitosis. However, the role of CTCF in the maintenance and propagation of genome architectures throughout the cell cycle remains elusive.<br><br>RESULTS: We performed a comprehensive bioinformatics analysis on public datasets of Drosophila CTCF (dCTCF). We characterized dCTCF-binding sites according to their occupancy status during the cell cycle, and identified three classes: interphase-mitosis-common (IM), interphase-only (IO) and mitosis-only (MO) sites. Integrated function analysis showed dCTCF-binding sites of different classes might be involved in different biological processes, and IM sites were more conserved and more intensely bound. dCTCF-binding sites of the same class preferentially localized closer to each other, and were highly enriched at chromatin syntenic and topologically associating domains boundaries.<br><br>CONCLUSIONS: Our results revealed different functions of dCTCF during the cell cycle and suggested that dCTCF might contribute to the establishment of the three-dimensional architecture of the Drosophila genome by maintaining local chromatin compartments throughout the whole cell cycle.},
}
@article {pmid26012375,
year = {2015},
author = {Le Dily, F and Beato, M},
title = {TADs as modular and dynamic units for gene regulation by hormones.},
journal = {FEBS letters},
volume = {589},
number = {20 Pt A},
pages = {2885-2892},
doi = {10.1016/j.febslet.2015.05.026},
pmid = {26012375},
issn = {1873-3468},
mesh = {Animals ; Chromatin/genetics ; *Gene Expression Regulation ; Hormones/*physiology ; Humans ; Nucleic Acid Conformation ; *Regulatory Sequences, Nucleic Acid ; },
abstract = {During cell differentiation epigenetic processes permit the establishment of a cell type specific transcriptome by limiting the fraction of the genome that will be expressed. Based upon steady-state requirements and transcription factor expression, differentiated cells respond transiently to external cues by modulating the expression levels of subsets of genes. Increasing evidence demonstrates that the genome is organized non-randomly in a hierarchy of structures within the nuclear space, where chromosome territories are segmented into Topologically Associating Domains (TADs) and sub-domains. It remains poorly understood how this three-dimensional organization of the genome participates in the acquisition of a cell-specific program of gene expression. Furthermore, it is unknown whether this spatial framework influences the dynamic changes of gene expression that accompany alterations in the cell environment. In this review, we will discuss the impact of genome topology on the response of breast cancer cells to steroid hormones. We will cover steroid nuclear receptor mechanisms of action and discuss how topological organization of the genome, including segmentation into TADs, acts as a combinatorial platform to integrate signals whilst ultimately ensuring coordinate regulation of gene expression.},
}
@article {pmid26008126,
year = {2015},
author = {Cubeñas-Potts, C and Corces, VG},
title = {Architectural proteins, transcription, and the three-dimensional organization of the genome.},
journal = {FEBS letters},
volume = {589},
number = {20 Pt A},
pages = {2923-2930},
pmid = {26008126},
issn = {1873-3468},
support = {R01 GM035463/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Binding Sites ; Chromatin/physiology/ultrastructure ; DNA-Binding Proteins/physiology ; *Epigenesis, Genetic ; Genome, Human ; Humans ; Nucleic Acid Conformation ; Protein Binding ; Regulatory Sequences, Nucleic Acid ; *Transcription, Genetic ; },
abstract = {Architectural proteins mediate interactions between distant sequences in the genome. Two well-characterized functions of architectural protein interactions include the tethering of enhancers to promoters and bringing together Polycomb-containing sites to facilitate silencing. The nature of which sequences interact genome-wide appears to be determined by the orientation of the architectural protein binding sites as well as the number and identity of architectural proteins present. Ultimately, long range chromatin interactions result in the formation of loops within the chromatin fiber. In this review, we discuss data suggesting that architectural proteins mediate long range chromatin interactions that both facilitate and hinder neighboring interactions, compartmentalizing the genome into regions of highly interacting chromatin domains.},
}
@article {pmid25995270,
year = {2015},
author = {Dileep, V and Ay, F and Sima, J and Vera, DL and Noble, WS and Gilbert, DM},
title = {Topologically associating domains and their long-range contacts are established during early G1 coincident with the establishment of the replication-timing program.},
journal = {Genome research},
volume = {25},
number = {8},
pages = {1104-1113},
pmid = {25995270},
issn = {1549-5469},
support = {AI106775/AI/NIAID NIH HHS/United States ; R01 AI106775/AI/NIAID NIH HHS/United States ; HG00700/HG/NHGRI NIH HHS/United States ; P01 GM085354/GM/NIGMS NIH HHS/United States ; GM085354/GM/NIGMS NIH HHS/United States ; R01 GM083337/GM/NIGMS NIH HHS/United States ; GM083337/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Cell Line ; Chromatin/*chemistry/*genetics ; Chromatin Assembly and Disassembly ; *DNA Replication Timing ; Epithelial Cells/cytology ; *G1 Phase ; Gene Expression Regulation, Developmental ; Genome ; Mice ; Sequence Analysis, DNA/methods ; },
abstract = {Mammalian genomes are partitioned into domains that replicate in a defined temporal order. These domains can replicate at similar times in all cell types (constitutive) or at cell type-specific times (developmental). Genome-wide chromatin conformation capture (Hi-C) has revealed sub-megabase topologically associating domains (TADs), which are the structural counterparts of replication domains. Hi-C also segregates inter-TAD contacts into defined 3D spatial compartments that align precisely to genome-wide replication timing profiles. Determinants of the replication-timing program are re-established during early G1 phase of each cell cycle and lost in G2 phase, but it is not known when TAD structure and inter-TAD contacts are re-established after their elimination during mitosis. Here, we use multiplexed 4C-seq to study dynamic changes in chromatin organization during early G1. We find that both establishment of TADs and their compartmentalization occur during early G1, within the same time frame as establishment of the replication-timing program. Once established, this 3D organization is preserved either after withdrawal into quiescence or for the remainder of interphase including G2 phase, implying 3D structure is not sufficient to maintain replication timing. Finally, we find that developmental domains are less well compartmentalized than constitutive domains and display chromatin properties that distinguish them from early and late constitutive domains. Overall, this study uncovers a strong connection between chromatin re-organization during G1, establishment of replication timing, and its developmental control.},
}
@article {pmid25918364,
year = {2015},
author = {Zhang, B and Wolynes, PG},
title = {Topology, structures, and energy landscapes of human chromosomes.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {112},
number = {19},
pages = {6062-6067},
pmid = {25918364},
issn = {1091-6490},
mesh = {Cell Differentiation ; Chromatin/chemistry ; Chromosomes/chemistry ; Chromosomes, Human/*chemistry ; DNA/chemistry ; Gene Expression Regulation ; Genome, Human ; Humans ; Interphase/genetics ; Models, Molecular ; Molecular Conformation ; Probability ; Thermodynamics ; },
abstract = {Chromosome conformation capture experiments provide a rich set of data concerning the spatial organization of the genome. We use these data along with a maximum entropy approach to derive a least-biased effective energy landscape for the chromosome. Simulations of the ensemble of chromosome conformations based on the resulting information theoretic landscape not only accurately reproduce experimental contact probabilities, but also provide a picture of chromosome dynamics and topology. The topology of the simulated chromosomes is probed by computing the distribution of their knot invariants. The simulated chromosome structures are largely free of knots. Topologically associating domains are shown to be crucial for establishing these knotless structures. The simulated chromosome conformations exhibit a tendency to form fibril-like structures like those observed via light microscopy. The topologically associating domains of the interphase chromosome exhibit multistability with varying liquid crystalline ordering that may allow discrete unfolding events and the landscape is locally funneled toward "ideal" chromosome structures that represent hierarchical fibrils of fibrils.},
}
@article {pmid25913784,
year = {2015},
author = {Lonfat, N and Duboule, D},
title = {Structure, function and evolution of topologically associating domains (TADs) at HOX loci.},
journal = {FEBS letters},
volume = {589},
number = {20 Pt A},
pages = {2869-2876},
doi = {10.1016/j.febslet.2015.04.024},
pmid = {25913784},
issn = {1873-3468},
mesh = {Animals ; Embryonic Development ; Evolution, Molecular ; Gene Expression Regulation, Developmental ; Genetic Loci ; Genetic Pleiotropy ; Homeodomain Proteins/*genetics ; Humans ; Multigene Family ; Organ Specificity ; },
abstract = {Hox genes encode transcription factors necessary for patterning the major developing anterior to posterior embryonic axis. In addition, during vertebrate evolution, various subsets of this gene family were co-opted along with the emergence of novel body structures, such as the limbs or the external genitalia. The morphogenesis of these axial structures thus relies in part upon the precisely controlled transcription of specific Hox genes, a mechanism involving multiple long-range enhancers. Recently, it was reported that such regulatory mechanisms were largely shared between different developing tissues, though with some specificities, suggesting the recruitment of ancestral regulatory modalities from one tissue to another. The analysis of chromatin architectures at HoxD and HoxA loci revealed the existence of two flanking topologically associating domains (TADs), precisely encompassing the adjacent regulatory landscapes. Here, we discuss the function of these TADs in the control of Hox gene regulation and we speculate about their capacity to serve as structural frameworks for the emergence of novel enhancers. In this view, TADs may have been used as genomic niches to evolve pleiotropic regulations found at many developmental loci.},
}
@article {pmid25855284,
year = {2015},
author = {Umlauf, D},
title = {[The intimate genome… in three dimensions].},
journal = {Medecine sciences : M/S},
volume = {31},
number = {3},
pages = {304-311},
doi = {10.1051/medsci/20153103016},
pmid = {25855284},
issn = {0767-0974},
mesh = {Animals ; Chromosomes/*chemistry ; *Genome ; Humans ; *Imaging, Three-Dimensional ; *Molecular Conformation ; Oligonucleotide Array Sequence Analysis/methods ; },
abstract = {Over the past decade, techniques based on chromosome conformation capture (3C) have accelerated our understanding of eukaryote's nuclear architecture. Coupled to high throughput sequencing and bioinformatics they have unveiled different organizational levels of the genome at an unprecedented scale. Initially performed using large populations of cells, a new variant of these techniques can be applied to single cell. Although it can be shown that chromosome folding varies from one cell to the other, their overall organization into topologically associating domains is conserved between cells of the same population. Interestingly, the predicted chromosome structures reveal that regions engaged in trans-chromosomal interactions are preferentially localized at the surface of the chromosome territory. These results confirm and extend previous observations on individual loci therefore highlighting the power of 3C based techniques.},
}
@article {pmid25818644,
year = {2015},
author = {Li, L and Lyu, X and Hou, C and Takenaka, N and Nguyen, HQ and Ong, CT and Cubeñas-Potts, C and Hu, M and Lei, EP and Bosco, G and Qin, ZS and Corces, VG},
title = {Widespread rearrangement of 3D chromatin organization underlies polycomb-mediated stress-induced silencing.},
journal = {Molecular cell},
volume = {58},
number = {2},
pages = {216-231},
pmid = {25818644},
issn = {1097-4164},
support = {R01 GM035463/GM/NIGMS NIH HHS/United States ; R01 HG005119/HG/NHGRI NIH HHS/United States ; P30 CA023108/CA/NCI NIH HHS/United States ; //Intramural NIH HHS/United States ; DK015602/DK/NIDDK NIH HHS/United States ; R01 GM069462/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Cell Line ; Chromatin/*genetics ; Chromosomes/*genetics ; Drosophila Proteins/chemistry/*genetics/metabolism ; Drosophila melanogaster/*genetics/metabolism ; Enhancer Elements, Genetic ; Molecular Sequence Data ; Polycomb-Group Proteins/chemistry/genetics/*metabolism ; Promoter Regions, Genetic ; Regulatory Sequences, Nucleic Acid ; Stress, Physiological ; Temperature ; },
abstract = {Chromosomes of metazoan organisms are partitioned in the interphase nucleus into discrete topologically associating domains (TADs). Borders between TADs are formed in regions containing active genes and clusters of architectural protein binding sites. The transcription of most genes is repressed after temperature stress in Drosophila. Here we show that temperature stress induces relocalization of architectural proteins from TAD borders to inside TADs, and this is accompanied by a dramatic rearrangement in the 3D organization of the nucleus. TAD border strength declines, allowing for an increase in long-distance inter-TAD interactions. Similar but quantitatively weaker effects are observed upon inhibition of transcription or depletion of individual architectural proteins. Heat shock-induced inter-TAD interactions result in increased contacts among enhancers and promoters of silenced genes, which recruit Pc and form Pc bodies in the nucleolus. These results suggest that the TAD organization of metazoan genomes is plastic and can be reconfigured quickly.},
}
@article {pmid25800747,
year = {2015},
author = {Trussart, M and Serra, F and Baù, D and Junier, I and Serrano, L and Marti-Renom, MA},
title = {Assessing the limits of restraint-based 3D modeling of genomes and genomic domains.},
journal = {Nucleic acids research},
volume = {43},
number = {7},
pages = {3465-3477},
pmid = {25800747},
issn = {1362-4962},
support = {232913/ERC_/European Research Council/International ; 609989/ERC_/European Research Council/International ; },
mesh = {*Genome ; *Models, Genetic ; },
abstract = {Restraint-based modeling of genomes has been recently explored with the advent of Chromosome Conformation Capture (3C-based) experiments. We previously developed a reconstruction method to resolve the 3D architecture of both prokaryotic and eukaryotic genomes using 3C-based data. These models were congruent with fluorescent imaging validation. However, the limits of such methods have not systematically been assessed. Here we propose the first evaluation of a mean-field restraint-based reconstruction of genomes by considering diverse chromosome architectures and different levels of data noise and structural variability. The results show that: first, current scoring functions for 3D reconstruction correlate with the accuracy of the models; second, reconstructed models are robust to noise but sensitive to structural variability; third, the local structure organization of genomes, such as Topologically Associating Domains, results in more accurate models; fourth, to a certain extent, the models capture the intrinsic structural variability in the input matrices and fifth, the accuracy of the models can be a priori predicted by analyzing the properties of the interaction matrices. In summary, our work provides a systematic analysis of the limitations of a mean-field restrain-based method, which could be taken into consideration in further development of methods as well as their applications.},
}
@article {pmid25764331,
year = {2014},
author = {Shibayama, Y and Fanucchi, S and Magagula, L and Mhlanga, MM},
title = {lncRNA and gene looping: what's the connection?.},
journal = {Transcription},
volume = {5},
number = {3},
pages = {e28658},
pmid = {25764331},
issn = {2154-1272},
mesh = {CCCTC-Binding Factor ; Cell Cycle Proteins/metabolism ; Chromatin/*metabolism ; Chromosomal Proteins, Non-Histone/metabolism ; Enhancer Elements, Genetic ; *Gene Expression Regulation ; Humans ; RNA, Long Noncoding/*metabolism ; Repressor Proteins/metabolism ; Transcription Initiation, Genetic ; },
abstract = {Recent functional studies have unveiled the significant role chromatin topology plays in gene regulation. Several lines of evidence suggest genes access necessary factors for transcription by forming chromatin loops. A clearer picture of the players involved in chromatin organization, including lncRNA, is emerging.},
}
@article {pmid25563431,
year = {2015},
author = {Maeshima, K and Kaizu, K and Tamura, S and Nozaki, T and Kokubo, T and Takahashi, K},
title = {The physical size of transcription factors is key to transcriptional regulation in chromatin domains.},
journal = {Journal of physics. Condensed matter : an Institute of Physics journal},
volume = {27},
number = {6},
pages = {064116},
doi = {10.1088/0953-8984/27/6/064116},
pmid = {25563431},
issn = {1361-648X},
mesh = {Chromatin/*chemistry/genetics/*metabolism ; *Gene Expression Regulation ; Models, Molecular ; Molecular Weight ; *Monte Carlo Method ; Protein Structure, Tertiary ; Transcription Factors/*chemistry/*metabolism ; *Transcription, Genetic ; Transcriptional Activation ; },
abstract = {Genetic information, which is stored in the long strand of genomic DNA as chromatin, must be scanned and read out by various transcription factors. First, gene-specific transcription factors, which are relatively small (∼50 kDa), scan the genome and bind regulatory elements. Such factors then recruit general transcription factors, Mediators, RNA polymerases, nucleosome remodellers, and histone modifiers, most of which are large protein complexes of 1-3 MDa in size. Here, we propose a new model for the functional significance of the size of transcription factors (or complexes) for gene regulation of chromatin domains. Recent findings suggest that chromatin consists of irregularly folded nucleosome fibres (10 nm fibres) and forms numerous condensed domains (e.g., topologically associating domains). Although the flexibility and dynamics of chromatin allow repositioning of genes within the condensed domains, the size exclusion effect of the domain may limit accessibility of DNA sequences by transcription factors. We used Monte Carlo computer simulations to determine the physical size limit of transcription factors that can enter condensed chromatin domains. Small gene-specific transcription factors can penetrate into the chromatin domains and search their target sequences, whereas large transcription complexes cannot enter the domain. Due to this property, once a large complex binds its target site via gene-specific factors it can act as a 'buoy' to keep the target region on the surface of the condensed domain and maintain transcriptional competency. This size-dependent specialization of target-scanning and surface-tethering functions could provide novel insight into the mechanisms of various DNA transactions, such as DNA replication and repair/recombination.},
}
@article {pmid25555574,
year = {2015},
author = {Giorgetti, L and Piolot, T and Heard, E},
title = {High-resolution 3D DNA FISH using plasmid probes and computational correction of optical aberrations to study chromatin structure at the sub-megabase scale.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1262},
number = {},
pages = {37-53},
doi = {10.1007/978-1-4939-2253-6_3},
pmid = {25555574},
issn = {1940-6029},
mesh = {Cells, Cultured ; Chromatin/*genetics ; DNA Probes ; Embryonic Stem Cells ; Humans ; Image Interpretation, Computer-Assisted/*methods ; Imaging, Three-Dimensional ; In Situ Hybridization, Fluorescence/*methods ; Plasmids/*genetics ; },
abstract = {Characterizing the three-dimensional organization of chromosomes is a fundamental goal in molecular biology and will be critical to understand how gene expression is regulated by distal regulatory sequences such as enhancers. Chromosome conformation capture (3C) techniques have recently revealed that the interactions between regulatory elements appear to occur in the context of topologically associating domains (TADs), each spanning few hundreds kilobases, within which the chromatin fiber preferentially interacts. However, 3C-based data represent average interaction probabilities of the chromatin fiber over millions of cells. To understand how variable chromatin conformation is within each TAD, one needs to employ single-cell techniques such as 3D DNA FISH. Given the small size of TADs however (typically <1 Mb), classical DNA FISH design needs to be adapted to achieve high genomic and spatial resolution. Here, we describe a high-resolution 3D DNA FISH approach we recently developed, based on a combination of short plasmid probes and computational correction of optical aberrations. We describe probe design and generation and the 3D DNA FISH procedure. We further discuss how to optimize microscope settings and to implement calibration-bead-assisted computational corrections in order to achieve 50 nm resolution in two-color distance measurements between probes that can be as close as 50 kb along the genome.},
}
@article {pmid25437046,
year = {2014},
author = {Duttke, SH},
title = {Meeting report: 11th EMBL conference on transcription and chromatin - August 23-26, 2014 - Heidelberg, Germany.},
journal = {Epigenetics},
volume = {9},
number = {10},
pages = {1317-1321},
pmid = {25437046},
issn = {1559-2308},
support = {R01GM041249/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Chromatin/*genetics ; Circadian Rhythm ; Congresses as Topic ; DNA Methylation ; Enhancer Elements, Genetic ; Germany ; Heterochromatin/genetics ; Histones/metabolism ; Humans ; Nucleosomes/metabolism ; Promoter Regions, Genetic ; *Transcription, Genetic ; },
}
@article {pmid25409831,
year = {2014},
author = {Pope, BD and Ryba, T and Dileep, V and Yue, F and Wu, W and Denas, O and Vera, DL and Wang, Y and Hansen, RS and Canfield, TK and Thurman, RE and Cheng, Y and Gülsoy, G and Dennis, JH and Snyder, MP and Stamatoyannopoulos, JA and Taylor, J and Hardison, RC and Kahveci, T and Ren, B and Gilbert, DM},
title = {Topologically associating domains are stable units of replication-timing regulation.},
journal = {Nature},
volume = {515},
number = {7527},
pages = {402-405},
pmid = {25409831},
issn = {1476-4687},
support = {HG003991/HG/NHGRI NIH HHS/United States ; F31 CA165863/CA/NCI NIH HHS/United States ; DK065806/DK/NIDDK NIH HHS/United States ; RC2 HG005573/HG/NHGRI NIH HHS/United States ; R56 DK065806/DK/NIDDK NIH HHS/United States ; HG005573/HG/NHGRI NIH HHS/United States ; F31CA165863/CA/NCI NIH HHS/United States ; P01 GM085354/GM/NIGMS NIH HHS/United States ; R01 DA033775/DA/NIDA NIH HHS/United States ; GM085354/GM/NIGMS NIH HHS/United States ; HG005602/HG/NHGRI NIH HHS/United States ; R01 DK065806/DK/NIDDK NIH HHS/United States ; U54 HG006997/HG/NHGRI NIH HHS/United States ; R01 GM083337/GM/NIGMS NIH HHS/United States ; R01 HG003991/HG/NHGRI NIH HHS/United States ; GM083337/GM/NIGMS NIH HHS/United States ; RC2 HG005602/HG/NHGRI NIH HHS/United States ; },
mesh = {Animals ; Cell Compartmentation ; Chromatin/*chemistry/*genetics/metabolism ; Chromatin Assembly and Disassembly ; DNA/*biosynthesis/genetics ; *DNA Replication Timing ; Genome/genetics ; Heterochromatin/chemistry/genetics/metabolism ; Humans ; Mice ; Organ Specificity ; Time Factors ; },
abstract = {Eukaryotic chromosomes replicate in a temporal order known as the replication-timing program. In mammals, replication timing is cell-type-specific with at least half the genome switching replication timing during development, primarily in units of 400-800 kilobases ('replication domains'), whose positions are preserved in different cell types, conserved between species, and appear to confine long-range effects of chromosome rearrangements. Early and late replication correlate, respectively, with open and closed three-dimensional chromatin compartments identified by high-resolution chromosome conformation capture (Hi-C), and, to a lesser extent, late replication correlates with lamina-associated domains (LADs). Recent Hi-C mapping has unveiled substructure within chromatin compartments called topologically associating domains (TADs) that are largely conserved in their positions between cell types and are similar in size to replication domains. However, TADs can be further sub-stratified into smaller domains, challenging the significance of structures at any particular scale. Moreover, attempts to reconcile TADs and LADs to replication-timing data have not revealed a common, underlying domain structure. Here we localize boundaries of replication domains to the early-replicating border of replication-timing transitions and map their positions in 18 human and 13 mouse cell types. We demonstrate that, collectively, replication domain boundaries share a near one-to-one correlation with TAD boundaries, whereas within a cell type, adjacent TADs that replicate at similar times obscure replication domain boundaries, largely accounting for the previously reported lack of alignment. Moreover, cell-type-specific replication timing of TADs partitions the genome into two large-scale sub-nuclear compartments revealing that replication-timing transitions are indistinguishable from late-replicating regions in chromatin composition and lamina association and accounting for the reduced correlation of replication timing to LADs and heterochromatin. Our results reconcile cell-type-specific sub-nuclear compartmentalization and replication timing with developmentally stable structural domains and offer a unified model for large-scale chromosome structure and function.},
}
@article {pmid25367294,
year = {2015},
author = {Wang, C and Liu, C and Roqueiro, D and Grimm, D and Schwab, R and Becker, C and Lanz, C and Weigel, D},
title = {Genome-wide analysis of local chromatin packing in Arabidopsis thaliana.},
journal = {Genome research},
volume = {25},
number = {2},
pages = {246-256},
pmid = {25367294},
issn = {1549-5469},
mesh = {Arabidopsis/*genetics/*metabolism ; Chromatin/*metabolism ; *Chromatin Assembly and Disassembly ; Cluster Analysis ; Computational Biology/methods ; Epigenesis, Genetic ; Genome, Plant ; *Genomics/methods ; Histones/metabolism ; Insulator Elements ; },
abstract = {The spatial arrangement of interphase chromosomes in the nucleus is important for gene expression and genome function in animals and in plants. The recently developed Hi-C technology is an efficacious method to investigate genome packing. Here we present a detailed Hi-C map of the three-dimensional genome organization of the plant Arabidopsis thaliana. We find that local chromatin packing differs from the patterns seen in animals, with kilobasepair-sized segments that have much higher intrachromosome interaction rates than neighboring regions, representing a dominant local structural feature of genome conformation in A. thaliana. These regions, which appear as positive strips on two-dimensional representations of chromatin interaction, are enriched in epigenetic marks H3K27me3, H3.1, and H3.3. We also identify more than 400 insulator-like regions. Furthermore, although topologically associating domains (TADs), which are prominent in animals, are not an obvious feature of A. thaliana genome packing, we found more than 1000 regions that have properties of TAD boundaries, and a similar number of regions analogous to the interior of TADs. The insulator-like, TAD-boundary-like, and TAD-interior-like regions are each enriched for distinct epigenetic marks and are each correlated with different gene expression levels. We conclude that epigenetic modifications, gene density, and transcriptional activity combine to shape the local packing of the A. thaliana nuclear genome.},
}
@article {pmid25280896,
year = {2015},
author = {Ciabrelli, F and Cavalli, G},
title = {Chromatin-driven behavior of topologically associating domains.},
journal = {Journal of molecular biology},
volume = {427},
number = {3},
pages = {608-625},
doi = {10.1016/j.jmb.2014.09.013},
pmid = {25280896},
issn = {1089-8638},
support = {232947/ERC_/European Research Council/International ; },
mesh = {Animals ; Cell Nucleus/*genetics ; Chromatin/*genetics ; *Epigenomics ; *Genome ; Humans ; },
abstract = {Metazoan genomes are highly organized inside the cell nucleus. Topologically associating domains (TADs) represent the building blocks of genome organization, but their linear modularity does not explain alone their spatial organization. Indeed, the chromatin type adorning a TAD can shape its structure and drives its nuclear positioning and its function. Genome-wide association studies revealed mainly four chromatin types: active chromatin, Polycomb-repressed chromatin, null chromatin and constitutive heterochromatin. In this review, we will describe the main three-dimensional features of each chromatin type and finally their relationships with TAD organization and epigenetic memory.},
}
@article {pmid25274727,
year = {2014},
author = {Le Dily, F and Baù, D and Pohl, A and Vicent, GP and Serra, F and Soronellas, D and Castellano, G and Wright, RH and Ballare, C and Filion, G and Marti-Renom, MA and Beato, M},
title = {Distinct structural transitions of chromatin topological domains correlate with coordinated hormone-induced gene regulation.},
journal = {Genes &amp; development},
volume = {28},
number = {19},
pages = {2151-2162},
pmid = {25274727},
issn = {1549-5477},
mesh = {Cell Line, Tumor ; Chromatin/chemistry/*drug effects ; Chromatin Assembly and Disassembly/drug effects ; Gene Expression Regulation/*drug effects ; Hormones/pharmacology ; Humans ; Progestins/*pharmacology ; },
abstract = {The human genome is segmented into topologically associating domains (TADs), but the role of this conserved organization during transient changes in gene expression is not known. Here we describe the distribution of progestin-induced chromatin modifications and changes in transcriptional activity over TADs in T47D breast cancer cells. Using ChIP-seq (chromatin immunoprecipitation combined with high-throughput sequencing), Hi-C (chromosome capture followed by high-throughput sequencing), and three-dimensional (3D) modeling techniques, we found that the borders of the ∼ 2000 TADs in these cells are largely maintained after hormone treatment and that up to 20% of the TADs could be considered as discrete regulatory units where the majority of the genes are either transcriptionally activated or repressed in a coordinated fashion. The epigenetic signatures of the TADs are homogeneously modified by hormones in correlation with the transcriptional changes. Hormone-induced changes in gene activity and chromatin remodeling are accompanied by differential structural changes for activated and repressed TADs, as reflected by specific and opposite changes in the strength of intra-TAD interactions within responsive TADs. Indeed, 3D modeling of the Hi-C data suggested that the structure of TADs was modified upon treatment. The differential responses of TADs to progestins and estrogens suggest that TADs could function as "regulons" to enable spatially proximal genes to be coordinately transcribed in response to hormones.},
}
@article {pmid24981874,
year = {2014},
author = {Van Bortle, K and Nichols, MH and Li, L and Ong, CT and Takenaka, N and Qin, ZS and Corces, VG},
title = {Insulator function and topological domain border strength scale with architectural protein occupancy.},
journal = {Genome biology},
volume = {15},
number = {6},
pages = {R82},
pmid = {24981874},
issn = {1474-760X},
support = {R01 GM035463/GM/NIGMS NIH HHS/United States ; T32 GM008367/GM/NIGMS NIH HHS/United States ; OD010949-10/OD/NIH HHS/United States ; R01GM035463/GM/NIGMS NIH HHS/United States ; T32 GM008490/GM/NIGMS NIH HHS/United States ; },
mesh = {Adenosine Triphosphatases/metabolism ; Animals ; Base Sequence ; Binding Sites ; CCCTC-Binding Factor ; Cell Cycle Proteins/metabolism ; Chromatin/genetics ; Chromatin Immunoprecipitation ; Chromosomal Proteins, Non-Histone/metabolism ; Chromosome Mapping ; Consensus Sequence ; DNA-Binding Proteins/metabolism ; Drosophila Proteins/physiology ; Drosophila melanogaster/*genetics ; *Genes, Insect ; Humans ; K562 Cells ; Mice ; Multigene Family ; Multiprotein Complexes/metabolism ; Protein Binding ; Repressor Proteins/genetics ; Transcription Factors, TFIII/physiology ; },
abstract = {BACKGROUND: Chromosome conformation capture studies suggest that eukaryotic genomes are organized into structures called topologically associating domains. The borders of these domains are highly enriched for architectural proteins with characterized roles in insulator function. However, a majority of architectural protein binding sites localize within topological domains, suggesting sites associated with domain borders represent a functionally different subclass of these regulatory elements. How topologically associating domains are established and what differentiates border-associated from non-border architectural protein binding sites remain unanswered questions.<br><br>RESULTS: By mapping the genome-wide target sites for several Drosophila architectural proteins, including previously uncharacterized profiles for TFIIIC and SMC-containing condensin complexes, we uncover an extensive pattern of colocalization in which architectural proteins establish dense clusters at the borders of topological domains. Reporter-based enhancer-blocking insulator activity as well as endogenous domain border strength scale with the occupancy level of architectural protein binding sites, suggesting co-binding by architectural proteins underlies the functional potential of these loci. Analyses in mouse and human stem cells suggest that clustering of architectural proteins is a general feature of genome organization, and conserved architectural protein binding sites may underlie the tissue-invariant nature of topologically associating domains observed in mammals.<br><br>CONCLUSIONS: We identify a spectrum of architectural protein occupancy that scales with the topological structure of chromosomes and the regulatory potential of these elements. Whereas high occupancy architectural protein binding sites associate with robust partitioning of topologically associating domains and robust insulator function, low occupancy sites appear reserved for gene-specific regulation within topological domains.},
}
@article {pmid24813616,
year = {2014},
author = {Giorgetti, L and Galupa, R and Nora, EP and Piolot, T and Lam, F and Dekker, J and Tiana, G and Heard, E},
title = {Predictive polymer modeling reveals coupled fluctuations in chromosome conformation and transcription.},
journal = {Cell},
volume = {157},
number = {4},
pages = {950-963},
pmid = {24813616},
issn = {1097-4172},
support = {R01 HG003143/HG/NHGRI NIH HHS/United States ; R01HG003143/HG/NHGRI NIH HHS/United States ; },
mesh = {Animals ; Chromatin/chemistry ; Chromosomes/*chemistry ; Female ; In Situ Hybridization, Fluorescence ; Male ; Mice ; Models, Biological ; Models, Molecular ; RNA, Long Noncoding/metabolism ; *Transcription, Genetic ; *X Chromosome Inactivation ; },
abstract = {A new level of chromosome organization, topologically associating domains (TADs), was recently uncovered by chromosome conformation capture (3C) techniques. To explore TAD structure and function, we developed a polymer model that can extract the full repertoire of chromatin conformations within TADs from population-based 3C data. This model predicts actual physical distances and to what extent chromosomal contacts vary between cells. It also identifies interactions within single TADs that stabilize boundaries between TADs and allows us to identify and genetically validate key structural elements within TADs. Combining the model's predictions with high-resolution DNA FISH and quantitative RNA FISH for TADs within the X-inactivation center (Xic), we dissect the relationship between transcription and spatial proximity to cis-regulatory elements. We demonstrate that contacts between potential regulatory elements occur in the context of fluctuating structures rather than stable loops and propose that such fluctuations may contribute to asymmetric expression in the Xic during X inactivation.},
}
@article {pmid24614316,
year = {2014},
author = {Ong, CT and Corces, VG},
title = {CTCF: an architectural protein bridging genome topology and function.},
journal = {Nature reviews. Genetics},
volume = {15},
number = {4},
pages = {234-246},
pmid = {24614316},
issn = {1471-0064},
support = {R01 GM035463/GM/NIGMS NIH HHS/United States ; },
mesh = {Alternative Splicing ; Animals ; Base Sequence ; CCCTC-Binding Factor ; Chromatin/metabolism ; Consensus Sequence ; Epigenesis, Genetic ; *Genome ; Humans ; Models, Molecular ; Multigene Family ; Nucleic Acid Conformation ; Promoter Regions, Genetic ; Protein Binding ; Recombination, Genetic ; Repressor Proteins/*physiology ; Transcription, Genetic ; },
abstract = {The eukaryotic genome is organized in the three-dimensional nuclear space in a specific manner that is both a cause and a consequence of its function. This organization is partly established by a special class of architectural proteins, of which CCCTC-binding factor (CTCF) is the best characterized. Although CTCF has been assigned various roles that are often contradictory, new results now help to draw a unifying model to explain the many functions of this protein. CTCF creates boundaries between topologically associating domains in chromosomes and, within these domains, facilitates interactions between transcription regulatory sequences. Thus, CTCF links the architecture of the genome to its function.},
}
@article {pmid24486021,
year = {2014},
author = {Liang, J and Lacroix, L and Gamot, A and Cuddapah, S and Queille, S and Lhoumaud, P and Lepetit, P and Martin, PG and Vogelmann, J and Court, F and Hennion, M and Micas, G and Urbach, S and Bouchez, O and Nöllmann, M and Zhao, K and Emberly, E and Cuvier, O},
title = {Chromatin immunoprecipitation indirect peaks highlight long-range interactions of insulator proteins and Pol II pausing.},
journal = {Molecular cell},
volume = {53},
number = {4},
pages = {672-681},
pmid = {24486021},
issn = {1097-4164},
support = {260787/ERC_/European Research Council/International ; R01 ES023174/ES/NIEHS NIH HHS/United States ; ZIA HL005801-07/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Animals ; Binding Sites ; CCCTC-Binding Factor ; Chromatin Immunoprecipitation/*methods ; DNA-Binding Proteins/metabolism ; Drosophila Proteins/metabolism ; Drosophila melanogaster ; Eye Proteins/metabolism ; *Gene Expression Regulation ; Gene Regulatory Networks ; Insulator Elements/*physiology ; Mutation ; Promoter Regions, Genetic ; Protein Binding ; Protein Interaction Mapping ; RNA Interference ; RNA Polymerase II/*metabolism ; Repressor Proteins/metabolism ; Transcription Factors/metabolism ; },
abstract = {Eukaryotic chromosomes are partitioned into topologically associating domains (TADs) that are demarcated by distinct insulator-binding proteins (IBPs) in Drosophila. Whether IBPs regulate specific long-range contacts and how this may impact gene expression remains unclear. Here we identify "indirect peaks" of multiple IBPs that represent their distant sites of interactions through long-range contacts. Indirect peaks depend on protein-protein interactions among multiple IBPs and their common cofactors, including CP190, as confirmed by high-resolution analyses of long-range contacts. Mutant IBPs unable to interact with CP190 impair long-range contacts as well as the expression of hundreds of distant genes that are specifically flanked by indirect peaks. Regulation of distant genes strongly correlates with RNAPII pausing, highlighting how this key transcriptional stage may trap insulator-based long-range interactions. Our data illustrate how indirect peaks may decipher gene regulatory networks through specific long-range interactions.},
}
@article {pmid24434548,
year = {2014},
author = {Cheutin, T and Cavalli, G},
title = {Polycomb silencing: from linear chromatin domains to 3D chromosome folding.},
journal = {Current opinion in genetics &amp; development},
volume = {25},
number = {},
pages = {30-37},
doi = {10.1016/j.gde.2013.11.016},
pmid = {24434548},
issn = {1879-0380},
support = {232947/ERC_/European Research Council/International ; },
mesh = {Animals ; Chromatin/*chemistry ; Chromosomes/*chemistry ; Gene Expression Regulation ; Gene Silencing ; Histones/metabolism ; Humans ; Polycomb-Group Proteins/genetics/*metabolism ; },
abstract = {Polycomb group (PcG) proteins are conserved chromatin factors that regulate key developmental genes. Genome wide studies have shown that PcG proteins and their associated H3K27me3 histone mark cover long genomic domains. PcG proteins and H3K27me3 accumulate in Pc nuclear foci, which are the cellular counterparts of genomic domains silenced by PcG proteins. One explanation for how large genomic domains form nuclear foci may rely on loops occurring between specific elements located within domains. However, recent improvement of the chromosome conformation capture (3C) technology, which allowed monitoring genome wide contacts depicts a more complex picture in which chromosomes are composed of many topologically associating domains (TADs). Chromatin regions marked with H3K27me3 correspond to one class of TADs and PcG proteins participate in long-range interactions of H3K27me3 TADs, whereas insulator proteins seem to be important for separating TADs and may also participate in the regulation of intra TAD architecture. Recent data converge to suggest that this hierarchical organization of chromosome domains plays an important role in genome function during cell proliferation and differentiation.},
}
@article {pmid26054763,
year = {2015},
author = {Perkel, J},
title = {MAPPING CHROMOSOME NEIGHBORHOODS.},
journal = {BioTechniques},
volume = {58},
number = {6},
pages = {280-284},
doi = {10.2144/000114296},
pmid = {26054763},
issn = {1940-9818},
mesh = {Animals ; Chromosome Mapping/*methods ; Chromosomes/*chemistry/*genetics/metabolism ; Gene Expression Regulation ; Humans ; Models, Molecular ; },
abstract = {The discovery of topologically associating domains (TADs) changed the way researchers think about gene expression and chromosome structure. Jeffrey Perkel takes a closer look into these “chromosome neighborhoods."},
}
@article {pmid23832846,
year = {2013},
author = {Nora, EP and Dekker, J and Heard, E},
title = {Segmental folding of chromosomes: a basis for structural and regulatory chromosomal neighborhoods?.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {35},
number = {9},
pages = {818-828},
pmid = {23832846},
issn = {1521-1878},
support = {R01 HG003143/HG/NHGRI NIH HHS/United States ; },
mesh = {Animals ; Chromatin/*chemistry/*genetics ; DNA/genetics ; DNA Replication Timing ; Evolution, Molecular ; *Gene Expression Regulation ; Genome ; Humans ; Promoter Regions, Genetic ; Transcriptional Activation ; },
abstract = {We discuss here a series of testable hypotheses concerning the role of chromosome folding into topologically associating domains (TADs). Several lines of evidence suggest that segmental packaging of chromosomal neighborhoods may underlie features of chromatin that span large domains, such as heterochromatin blocks, association with the nuclear lamina and replication timing. By defining which DNA elements preferentially contact each other, the segmentation of chromosomes into TADs may also underlie many properties of long-range transcriptional regulation. Several observations suggest that TADs can indeed provide a structural basis to regulatory landscapes, by controlling enhancer sharing and allocation. We also discuss how TADs may shape the evolution of chromosomes, by causing maintenance of synteny over large chromosomal segments. Finally we suggest a series of experiments to challenge these ideas and provide concrete examples illustrating how they could be practically applied.},
}
@article {pmid23473598,
year = {2013},
author = {Gibcus, JH and Dekker, J},
title = {The hierarchy of the 3D genome.},
journal = {Molecular cell},
volume = {49},
number = {5},
pages = {773-782},
pmid = {23473598},
issn = {1097-4164},
support = {R01 HG003143/HG/NHGRI NIH HHS/United States ; U54 HG004592/HG/NHGRI NIH HHS/United States ; HG003143/HG/NHGRI NIH HHS/United States ; HG004592/HG/NHGRI NIH HHS/United States ; },
mesh = {Animals ; Cell Nucleus/metabolism ; Chromatin ; Chromosomes/genetics ; Gene Expression Regulation ; *Genome ; Humans ; Models, Biological ; },
abstract = {Mammalian genomes encode genetic information in their linear sequence, but appropriate expression of their genes requires chromosomes to fold into complex three-dimensional structures. Transcriptional control involves the establishment of physical connections among genes and regulatory elements, both along and between chromosomes. Recent technological innovations in probing the folding of chromosomes are providing new insights into the spatial organization of genomes and its role in gene regulation. It is emerging that folding of large complex chromosomes involves a hierarchy of structures, from chromatin loops that connect genes and enhancers to larger chromosomal domains and nuclear compartments. The larger these structures are along this hierarchy, the more stable they are within cells, while becoming more stochastic between cells. Here, we review the experimental and theoretical data on this hierarchy of structures and propose a key role for the recently discovered topologically associating domains.},
}
@article {pmid22495304,
year = {2012},
author = {Nora, EP and Lajoie, BR and Schulz, EG and Giorgetti, L and Okamoto, I and Servant, N and Piolot, T and van Berkum, NL and Meisig, J and Sedat, J and Gribnau, J and Barillot, E and Blüthgen, N and Dekker, J and Heard, E},
title = {Spatial partitioning of the regulatory landscape of the X-inactivation centre.},
journal = {Nature},
volume = {485},
number = {7398},
pages = {381-385},
pmid = {22495304},
issn = {1476-4687},
support = {R01 HG003143/HG/NHGRI NIH HHS/United States ; },
mesh = {Animals ; Cell Differentiation ; DNA, Intergenic/genetics ; Embryonic Stem Cells/cytology/metabolism ; Epigenesis, Genetic ; Epigenomics ; Female ; Fibroblasts ; Gene Expression Regulation ; Histones/metabolism ; In Situ Hybridization, Fluorescence ; Male ; Methylation ; Mice ; Molecular Sequence Data ; Promoter Regions, Genetic/genetics ; RNA, Long Noncoding ; RNA, Untranslated/*genetics ; Transcriptome ; X Chromosome/chemistry/*genetics ; X Chromosome Inactivation/*genetics ; },
abstract = {In eukaryotes transcriptional regulation often involves multiple long-range elements and is influenced by the genomic environment. A prime example of this concerns the mouse X-inactivation centre (Xic), which orchestrates the initiation of X-chromosome inactivation (XCI) by controlling the expression of the non-protein-coding Xist transcript. The extent of Xic sequences required for the proper regulation of Xist remains unknown. Here we use chromosome conformation capture carbon-copy (5C) and super-resolution microscopy to analyse the spatial organization of a 4.5-megabases (Mb) region including Xist. We discover a series of discrete 200-kilobase to 1 Mb topologically associating domains (TADs), present both before and after cell differentiation and on the active and inactive X. TADs align with, but do not rely on, several domain-wide features of the epigenome, such as H3K27me3 or H3K9me2 blocks and lamina-associated domains. TADs also align with coordinately regulated gene clusters. Disruption of a TAD boundary causes ectopic chromosomal contacts and long-range transcriptional misregulation. The Xist/Tsix sense/antisense unit illustrates how TADs enable the spatial segregation of oppositely regulated chromosomal neighbourhoods, with the respective promoters of Xist and Tsix lying in adjacent TADs, each containing their known positive regulators. We identify a novel distal regulatory region of Tsix within its TAD, which produces a long intervening RNA, Linx. In addition to uncovering a new principle of cis-regulatory architecture of mammalian chromosomes, our study sets the stage for the full genetic dissection of the X-inactivation centre.},
}