@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 = {RR190071//Cancer Prevention and Research Institute of Texas (Cancer Prevention Research Institute of Texas)/ ; DP2GM146336//U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ ; },
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 = {},
number = {},
pages = {},
doi = {10.1093/nar/gkac318},
pmid = {35524567},
issn = {1362-4962},
support = {NCN 2019/33/N/ST6/03110//National Science Centre/ ; //Foundation for Polish Science/ ; },
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},
support = {115200S001//Beijing Advanced Discipline Fund/ ; 2019FY100102//Special investigation on science and technology basic resources of the MOST, China/ ; XDA24020307//State Key Laboratory of Drug Research/ ; 31671342//National Natural Science Foundation of China/ ; 31871331//National Natural Science Foundation of China/ ; 91940304//National Natural Science Foundation of China/ ; 31802044//National Natural Science Foundation of China/ ; U19A2036//National Natural Science Foundation of China/ ; 31872335//National Natural Science Foundation of China/ ; 31772576//National Natural Science Foundation of China/ ; Z200021//Beijing Natural Science Foundation/ ; 2018YFC2000400//National Key R&D Program of China/ ; 2020YFA0509500//National Key R&D Program of China/ ; 2021YFYZ0009//Sichuan Science and Technology Program/ ; 2021YFYZ0030//Sichuan Science and Technology Program/ ; },
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},
support = {C59392/A25064//Cancer Research UK Career Development Fellowship/ ; SFF1920_CB_MSD_759707//The Clarendon Fund and St Edmund Hall Scholarship/ ; SFF2122_CSCUO_1284663 (No. 202108330024)//China Scholarship Council - University of Oxford Scholarship/ ; },
mesh = {*Chromatin ; Gene Expression Regulation ; Humans ; Male ; *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},
doi = {10.1016/j.celrep.2022.110769},
pmid = {35508135},
issn = {2211-1247},
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 = {},
doi = {10.1242/dev.200568},
pmid = {35502750},
issn = {1477-9129},
support = {DIM Biothrapies Fellowship//Region Ile-de-France/ ; FDT20160435295 Fellowship//Fondation pour la Recherche Medicale/ ; DEI20151234398//Labelisation La Ligue, FRM/ ; ANR-11-LBX-0044//ANR DoseX 2017, Labex DEEP/ ; ANR-10-IDEX-0001-02 PSL//IDEX PSL/ ; ANR-11-BINF-0001//ABS4NGS/ ; DIM Biothérapies Fellowship//Région Ile-de-France/ ; ERC-2014-AdG no. 671027 Advanced Investigator award/ERC_/European Research Council/International ; Labélisation//La Ligue contre le cancer/ ; DEI20151234398//Fondation pour la Recherche Médicale/ ; DoseX 2017//Agence Nationale de la Recherche/ ; ANR-11-LBX-0044//Labex DEEP/ ; ANR-10-IDEX-0001-02 PSL//Université de Recherche Paris Sciences et Lettres/ ; },
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},
doi = {10.1073/pnas.2201029119},
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 = {},
number = {},
pages = {},
doi = {10.1111/cge.14141},
pmid = {35470444},
issn = {1399-0004},
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},
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 = {U01DA052713/NH/NIH HHS/United States ; R01MH123724/NH/NIH HHS/United States ; P50HD103573/NH/NIH HHS/United States ; R01NR019245/NH/NIH HHS/United States ; R35HG011922/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},
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 ; P50 HG007735/HG/NHGRI NIH HHS/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 = {},
number = {},
pages = {},
doi = {10.1161/CIRCULATIONAHA.121.055781},
pmid = {35400201},
issn = {1524-4539},
support = {R01 HL136025/HL/NHLBI NIH HHS/United States ; R01 HL139006/HL/NHLBI NIH HHS/United States ; R38 HL155775/HL/NHLBI NIH HHS/United States ; },
abstract = {Background: Transcriptional reconfiguration is central to heart failure, the common cause of which is dilated cardiomyopathy (DCM). However, the impact of three-dimensional (3D) chromatin topology on transcriptional dysregulation and pathogenesis in human DCM remains elusive. Methods: We generated a compendium of 3D-epigenome and transcriptome maps from 101 biobanked human DCM and non-failing heart tissues through HiChIP (H3K27ac), in situ Hi-C, ChIP-seq, ATAC-seq and RNA-seq profiling. We employed human iPSC-derived cardiomyocytes (hiPSC-CMs) and mouse models to further interrogate the key transcription factor implicated in 3D chromatin organization and transcriptional regulation in DCM pathogenesis. 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 for DCM development. For example, we identified that non-transcribing NPPA-AS1 promoter functions as an enhancer and physically interacts with the NPPA and NPPB promoters, leading to the co-transcription of NPPA and NPPB in DCM hearts. We uncovered that DCM-enriched H3K27ac loops largely resided in conserved high-order chromatin architectures (Compartments, Topologically Associating Domains) and unexpectedly their anchors had equivalent chromatin accessibility. Intriguingly, we discovered that the DCM-enriched H3K27ac loop anchors exhibited a strong enrichment for Heart and Neural Crest Derivatives Expressed 1 (HAND1), 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 3D epigenome mappings in hiPSC-CMs. We found that forced overexpression of HAND1 in hiPSC-CM induced a distinct gain of enhancer/promoter connectivity and, correspondingly, increased the expression of their connected genes implicated in DCM etiology, thus recapitulating the transcriptional signature in human DCM hearts. Moreover, electrophysiology analysis demonstrated that forced overexpression of HAND1 in hiPSC-CM induced abnormal calcium handling. Furthermore, cardiomyocyte-specific overexpression of Hand1 in the mouse hearts resulted in a dilated cardiac remodeling with impaired contractility/Ca2+ handling in cardiomyocytes, increased ratio of heart weight/body weight and compromised cardiac function, which were ascribed to recapitulation of transcriptional reprogramming in DCM. 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 = {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 ; },
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},
doi = {10.1016/j.ygeno.2022.110350},
pmid = {35346781},
issn = {1089-8646},
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 ; T32 GM008056/GM/NIGMS NIH HHS/United States ; },
mesh = {*Chromatin/metabolism ; *Cystic Fibrosis Transmembrane Conductance Regulator/genetics/metabolism ; Epithelial Cells ; Humans ; Kruppel-Like Transcription Factors/genetics/metabolism ; Transcription Factors/metabolism ; },
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 ; U01MH103392//U.S. Department of Health &amp; Human Services | NIH | National Institute of Mental Health (NIMH)/ ; U01 MH103392/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 ; R21 MH105881/MH/NIMH NIH HHS/United States ; P50 MH106934/MH/NIMH NIH HHS/United States ; Z01 MH002903/ImNIH/Intramural NIH HHS/United States ; U01 MH103365/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, 104-106-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},
support = {2020YFA0509500//the National Key R &amp; D Program of China/ ; U19A2036, 31772576, 31530073 and 31802044//the National Natural Science Foundation of China/ ; 2021YFYZ0009 and 2021YFYZ0030//the Sichuan Science and Technology Program/ ; 2021YFH0033//the International Cooperation Project of Science and Technology Department of Sichuan Province/ ; },
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 = {},
number = {},
pages = {},
pmid = {35274679},
issn = {1367-4811},
abstract = {MOTIVATION: High throughput chromosome conformation capture (Hi-C) contact matrices are used to predict three-dimensional (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 (TADs), chromosome 3D structure, and chromatin loop predictions from the enhanced data shows that HiCARN can proficiently reconstruct biologically significant regions.<br><br>AVAILABILITY: 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 = {},
number = {},
pages = {},
pmid = {35228717},
issn = {1471-0080},
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},
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 = {108-2628-E-004-001-MY3//Ministry of Science and Technology, Taiwan/ ; 106-2813-C-004-036-E//Ministry of Science and Technology, Taiwan/ ; Advanced Grant 3DEpi/ERC_/European Research Council/International ; 788972/ERC_/European Research Council/International ; MuG//H2020 European Research Council/ ; No 676556//H2020 European Research Council/ ; ANR-15-CE12-0006 EpiDevoMath//the Agence Nationale de la Recherche/ ; DEI20151234396//the Fondation pour la Recherche Médicale/ ; GENE-IGH//the MSDAVENIR foundation/ ; },
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++ 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 = {MC_U142684171/MRC_/Medical Research Council/United Kingdom ; UM1 HG006370/HG/NHGRI NIH HHS/United States ; 203141/Z/16/Z/WT_/Wellcome Trust/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},
doi = {10.1002/aur.2677},
pmid = {35088940},
issn = {1939-3806},
mesh = {Animals ; *Autism Spectrum Disorder/genetics ; *Autistic Disorder/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},
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},
support = {2017YFA0504201//National key research and development program of China/ ; 2018YFC1003501//National key research and development program of China/ ; 81720108017//National Nature Science Foundation of China/ ; 31871329//National Nature Science Foundation of China/ ; 61827814//the National Major Scientific Instruments and Equipment Development Project, National Nature Science Foundation of China/ ; },
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},
doi = {10.1016/j.jbc.2021.101559},
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 = {2021},
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 = {},
number = {},
pages = {},
pmid = {34741515},
issn = {1367-4811},
support = {P50 AA022537/AA/NIAAA NIH HHS/United States ; },
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>AVAILABILITY: 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/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},
support = {//Davies Research Centre/ ; },
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},
support = {SP1532/3-1//Deutsche Forschungsgemeinschaft/ ; SP1532/5-1//Deutsche Forschungsgemeinschaft/ ; MU 880/16-1//Deutsche Forschungsgemeinschaft/ ; KU 1240/10-1//Deutsche Forschungsgemeinschaft/ ; },
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},
support = {61871294//National Natural Science Foundation of China (National Science Foundation of China)/ ; LR19C060001//Natural Science Foundation of Zhejiang Province (Zhejiang Provincial Natural Science Foundation)/ ; },
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 ; 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 (χ2 = 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},
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},
support = {The financial support of the Deutsch-Baltisch Hochschulkontor, Riga to J.E. and M.H//Deutscher Akademischer Austauschdienst/ ; CA15124//European Cooperation in Science and Technology/ ; CA18127//European Cooperation in Science and Technology/ ; 1.1.1.2/VIAA/3/19/463//European Regional Development Fund/ ; },
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 ; R35 CA210030/CA/NCI NIH HHS/United States ; R01 CA227388/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},
doi = {10.1093/molbev/msab128},
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 = {},
doi = {10.1101/cshperspect.a040386},
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 ; 2017YFA0505503//SKR and DPC/ ; DMS-1612501//National Science Foundation/ ; },
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},
support = {31922061//National Natural Science Foundation of China (National Science Foundation of China)/ ; 31500502//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
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 = {2021},
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 = {},
number = {},
pages = {},
doi = {10.1016/j.gpb.2020.06.017},
pmid = {33631432},
issn = {2210-3244},
abstract = {Recent studies have characterized the genomic structures of many eukaryotic cells, often with a focus on their relation to gene expression. So far, these studies have largely only investigated cells grown in 2D culture, 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 at the TAD level. RNA-seq analysis reveals an up-regulation in the 3D cultured cells of those genes involved in physiological hepatocyte functions. We find that these genes are associated with a subset of the structural changes, suggesting that the differences in genomic structure are indeed critically important for transcriptional regulation. However, there are also many structural differences that are not directly associated with changed 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 foci1. 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 processes2,3. 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 = {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 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 < 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 = {T32 GM008666/GM/NIGMS NIH HHS/United States ; U54 DK107965/DK/NIDDK NIH HHS/United States ; U54 DK107977/DK/NIDDK NIH HHS/United States ; UM1 HG011585/HG/NHGRI 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},
support = {C026415//NYSTEM/ ; C026714//NYSTEM/ ; CBET-1555720//National Science Foundation/ ; CBET-1706050//National Science Foundation/ ; Graduate Student Fellowships//Patrick P. Lee Foundation/ ; },
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 species1. 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 ; none//Tulane Cancer Center/ ; },
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 ∼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},
doi = {10.1016/j.molcel.2020.10.001},
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},
doi = {10.1038/s41588-020-00716-8},
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 of 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},
doi = {10.1038/s41588-020-0708-0},
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 cells3-7, 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},
support = {BFU2017-82805-C2-1-P//Spanish Ministry of Science and Innovation/ ; BFU2017-85926-P//Spanish Ministry of Science and Innovation/ ; 609989//European Union's Seventh Framework Programme/ ; 676556//European Union's Horizon 2020/ ; 2017-SGR-597//Generalitat de Catalunya Suport Grups de Recerca AGAUR/ ; 2017-SGR-468//Generalitat de Catalunya Suport Grups de Recerca AGAUR/ ; SEV-2012-0208//Centro de Excelencia Severo Ochoa 2013-2017/ ; //CERCA Programme/Generalitat de Catalunya/ ; },
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},
support = {E/U2AD/CF520/DF554//Bundesministerium der Verteidigung/ ; },
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, GÉ 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 regulation1-7. 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 changes13-16. In contrast, CTCF is required for cell cycle regulation17, embryonic development and formation of various adult cell types18. 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/K017047/1/MRC_/Medical Research Council/United Kingdom ; MR/S007644/1/MRC_/Medical Research Council/United Kingdom ; BBSRC_BB/H008500/1/BB_/Biotechnology and Biological Sciences Research Council/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},
support = {KAKENHI 18H02490//Ministry of Education, Culture, Sports, Science and Technology/ ; },
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 {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 + 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},
doi = {10.1016/j.celrep.2019.11.065},
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 = 4 × [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 = 3.9 × [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 nucleus1,2, which has an important role in regulating gene expression3-6. 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, 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 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 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 bead-pairs with zero Hi-C contact 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 mitosis1,2. 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},
doi = {10.1016/j.molmed.2019.09.011},
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},
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 chromosomes1. This form of genome surveillance is orchestrated by 53BP1, whose accumulation at DSBs triggers sequential recruitment of RIF1 and the shieldin-CST-POLα complex2. 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 = {Asians/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 (r2 = 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 AD SNPs with GWAS p-values of less than 1.00 × 10- 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 = {2019},
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 = {},
number = {},
pages = {},
doi = {10.1002/gcc.22793},
pmid = {31385379},
issn = {1098-2264},
support = {2016M602797//China Postdoctoral Science Foundation/ ; 2018T111037//China Postdoctoral Science Foundation/ ; 2018KJXX-010//Innovative Talent Promotion Plan of Shaanxi Province for Young Sci-Tech New Star/ ; 81573241//National Natural Science Foundation of China/ ; 81872490//National Natural Science Foundation of China/ ; LGF18C060002//Natural Science Foundation of Zhejiang Province/ ; },
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 genome1,2. However, the contribution of spatial genome organization to the regulation of developmental programs is unclear3. 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 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 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 = {P30 DK017047/DK/NIDDK NIH HHS/United States ; R01 AR065952/AR/NIAMS NIH HHS/United States ; R01 DK103667/DK/NIDDK NIH HHS/United States ; T32 GM095421/GM/NIGMS NIH HHS/United States ; T32 LM012419/LM/NLM 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 ; },
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 ; R15GM120650//National Institute of General Medical Sciences (US)/ ; },
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 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 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 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 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 D structures (at both 500 and 50 kb resolutions) using multiple criteria and compared them with the ones generated by another modeling software program. The results indicate that the 3 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 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 nucleus1. 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 domains4 with frequent chromatin contacts, and have identified chromatin loops mediated by specific protein factors for insulation and regulation of transcription5-7. 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-C8 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 analysis9 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* (EZH2Y646X)) 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 EZH2Y646X. Our results indicate that EZH2Y646X 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 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 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 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 kb high-resolution 3D chromosomal structures of mouse male ES cells. The high-resolution structures successfully 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 m6A 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 n3 . 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 = {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 (r2 = 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//National Institutes of Health/ ; R21 HD089824/HD/NICHD NIH HHS/United States ; P30 ES013508/ES/NIEHS NIH HHS/United States ; R01 LM010098/LM/NLM NIH HHS/United States ; Center for Spatial and Functional Genomics//The Children's Hospital of Philadelphia/ ; ES013508//National Institutes of Health/ ; UC4 DK112217/DK/NIDDK NIH HHS/United States ; DK112217//National Institutes of Health/ ; LM010098//National Institutes of Health/ ; },
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 (Mg2+) cations. Both DNA and chromatin demonstrated compaction under comparable conditions in the presence of poly(ethylene glycol) and Na+ or Mg2+ 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 assigned is incremental when more elements in a segment are predicted accurately. Furthermore, our improved SOV has achieved a higher correlation with the quality of protein models measured by GDT-TS score and TM-score, indicating its better abilities to evaluate tertiary structure quality at the secondary structure level. We analyzed the statistical significance of SOV scores and found the threshold values for distinguishing two protein structures (SOV_refine > 0.19) and indicating whether two proteins are under the same CATH fold (SOV_refine > 0.94 and > 0.90 for three- and eight-state secondary structures respectively). We provided another two example applications, which are when used as a machine learning feature for protein model quality assessment and comparing different definitions of topologically associating domains. We proved that our newly defined SOV score resulted in better performance.<br><br>CONCLUSIONS: The SOV score can be widely used in bioinformatics research and other fields that need to compare two sequences of letters in which continuous segments have important 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 protein secondary structures). A standalone software package has been implemented in Perl with source code released. The software can be downloaded 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 = {},
number = {},
pages = {},
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 = {},
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 met