@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},
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 = {},
doi = {10.1242/jcs.220491},
pmid = {30733374},
issn = {1477-9137},
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 reorganisation during neuronal cell differentiation in Drosophila genome.},
journal = {Genome research},
volume = {},
number = {},
pages = {},
doi = {10.1101/gr.246710.118},
pmid = {30709849},
issn = {1549-5469},
abstract = {The organization of the genome into topologically associating domains (TADs) was shown to have a regulatory role in development and cellular functioning, but the mechanism involved in TAD establishment is still unclear. Here, we presented the first high-resolution contact map of Drosophila neuronal cells (BG3) and identified 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-specific TADs. 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 observed 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 = {},
doi = {10.7554/eLife.38070},
pmid = {30702424},
issn = {2050-084X},
support = {HG009744//National Human Genome Research Institute/ ; Institute Leadership Funds//La Jolla Institute for Allergy and Immunology/ ; HG007019//National Human Genome Research Institute/ ; },
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},
doi = {10.3389/fcvm.2018.00186},
pmid = {30697540},
issn = {2297-055X},
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 = {},
number = {},
pages = {},
doi = {10.1038/s41588-018-0338-y},
pmid = {30692681},
issn = {1546-1718},
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},
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 & cancer},
volume = {},
number = {},
pages = {},
doi = {10.1002/gcc.22732},
pmid = {30664301},
issn = {1098-2264},
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 CD 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 suggests 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 are 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. This article is protected by copyright. All rights reserved.},
}
@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 = {},
number = {},
pages = {},
doi = {10.1016/j.cell.2018.12.014},
pmid = {30661750},
issn = {1097-4172},
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 = {},
number = {},
pages = {},
doi = {10.1101/gr.241547.118},
pmid = {30655336},
issn = {1549-5469},
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&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},
doi = {10.1371/journal.pcbi.1006686},
pmid = {30596637},
issn = {1553-7358},
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 a 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 and the modelling of chromatin dynamics to explore 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 = {2018},
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 = {},
number = {},
pages = {},
doi = {10.1016/j.cell.2018.11.036},
pmid = {30595451},
issn = {1097-4172},
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 = {2018},
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 = {},
number = {},
pages = {},
doi = {10.1016/j.ydbio.2018.11.023},
pmid = {30594504},
issn = {1095-564X},
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 209kb Cre-expressing Tbx18 transgene, to partition enhancers for specific precursor types into two rough spatial domains. Within this central 209kb 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},
doi = {10.1186/s12859-018-2464-z},
pmid = {30591009},
issn = {1471-2105},
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},
doi = {10.1126/sciadv.aav8550},
pmid = {30555922},
issn = {2375-2548},
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 = {2018},
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 = {},
number = {},
pages = {},
doi = {10.1101/gr.243824.118},
pmid = {30552103},
issn = {1549-5469},
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 = {},
doi = {10.1126/science.aat8464},
pmid = {30545857},
issn = {1095-9203},
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 = {2018},
author = {Amat, R and Böttcher, R and LeDily, 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 hyper-osmotic shock.},
journal = {Genome research},
volume = {},
number = {},
pages = {},
doi = {10.1101/gr.238527.118},
pmid = {30523037},
issn = {1549-5469},
abstract = {Nuclear architecture is decisive for the assembly of transcriptional responses. However, how chromosome organization is dynamically modulated to permit rapid and transient changes of transcription in response to environmental challenges remains unclear. Here we show that hyper-osmotic 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 re-organization while compartment recovery is partially 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},
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 = {2018},
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 = {},
number = {},
pages = {},
doi = {10.1093/bioinformatics/bty1014},
pmid = {30535005},
issn = {1367-4811},
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>Supplementary information: Supplementary data are available at Bioinformatics online.},
}
@article {pmid30531872,
year = {2018},
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 = {},
number = {},
pages = {},
doi = {10.1038/s41588-018-0298-2},
pmid = {30531872},
issn = {1546-1718},
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 = {2018},
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 = {},
number = {},
pages = {},
doi = {10.1016/j.molcel.2018.10.039},
pmid = {30527662},
issn = {1097-4164},
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},
doi = {10.1186/s13059-018-1596-9},
pmid = {30526631},
issn = {1474-760X},
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},
doi = {10.1016/j.cels.2018.09.003},
pmid = {30414923},
issn = {2405-4712},
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},
doi = {10.1534/genetics.118.301641},
pmid = {30401760},
issn = {1943-2631},
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 = {2018},
author = {Racko, D and Benedetti, F and Dorier, J and Stasiak, A},
title = {Are TADs supercoiled?.},
journal = {Nucleic acids research},
volume = {},
number = {},
pages = {},
doi = {10.1093/nar/gky1091},
pmid = {30395328},
issn = {1362-4962},
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},
doi = {10.1038/s41576-018-0060-8},
pmid = {30367165},
issn = {1471-0064},
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 = {},
doi = {10.1126/science.aau1783},
pmid = {30361340},
issn = {1095-9203},
support = {/HHMI/Howard Hughes Medical Institute/United States ; },
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 = {2018},
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 = {},
number = {},
pages = {},
doi = {10.1136/jmedgenet-2018-105527},
pmid = {30352868},
issn = {1468-6244},
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 = {},
doi = {10.3791/57001},
pmid = {30346395},
issn = {1940-087X},
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 auto-regulation during human PU.1 locus SubTAD formation.},
journal = {Blood},
volume = {},
number = {},
pages = {},
doi = {10.1182/blood-2018-02-834721},
pmid = {30315124},
issn = {1528-0020},
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 ~75kb 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 auto-regulation 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 auto-regulation. Thus, our data support that PU.1 auto-regulates 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},
doi = {10.1073/pnas.1809872115},
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 ; R01 DK104764/DK/NIDDK NIH HHS/United States ; R01 EY027004/EY/NEI NIH HHS/United States ; R01 DK090382/DK/NIDDK NIH HHS/United States ; R01 HL138424/HL/NHLBI NIH HHS/United States ; },
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 = {},
doi = {10.3390/ht7040030},
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},
doi = {10.7150/ijbs.25328},
pmid = {30263009},
issn = {1449-2288},
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 = {2018},
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 = {},
number = {},
pages = {},
doi = {10.1002/jcb.27737},
pmid = {30260021},
issn = {1097-4644},
support = {18-14-00011//Russian Science Foundation/ ; },
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},
doi = {10.1371/journal.pone.0203843},
pmid = {30248133},
issn = {1932-6203},
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},
doi = {10.1093/nar/gky763},
pmid = {30239812},
issn = {1362-4962},
support = {MR/K010867/1//Medical Research Council/United Kingdom ; },
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},
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},
doi = {10.1016/j.cell.2018.08.005},
pmid = {30173918},
issn = {1097-4172},
support = {DP2 MH110247/MH/NIMH NIH HHS/United States ; R01 GM113929/GM/NIGMS NIH HHS/United States ; U01 HL129998/HL/NHLBI NIH HHS/United States ; },
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},
doi = {10.1016/j.celrep.2018.07.091},
pmid = {30157436},
issn = {2211-1247},
support = {T32 GM007281/GM/NIGMS NIH HHS/United States ; },
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},
doi = {10.1038/s41467-018-05912-z},
pmid = {30143639},
issn = {2041-1723},
support = {609989//European Research Council/International ; },
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},
doi = {10.1038/s41467-018-05691-7},
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},
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},
doi = {10.1038/s41467-018-05606-6},
pmid = {30089831},
issn = {2041-1723},
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},
doi = {10.1186/s12915-018-0556-x},
pmid = {30086749},
issn = {1741-7007},
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 = {},
doi = {10.7554/eLife.37750},
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 ; },
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},
doi = {10.1016/j.ccell.2018.06.008},
pmid = {30017478},
issn = {1878-3686},
support = {R01 CA186714/CA/NCI NIH HHS/United States ; },
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},
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},
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 = {2018},
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 = {},
number = {},
pages = {},
doi = {10.1016/j.semcdb.2018.07.010},
pmid = {30004017},
issn = {1096-3634},
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 = {2018},
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 = {},
number = {},
pages = {},
doi = {10.1109/TCBB.2018.2851200},
pmid = {29994683},
issn = {1557-9964},
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 and licensed under GPL v3; it is available at https://github.com/COMBINE-lab/matryoshka.},
}
@article {pmid29981443,
year = {2018},
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 = {},
number = {},
pages = {},
doi = {10.1016/j.semcdb.2018.07.006},
pmid = {29981443},
issn = {1096-3634},
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},
doi = {10.1016/j.celrep.2018.06.003},
pmid = {29972771},
issn = {2211-1247},
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},
doi = {10.1073/pnas.1717730115},
pmid = {29967174},
issn = {1091-6490},
support = {R01 GM114190/GM/NIGMS 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},
doi = {10.1093/bioinformatics/bty265},
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 ; },
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},
doi = {10.1002/gepi.22136},
pmid = {29932245},
issn = {1098-2272},
support = {RC2 HL102419/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 ; U01HL137162/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 ; R01 HL105756/HL/NHLBI NIH HHS/United States ; HHSN268201200036C/HL/NHLBI NIH HHS/United States ; HHSN268201700001I/HL/NHLBI NIH HHS/United States ; R01AG023629/AG/NIA NIH HHS/United States ; HHSN268201700004I/HL/NHLBI 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 ; N02 HL64278/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 4 , 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},
doi = {10.1101/gr.233874.117},
pmid = {29914971},
issn = {1549-5469},
support = {P51 OD011092/OD/NIH HHS/United States ; T15 LM007088/LM/NLM NIH HHS/United States ; U24 HG009084/HG/NHGRI NIH HHS/United States ; },
mesh = {Animals ; Chromatin/genetics ; CpG Islands/genetics ; Epigenesis, Genetic/*genetics ; Epigenomics/methods ; Genome/*genetics ; Genomics/methods ; Humans ; Synteny/genetics ; },
abstract = {The relationship between evolutionary genome remodeling and the three-dimensional structure of the genome remain largely unexplored. Here, we use the heavily rearranged gibbon genome to examine how evolutionary chromosomal rearrangements impact genome-wide chromatin interactions, topologically associating domains (TADs), and their epigenetic landscape. We use high-resolution maps of gibbon-human breaks of synteny (BOS), apply Hi-C in gibbon, measure an array of epigenetic features, and perform cross-species comparisons. We find that gibbon rearrangements occur at TAD boundaries, independent of the parameters used to identify TADs. This overlap is supported by a remarkable genetic and epigenetic similarity between BOS and TAD boundaries, namely presence of CpG islands and SINE elements, and enrichment in CTCF and H3K4me3 binding. Cross-species comparisons reveal that regions orthologous to BOS also correspond with boundaries of large (400-600 kb) TADs in human and other mammalian species. The colocalization of rearrangement breakpoints and TAD boundaries may be due to higher chromatin fragility at these locations and/or increased selective pressure against rearrangements that disrupt TAD integrity. We also examine the small portion of BOS that did not overlap with TAD boundaries and gave rise to novel TADs in the gibbon genome. We postulate that these new TADs generally lack deleterious consequences. Last, we show that limited epigenetic homogenization occurs across breakpoints, irrespective of their time of occurrence in the gibbon lineage. Overall, our findings demonstrate remarkable conservation of chromatin interactions and epigenetic landscape in gibbons, in spite of extensive genomic shuffling.},
}
@article {pmid29887375,
year = {2018},
author = {Wang, CY and Jégu, T and Chu, HP and Oh, HJ and Lee, JT},
title = {SMCHD1 Merges Chromosome Compartments and Assists Formation of Super-Structures on the Inactive X.},
journal = {Cell},
volume = {174},
number = {2},
pages = {406-421.e25},
doi = {10.1016/j.cell.2018.05.007},
pmid = {29887375},
issn = {1097-4172},
support = {R01 GM090278/GM/NIGMS NIH HHS/United States ; },
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 &quot;S1&quot; and &quot;S2&quot; 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},
doi = {10.3389/fgene.2018.00132},
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},
doi = {10.1534/genetics.118.301116},
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},
doi = {10.1038/s41594-018-0070-4},
pmid = {29867216},
issn = {1545-9985},
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},
doi = {10.15252/msb.20188214},
pmid = {29858282},
issn = {1744-4292},
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},
doi = {10.18632/oncotarget.24918},
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},
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},
doi = {10.1007/s00439-018-1893-0},
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/ ; },
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},
doi = {10.1093/hmg/ddy193},
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 ; },
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},
doi = {10.1016/j.ymeth.2018.05.005},
pmid = {29772275},
issn = {1095-9130},
support = {DP2 MH110247/MH/NIMH NIH HHS/United States ; U01 HL129998/HL/NHLBI NIH HHS/United States ; },
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},
doi = {10.1371/journal.pgen.1007395},
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 = {},
doi = {10.7554/eLife.34077},
pmid = {29757144},
issn = {2050-084X},
support = {R01 DK033765/DK/NIDDK NIH HHS/United States ; ES024421//National Institutes of Health/ ; R01 ES024421/ES/NIEHS NIH HHS/United States ; DK33765//National Institutes of Health/ ; DGE-1247312//National Science Foundation/ ; },
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},
doi = {10.1016/j.bpj.2018.04.012},
pmid = {29729833},
issn = {1542-0086},
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},
doi = {10.1186/s13029-018-0068-7},
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},
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},
doi = {10.1016/j.tibs.2018.03.006},
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},
doi = {10.1038/s41588-018-0098-8},
pmid = {29662163},
issn = {1546-1718},
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},
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},
doi = {10.1093/toxsci/kfy070},
pmid = {29617930},
issn = {1096-0929},
support = {R01 ES024421/ES/NIEHS NIH HHS/United States ; },
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},
doi = {10.1038/s41598-018-23276-8},
pmid = {29581440},
issn = {2045-2322},
support = {U54 DK107967/DK/NIDDK NIH HHS/United States ; },
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},
doi = {10.1083/jcb.201709074},
pmid = {29572382},
issn = {1540-8140},
support = {U01 EB021223/EB/NIBIB NIH HHS/United States ; },
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},
doi = {10.1186/s13039-018-0368-2},
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},
doi = {10.1186/s13059-018-1405-5},
pmid = {29540241},
issn = {1474-760X},
support = {092096//Wellcome Trust/United Kingdom ; R01 GM078455/GM/NIGMS NIH HHS/United States ; //Wellcome Trust/United Kingdom ; C6/A18796//Cancer Research UK/United Kingdom ; 268569//European Research Council/International ; C6946/A14492//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},
doi = {10.1093/nar/gky153},
pmid = {29538766},
issn = {1362-4962},
support = {R01 GM084070/GM/NIGMS NIH HHS/United States ; R15 GM109254/GM/NIGMS NIH HHS/United States ; },
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},
doi = {10.1126/sciadv.aar8082},
pmid = {29503869},
issn = {2375-2548},
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},
doi = {10.1016/j.immuni.2018.01.013},
pmid = {29466755},
issn = {1097-4180},
support = {R01 AI083514/AI/NIAID NIH HHS/United States ; Z01 HL005801-05//NULL/International ; },
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 = {},
doi = {10.1101/gr.227272.117},
pmid = {29429976},
issn = {1549-5469},
support = {//Wellcome Trust/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},
doi = {10.1038/nprot.2017.132},
pmid = {29419817},
issn = {1750-2799},
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},
doi = {10.1038/s41467-018-03017-1},
pmid = {29416042},
issn = {2041-1723},
support = {P30 CA016087/CA/NCI NIH HHS/United States ; R01 CA216421/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},
doi = {10.1136/jmedgenet-2017-105125},
pmid = {29378768},
issn = {1468-6244},
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},
doi = {10.1093/nar/gky009},
pmid = {29365171},
issn = {1362-4962},
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},
doi = {10.1007/s10577-018-9571-6},
pmid = {29335803},
issn = {1573-6849},
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},
doi = {10.1038/s41467-017-02525-w},
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},
doi = {10.1038/s41467-017-02526-9},
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},
doi = {10.1038/nmeth.4560},
pmid = {29334377},
issn = {1548-7105},
support = {DP2 MH110247/MH/NIMH NIH HHS/United States ; U01 HL129998/HL/NHLBI NIH HHS/United States ; },
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},
doi = {10.1038/s41431-017-0011-4},
pmid = {29289958},
issn = {1476-5438},
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},
doi = {10.1158/2159-8290.CD-17-0993},
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 ; },
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},
doi = {10.1101/gad.307769.117},
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},
doi = {10.1101/gr.224576.117},
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},
doi = {10.1093/nar/gkx1246},
pmid = {29272504},
issn = {1362-4962},
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},
doi = {10.1038/s41467-017-02386-3},
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},
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},
doi = {10.15252/embj.201798004},
pmid = {29217591},
issn = {1460-2075},
support = {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},
doi = {10.1038/s41467-017-01793-w},
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 = {},
doi = {10.1093/gigascience/gix103},
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},
doi = {10.1093/nar/gkx1123},
pmid = {29140466},
issn = {1362-4962},
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},
doi = {10.1073/pnas.1712350114},
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},
doi = {10.1080/19491034.2017.1389365},
pmid = {29077530},
issn = {1949-1042},
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},
doi = {10.1038/nsmb.3482},
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},
doi = {10.1093/nar/gkx735},
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},
doi = {10.1093/nar/gkx722},
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},
doi = {10.1186/s13059-017-1310-3},
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},
doi = {10.1038/s41467-017-00478-8},
pmid = {28912419},
issn = {2041-1723},
support = {R01 AA024486/AA/NIAAA NIH HHS/United States ; R01 GM104369/GM/NIGMS NIH HHS/United States ; R01 GM108716/GM/NIGMS NIH HHS/United States ; R01 HG006130/HG/NHGRI 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},
doi = {10.1080/19491034.2017.1361578},
pmid = {28910577},
issn = {1949-1042},
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},
doi = {10.1371/journal.pcbi.1005708},
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 &quot;CODs&quot;). 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},
doi = {10.1038/s41467-017-00524-5},
pmid = {28874668},
issn = {2041-1723},
support = {MC_U120027516//Medical Research Council/United Kingdom ; MC_UP_1102/1//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},
doi = {10.1016/j.cell.2017.07.041},
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},
doi = {10.1371/journal.pgen.1006966},
pmid = {28863138},
issn = {1553-7404},
support = {MR/M010015/1//Medical Research Council/United Kingdom ; R01 AR064580/AR/NIAMS NIH HHS/United States ; R01 AR071727/AR/NIAMS NIH HHS/United States ; R37 CA039681/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; CCCTC-Binding Factor ; 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},
doi = {10.1016/j.molcel.2017.07.022},
pmid = {28826674},
issn = {1097-4164},
support = {F32 GM113570/GM/NIGMS NIH HHS/United States ; P30 CA034196/CA/NCI NIH HHS/United States ; R01 CA186714/CA/NCI NIH HHS/United States ; R01 GM035463/GM/NIGMS 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},
doi = {10.1161/CIRCULATIONAHA.117.029430},
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},
doi = {10.1038/ejhg.2017.108},
pmid = {28792001},
issn = {1476-5438},
support = {F32 DE026346/DE/NIDCR NIH HHS/United States ; P30 ES013508/ES/NIEHS 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},
doi = {10.1186/s13059-017-1278-z},
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},
doi = {10.1146/annurev-cellbio-100616-060531},
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},
doi = {10.1371/journal.pcbi.1005647},
pmid = {28742097},
issn = {1553-7358},
support = {U24 HG009446/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 &quot;Mr&quot; 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},
doi = {10.1038/nature23263},
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},
doi = {10.1186/s13072-017-0142-4},
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},
doi = {10.1186/s13059-017-1225-z},
pmid = {28615069},
issn = {1474-760X},
mesh = {Forkhead Box Protein O1/*genetics ; Gene Expression Regulation, Neoplastic ; Genome, Human ; Humans ; Oncogene Proteins, Fusion/genetics ; PAX3 Transcription Factor/*genetics ; Promoter Regions, Genetic ; Protein Domains/genetics ; Protein Interaction Maps/*genetics ; Regulatory Sequences, Nucleic Acid/genetics ; Rhabdomyosarcoma, Alveolar/*genetics/pathology ; Translocation, Genetic/genetics ; },
abstract = {BACKGROUND: The organisation of vertebrate genomes into topologically associating domains (TADs) is believed to facilitate the regulation of the genes located within them. A remaining question is whether TAD organisation is achieved through the interactions of the regulatory elements within them or if these interactions are favoured by the pre-existence of TADs. If the latter is true, the fusion of two independent TADs should result in the rewiring of the transcriptional landscape and the generation of ectopic contacts.<br><br>RESULTS: We show that interactions within the PAX3 and FOXO1 domains are restricted to their respective TADs in normal conditions, while in a patient-derived alveolar rhabdomyosarcoma cell line, harbouring the diagnostic t(2;13)(q35;q14) translocation that brings together the PAX3 and FOXO1 genes, the PAX3 promoter interacts ectopically with FOXO1 sequences. Using a combination of 4C-seq datasets, we have modelled the three-dimensional organisation of the fused landscape in alveolar rhabdomyosarcoma.<br><br>CONCLUSIONS: The chromosomal translocation that leads to alveolar rhabdomyosarcoma development generates a novel TAD that is likely to favour ectopic PAX3:FOXO1 oncogene activation in non-PAX3 territories. Rhabdomyosarcomas may therefore arise from cells which do not normally express PAX3. The borders of this novel TAD correspond to the original 5'- and 3'- borders of the PAX3 and FOXO1 TADs, respectively, suggesting that TAD organisation precedes the formation of regulatory long-range interactions. Our results demonstrate that, upon translocation, novel regulatory landscapes are formed allowing new intra-TAD interactions between the original loci involved.},
}
@article {pmid28604721,
year = {2017},
author = {Forcato, M and Nicoletti, C and Pal, K and Livi, CM and Ferrari, F and Bicciato, S},
title = {Comparison of computational methods for Hi-C data analysis.},
journal = {Nature methods},
volume = {14},
number = {7},
pages = {679-685},
doi = {10.1038/nmeth.4325},
pmid = {28604721},
issn = {1548-7105},
support = {670126//European Research Council/International ; },
mesh = {Animals ; Chromatin/chemistry ; Chromosome Mapping/*methods ; Chromosomes/*chemistry/genetics ; Computational Biology/*methods ; Computer Simulation ; Genome ; Genome-Wide Association Study/*methods ; },
abstract = {Hi-C is a genome-wide sequencing technique used to investigate 3D chromatin conformation inside the nucleus. Computational methods are required to analyze Hi-C data and identify chromatin interactions and topologically associating domains (TADs) from genome-wide contact probability maps. We quantitatively compared the performance of 13 algorithms in their analyses of Hi-C data from six landmark studies and simulations. This comparison revealed differences in the performance of methods for chromatin interaction identification, but more comparable results for TAD detection between algorithms.},
}
@article {pmid28593374,
year = {2017},
author = {Sawyer, IA and Dundr, M},
title = {Chromatin loops and causality loops: the influence of RNA upon spatial nuclear architecture.},
journal = {Chromosoma},
volume = {126},
number = {5},
pages = {541-557},
doi = {10.1007/s00412-017-0632-y},
pmid = {28593374},
issn = {1432-0886},
support = {R01 GM090156/GM/NIGMS NIH HHS/United States ; R01GM090156//National Institute of General Medical Sciences/ ; },
mesh = {Animals ; Cell Nucleus/*metabolism ; Chromatin/*metabolism ; DNA/metabolism ; Epigenesis, Genetic ; *Gene Expression Regulation ; Humans ; RNA, Long Noncoding/*metabolism ; Spatial Analysis ; },
abstract = {An intrinsic and essential trait exhibited by cells is the properly coordinated and integrated regulation of an astoundingly large number of simultaneous molecular decisions and reactions to maintain biochemical homeostasis. This is especially true inside the cell nucleus, where the recognition of DNA and RNA by a vast range of nucleic acid-interacting proteins organizes gene expression patterns. However, this dynamic system is not regulated by simple &quot;on&quot; or &quot;off&quot; signals. Instead, transcription factor and RNA polymerase recruitment to DNA are influenced by the local chromatin and epigenetic environment, a gene's relative position within the nucleus and the action of noncoding RNAs. In addition, major phase-separated structural features of the nucleus, such as nucleoli and paraspeckles, assemble in direct response to specific transcriptional activities and, in turn, influence global genomic function. Currently, the interpretation of these data is trapped in a causality dilemma reminiscent of the &quot;chicken and the egg&quot; paradox as it is unclear whether changes in nuclear architecture promote RNA function or vice versa. Here, we review recent advances that suggest a complex and interdependent interaction network between gene expression, chromatin topology, and noncoding RNA function. We also discuss the functional links between these essential nuclear processes from the nanoscale (gene looping) to the macroscale (sub-nuclear gene positioning and nuclear body function) and briefly highlight some of the challenges that researchers may encounter when studying these phenomena.},
}
@article {pmid28562241,
year = {2017},
author = {Albritton, SE and Kranz, AL and Winterkorn, LH and Street, LA and Ercan, S},
title = {Cooperation between a hierarchical set of recruitment sites targets the X chromosome for dosage compensation.},
journal = {eLife},
volume = {6},
number = {},
pages = {},
doi = {10.7554/eLife.23645},
pmid = {28562241},
issn = {2050-084X},
support = {R01 GM107293/GM/NIGMS NIH HHS/United States ; P40 OD010440/OD/NIH HHS/United States ; },
mesh = {Animals ; Caenorhabditis elegans/*genetics ; Chromatin/metabolism ; *Dosage Compensation, Genetic ; Syndecan-2/metabolism ; X Chromosome/*metabolism ; },
abstract = {In many organisms, it remains unclear how X chromosomes are specified for dosage compensation, since DNA sequence motifs shown to be important for dosage compensation complex (DCC) recruitment are themselves not X-specific. Here, we addressed this problem in C. elegans. We found that the DCC recruiter, SDC-2, is required to maintain open chromatin at a small number of primary DCC recruitment sites, whose sequence and genomic context are X-specific. Along the X, primary recruitment sites are interspersed with secondary sites, whose function is X-dependent. A secondary site can ectopically recruit the DCC when additional recruitment sites are inserted either in tandem or at a distance (>30 kb). Deletion of a recruitment site on the X results in reduced DCC binding across several megabases surrounded by topologically associating domain (TAD) boundaries. Our work elucidates that hierarchy and long-distance cooperativity between gene-regulatory elements target a single chromosome for regulation.},
}
@article {pmid28549169,
year = {2017},
author = {Stolzenburg, LR and Yang, R and Kerschner, JL and Fossum, S and Xu, M and Hoffmann, A and Lamar, KM and Ghosh, S and Wachtel, S and Leir, SH and Harris, A},
title = {Regulatory dynamics of 11p13 suggest a role for EHF in modifying CF lung disease severity.},
journal = {Nucleic acids research},
volume = {45},
number = {15},
pages = {8773-8784},
doi = {10.1093/nar/gkx482},
pmid = {28549169},
issn = {1362-4962},
support = {F31 HL126458/HL/NHLBI NIH HHS/United States ; R01 HL117843/HL/NHLBI NIH HHS/United States ; },
mesh = {Caco-2 Cells ; Cells, Cultured ; Chromatin/metabolism ; Chromosomes, Human, Pair 11/*genetics ; Cystic Fibrosis/*genetics/*pathology ; Enhancer Elements, Genetic ; *Gene Expression Regulation ; Genetic Loci ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; K562 Cells ; Polymorphism, Single Nucleotide ; Severity of Illness Index ; Transcription Factors/genetics/*physiology ; },
abstract = {Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF), but are not good predictors of lung phenotype. Genome-wide association studies (GWAS) previously identified additional genomic sites associated with CF lung disease severity. One of these, at chromosome 11p13, is an intergenic region between Ets homologous factor (EHF) and Apaf-1 interacting protein (APIP). Our goal was to determine the functional significance of this region, which being intergenic is probably regulatory. To identify cis-acting elements, we used DNase-seq and H3K4me1 and H3K27Ac ChIP-seq to map open and active chromatin respectively, in lung epithelial cells. Two elements showed strong enhancer activity for the promoters of EHF and the 5' adjacent gene E47 like ETS transcription factor 5 (ELF5) in reporter gene assays. No enhancers of the APIP promoter were found. Circular chromosome conformation capture (4C-seq) identified direct physical interactions of elements within 11p13. This confirmed the enhancer-promoter associations, identified additional interacting elements and defined topologically associating domain (TAD) boundaries, enriched for CCCTC-binding factor (CTCF). No strong interactions were observed with the APIP promoter, which lies outside the main TAD encompassing the GWAS signal. These results focus attention on the role of EHF in modifying CF lung disease severity.},
}
@article {pmid28525758,
year = {2017},
author = {Nora, EP and Goloborodko, A and Valton, AL and Gibcus, JH and Uebersohn, A and Abdennur, N and Dekker, J and Mirny, LA and Bruneau, BG},
title = {Targeted Degradation of CTCF Decouples Local Insulation of Chromosome Domains from Genomic Compartmentalization.},
journal = {Cell},
volume = {169},
number = {5},
pages = {930-944.e22},
doi = {10.1016/j.cell.2017.05.004},
pmid = {28525758},
issn = {1097-4172},
support = {U01 HL098179/HL/NHLBI NIH HHS/United States ; R01 GM112720/GM/NIGMS NIH HHS/United States ; R01 HG003143/HG/NHGRI NIH HHS/United States ; U01 HG007910/HG/NHGRI NIH HHS/United States ; UM1 HL098179/HL/NHLBI NIH HHS/United States ; U54 DK107980/DK/NIDDK NIH HHS/United States ; U01 HL131003/HL/NHLBI NIH HHS/United States ; //Howard Hughes Medical Institute/United States ; R01 AI117839/AI/NIAID NIH HHS/United States ; P30 AI027763/AI/NIAID NIH HHS/United States ; U01 DA040588/DA/NIDA NIH HHS/United States ; U54 HG007010/HG/NHGRI NIH HHS/United States ; U54 CA193419/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; CCCTC-Binding Factor ; Cell Cycle ; Chromatin/metabolism ; Chromosomes, Mammalian/*chemistry/genetics/metabolism ; Embryonic Stem Cells/metabolism ; Gene Expression Regulation ; Indoleacetic Acids/pharmacology ; Mice ; Repressor Proteins/metabolism ; Transcription, Genetic ; },
abstract = {The molecular mechanisms underlying folding of mammalian chromosomes remain poorly understood. The transcription factor CTCF is a candidate regulator of chromosomal structure. Using the auxin-inducible degron system in mouse embryonic stem cells, we show that CTCF is absolutely and dose-dependently required for looping between CTCF target sites and insulation of topologically associating domains (TADs). Restoring CTCF reinstates proper architecture on altered chromosomes, indicating a powerful instructive function for CTCF in chromatin folding. CTCF remains essential for TAD organization in non-dividing cells. Surprisingly, active and inactive genome compartments remain properly segregated upon CTCF depletion, revealing that compartmentalization of mammalian chromosomes emerges independently of proper insulation of TADs. Furthermore, our data support that CTCF mediates transcriptional insulator function through enhancer blocking but not as a direct barrier to heterochromatin spreading. Beyond defining the functions of CTCF in chromosome folding, these results provide new fundamental insights into the rules governing mammalian genome organization.},
}
@article {pmid28513628,
year = {2017},
author = {Carty, M and Zamparo, L and Sahin, M and González, A and Pelossof, R and Elemento, O and Leslie, CS},
title = {An integrated model for detecting significant chromatin interactions from high-resolution Hi-C data.},
journal = {Nature communications},
volume = {8},
number = {},
pages = {15454},
doi = {10.1038/ncomms15454},
pmid = {28513628},
issn = {2041-1723},
support = {P30 CA008748/CA/NCI NIH HHS/United States ; U01 HG009395/HG/NHGRI NIH HHS/United States ; },
mesh = {Animals ; Binding Sites/genetics ; Cell Line, Tumor ; Chromatin/genetics/*metabolism ; Chromosome Mapping/methods ; Chromosomes, Human, Pair 6/genetics/metabolism ; Computational Biology/*methods ; CpG Islands/genetics ; Datasets as Topic ; Genome/*genetics ; Genomics/*methods ; Histone Code/genetics ; Humans ; Mice ; *Models, Genetic ; Promoter Regions, Genetic/genetics ; Software ; },
abstract = {Here we present HiC-DC, a principled method to estimate the statistical significance (P values) of chromatin interactions from Hi-C experiments. HiC-DC uses hurdle negative binomial regression account for systematic sources of variation in Hi-C read counts-for example, distance-dependent random polymer ligation and GC content and mappability bias-and model zero inflation and overdispersion. Applied to high-resolution Hi-C data in a lymphoblastoid cell line, HiC-DC detects significant interactions at the sub-topologically associating domain level, identifying potential structural and regulatory interactions supported by CTCF binding sites, DNase accessibility, and/or active histone marks. CTCF-associated interactions are most strongly enriched in the middle genomic distance range (∼700 kb-1.5 Mb), while interactions involving actively marked DNase accessible elements are enriched both at short (<500 kb) and longer (>1.5 Mb) genomic distances. There is a striking enrichment of longer-range interactions connecting replication-dependent histone genes on chromosome 6, potentially representing the chromatin architecture at the histone locus body.},
}
@article {pmid28504305,
year = {2018},
author = {Fritz, AJ and Ghule, PN and Boyd, JR and Tye, CE and Page, NA and Hong, D and Shirley, DJ and Weinheimer, AS and Barutcu, AR and Gerrard, DL and Frietze, S and van Wijnen, AJ and Zaidi, SK and Imbalzano, AN and Lian, JB and Stein, JL and Stein, GS},
title = {Intranuclear and higher-order chromatin organization of the major histone gene cluster in breast cancer.},
journal = {Journal of cellular physiology},
volume = {233},
number = {2},
pages = {1278-1290},
doi = {10.1002/jcp.25996},
pmid = {28504305},
issn = {1097-4652},
support = {P01 CA082834/CA/NCI NIH HHS/United States ; R01 CA139322/CA/NCI NIH HHS/United States ; U01 CA196383/CA/NCI NIH HHS/United States ; },
mesh = {Breast Neoplasms/*genetics/metabolism/pathology ; Cell Line, Tumor ; Cell Nucleus/metabolism/pathology ; Cell Nucleus Shape ; Cell Proliferation ; Chromatin/*genetics/metabolism ; *Chromatin Assembly and Disassembly ; *Chromosomes, Human, Pair 6 ; Computational Biology ; Databases, Genetic ; Disease Progression ; Female ; Gene Expression Regulation, Neoplastic ; Genetic Predisposition to Disease ; Histones/*genetics/metabolism ; Humans ; *Multigene Family ; Phenotype ; Protein Binding ; Protein Interaction Domains and Motifs ; Up-Regulation ; },
abstract = {Alterations in nuclear morphology are common in cancer progression. However, the degree to which gross morphological abnormalities translate into compromised higher-order chromatin organization is poorly understood. To explore the functional links between gene expression and chromatin structure in breast cancer, we performed RNA-seq gene expression analysis on the basal breast cancer progression model based on human MCF10A cells. Positional gene enrichment identified the major histone gene cluster at chromosome 6p22 as one of the most significantly upregulated (and not amplified) clusters of genes from the normal-like MCF10A to premalignant MCF10AT1 and metastatic MCF10CA1a cells. This cluster is subdivided into three sub-clusters of histone genes that are organized into hierarchical topologically associating domains (TADs). Interestingly, the sub-clusters of histone genes are located at TAD boundaries and interact more frequently with each other than the regions in-between them, suggesting that the histone sub-clusters form an active chromatin hub. The anchor sites of loops within this hub are occupied by CTCF, a known chromatin organizer. These histone genes are transcribed and processed at a specific sub-nuclear microenvironment termed the major histone locus body (HLB). While the overall chromatin structure of the major HLB is maintained across breast cancer progression, we detected alterations in its structure that may relate to gene expression. Importantly, breast tumor specimens also exhibit a coordinate pattern of upregulation across the major histone gene cluster. Our results provide a novel insight into the connection between the higher-order chromatin organization of the major HLB and its regulation during breast cancer progression.},
}
@article {pmid28487148,
year = {2017},
author = {Agarwal, H and Reisser, M and Wortmann, C and Gebhardt, JCM},
title = {Direct Observation of Cell-Cycle-Dependent Interactions between CTCF and Chromatin.},
journal = {Biophysical journal},
volume = {112},
number = {10},
pages = {2051-2055},
doi = {10.1016/j.bpj.2017.04.018},
pmid = {28487148},
issn = {1542-0086},
mesh = {CCCTC-Binding Factor ; Cell Cycle/*physiology ; Cell Line ; Chromatin/*metabolism ; Humans ; Kinetics ; Molecular Imaging ; Protein Binding ; Repressor Proteins/*metabolism ; },
abstract = {The three-dimensional arrangement of chromatin encodes regulatory traits important for nuclear processes such as transcription and replication. Chromatin topology is in part mediated by the architectural protein CCCTC-binding factor (CTCF) that binds to the boundaries of topologically associating domains. Whereas sites of CTCF interactions are well characterized, little is known on how long CTCF binds to chromatin and how binding evolves during the cell cycle. We monitored CTCF-chromatin interactions by live cell single molecule tracking in different phases of the cell cycle. In G1-, S-, and G2-phases, a majority of CTCF molecules was bound transiently (∼0.2 s) to chromatin, whereas minor fractions were bound dynamically (∼4 s) or stably (>15 min). During mitosis, CTCF was mostly excluded from chromatin. Our data suggest that CTCF scans DNA in search for two different subsets of specific target sites and provide information on the timescales over which topologically associating domains might be restructured. During S-phase, dynamic and stable interactions decreased considerably compared to G1-phase, but were resumed in G2-phase, indicating that specific interactions need to be dissolved for replication to proceed.},
}
@article {pmid28475875,
year = {2017},
author = {Siersbæk, R and Madsen, JGS and Javierre, BM and Nielsen, R and Bagge, EK and Cairns, J and Wingett, SW and Traynor, S and Spivakov, M and Fraser, P and Mandrup, S},
title = {Dynamic Rewiring of Promoter-Anchored Chromatin Loops during Adipocyte Differentiation.},
journal = {Molecular cell},
volume = {66},
number = {3},
pages = {420-435.e5},
doi = {10.1016/j.molcel.2017.04.010},
pmid = {28475875},
issn = {1097-4164},
support = {MR/L007150/1//Medical Research Council/United Kingdom ; },
mesh = {3T3-L1 Cells ; Adipocytes/*metabolism ; *Adipogenesis ; Animals ; Cell Cycle Proteins/genetics/metabolism ; Chromatin/chemistry/genetics/*metabolism ; *Chromatin Assembly and Disassembly ; Chromatin Immunoprecipitation ; Chromosomal Proteins, Non-Histone/genetics/metabolism ; E1A-Associated p300 Protein/genetics/metabolism ; Enhancer Elements, Genetic ; Mediator Complex Subunit 1/genetics/metabolism ; Mice ; Nucleic Acid Conformation ; *Promoter Regions, Genetic ; RNA, Messenger/genetics/metabolism ; Sequence Analysis, RNA ; Time Factors ; Transcription, Genetic ; Transcriptional Activation ; },
abstract = {Interactions between transcriptional promoters and their distal regulatory elements play an important role in transcriptional regulation; however, the extent to which these interactions are subject to rapid modulations in response to signals is unknown. Here, we use promoter capture Hi-C to demonstrate a rapid reorganization of promoter-anchored chromatin loops within 4 hr after inducing differentiation of 3T3-L1 preadipocytes. The establishment of new promoter-enhancer loops is tightly coupled to activation of poised (histone H3 lysine 4 mono- and dimethylated) enhancers, as evidenced by the acquisition of histone H3 lysine 27 acetylation and the binding of MED1, SMC1, and P300 proteins to these regions, as well as to activation of target genes. Intriguingly, formation of loops connecting activated enhancers and promoters is also associated with extensive recruitment of corepressors such as NCoR and HDACs, indicating that this class of coregulators may play a previously unrecognized role during enhancer activation.},
}
@article {pmid28435001,
year = {2017},
author = {Belaghzal, H and Dekker, J and Gibcus, JH},
title = {Hi-C 2.0: An optimized Hi-C procedure for high-resolution genome-wide mapping of chromosome conformation.},
journal = {Methods (San Diego, Calif.)},
volume = {123},
number = {},
pages = {56-65},
doi = {10.1016/j.ymeth.2017.04.004},
pmid = {28435001},
issn = {1095-9130},
support = {R01 GM112720/GM/NIGMS NIH HHS/United States ; R01 HG003143/HG/NHGRI NIH HHS/United States ; U01 HG007910/HG/NHGRI NIH HHS/United States ; U54 DK107980/DK/NIDDK NIH HHS/United States ; R01 AI117839/AI/NIAID NIH HHS/United States ; U01 DA040588/DA/NIDA NIH HHS/United States ; U54 HG007010/HG/NHGRI NIH HHS/United States ; U54 CA193419/CA/NCI NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; },
mesh = {Base Sequence ; Biotin/chemistry ; Cell Line ; Chromosome Mapping/*methods ; Chromosomes/*chemistry/ultrastructure ; Cross-Linking Reagents/chemistry ; DNA/*chemistry ; Deoxyribonucleases, Type II Site-Specific/chemistry ; Formaldehyde/chemistry ; *Genome, Human ; High-Throughput Nucleotide Sequencing ; Humans ; Staining and Labeling/*methods ; },
abstract = {Chromosome conformation capture-based methods such as Hi-C have become mainstream techniques for the study of the 3D organization of genomes. These methods convert chromatin interactions reflecting topological chromatin structures into digital information (counts of pair-wise interactions). Here, we describe an updated protocol for Hi-C (Hi-C 2.0) that integrates recent improvements into a single protocol for efficient and high-resolution capture of chromatin interactions. This protocol combines chromatin digestion and frequently cutting enzymes to obtain kilobase (kb) resolution. It also includes steps to reduce random ligation and the generation of uninformative molecules, such as unligated ends, to improve the amount of valid intra-chromosomal read pairs. This protocol allows for obtaining information on conformational structures such as compartment and topologically associating domains, as well as high-resolution conformational features such as DNA loops.},
}
@article {pmid28420341,
year = {2017},
author = {Nikumbh, S and Pfeifer, N},
title = {Genetic sequence-based prediction of long-range chromatin interactions suggests a potential role of short tandem repeat sequences in genome organization.},
journal = {BMC bioinformatics},
volume = {18},
number = {1},
pages = {218},
doi = {10.1186/s12859-017-1624-x},
pmid = {28420341},
issn = {1471-2105},
mesh = {Chromatin/*genetics ; Genome/*genetics ; Humans ; Microsatellite Repeats/*genetics ; Promoter Regions, Genetic/*genetics ; Regulatory Sequences, Nucleic Acid ; },
abstract = {BACKGROUND: Knowing the three-dimensional (3D) structure of the chromatin is important for obtaining a complete picture of the regulatory landscape. Changes in the 3D structure have been implicated in diseases. While there exist approaches that attempt to predict the long-range chromatin interactions, they focus only on interactions between specific genomic regions - the promoters and enhancers, neglecting other possibilities, for instance, the so-called structural interactions involving intervening chromatin.<br><br>RESULTS: We present a method that can be trained on 5C data using the genetic sequence of the candidate loci to predict potential genome-wide interaction partners of a particular locus of interest. We have built locus-specific support vector machine (SVM)-based predictors using the oligomer distance histograms (ODH) representation. The method shows good performance with a mean test AUC (area under the receiver operating characteristic (ROC) curve) of 0.7 or higher for various regions across cell lines GM12878, K562 and HeLa-S3. In cases where any locus did not have sufficient candidate interaction partners for model training, we employed multitask learning to share knowledge between models of different loci. In this scenario, across the three cell lines, the method attained an average performance increase of 0.09 in the AUC. Performance evaluation of the models trained on 5C data regarding prediction on an independent high-resolution Hi-C dataset (which is a rather hard problem) shows 0.56 AUC, on average. Additionally, we have developed new, intuitive visualization methods that enable interpretation of sequence signals that contributed towards prediction of locus-specific interaction partners. The analysis of these sequence signals suggests a potential general role of short tandem repeat sequences in genome organization.<br><br>CONCLUSIONS: We demonstrated how our approach can 1) provide insights into sequence features of locus-specific interaction partners, and 2) also identify their cell-line specificity. That our models deem short tandem repeat sequences as discriminative for prediction of potential interaction partners, suggests that they could play a larger role in genome organization. Thus, our approach can (a) be beneficial to broadly understand, at the sequence-level, chromatin interactions and higher-order structures like (meta-) topologically associating domains (TADs); (b) study regions omitted from existing prediction approaches using various information sources (e.g., epigenetic information); and},
}
@article {pmid28408976,
year = {2017},
author = {Kaiser, VB and Semple, CA},
title = {When TADs go bad: chromatin structure and nuclear organisation in human disease.},
journal = {F1000Research},
volume = {6},
number = {},
pages = {},
doi = {10.12688/f1000research.10792.1},
pmid = {28408976},
issn = {2046-1402},
abstract = {Chromatin in the interphase nucleus is organised as a hierarchical series of structural domains, including self-interacting domains called topologically associating domains (TADs). This arrangement is thought to bring enhancers into closer physical proximity with their target genes, which often are located hundreds of kilobases away in linear genomic distance. TADs are demarcated by boundary regions bound by architectural proteins, such as CTCF and cohesin, although much remains to be discovered about the structure and function of these domains. Recent studies of TAD boundaries disrupted in engineered mouse models show that boundary mutations can recapitulate human developmental disorders as a result of aberrant promoter-enhancer interactions in the affected TADs. Similar boundary disruptions in certain cancers can result in oncogene overexpression, and CTCF binding sites at boundaries appear to be hyper-mutated across cancers. Further insights into chromatin organisation, in parallel with accumulating whole genome sequence data for disease cohorts, are likely to yield additional valuable insights into the roles of noncoding sequence variation in human disease.},
}
@article {pmid28399667,
year = {2017},
author = {Chatterjee, S and Ahituv, N},
title = {Gene Regulatory Elements, Major Drivers of Human Disease.},
journal = {Annual review of genomics and human genetics},
volume = {18},
number = {},
pages = {45-63},
doi = {10.1146/annurev-genom-091416-035537},
pmid = {28399667},
issn = {1545-293X},
support = {R01 CA197139/CA/NCI NIH HHS/United States ; UM1 HG009408/HG/NHGRI NIH HHS/United States ; R01 MH109907/MH/NIMH NIH HHS/United States ; P01 HD084387/HD/NICHD NIH HHS/United States ; },
mesh = {CRISPR-Cas Systems ; *Enhancer Elements, Genetic ; *Gene Regulatory Networks ; High-Throughput Nucleotide Sequencing/methods ; Humans ; *Promoter Regions, Genetic ; Sequence Analysis, DNA/methods ; },
abstract = {Gene expression changes, the driving forces for cellular diversity in multicellular organisms, are regulated by a diverse set of gene regulatory elements that direct transcription in specific cells. Mutations in these elements, ranging from chromosomal aberrations to single-nucleotide polymorphisms, are a major cause of human disease. However, we currently have a very limited understanding of how regulatory element genotypes lead to specific phenotypes. In this review, we discuss the various methods of regulatory element identification, the different types of mutations they harbor, and their impact on human disease. We highlight how these variations can affect transcription of multiple genes in gene regulatory networks. In addition, we describe how novel technologies, such as massively parallel reporter assays and CRISPR/Cas9 genome editing, are beginning to provide a better understanding of the functional roles that these elements have and how their alteration can lead to specific phenotypes.},
}
@article {pmid28388407,
year = {2017},
author = {Hug, CB and Grimaldi, AG and Kruse, K and Vaquerizas, JM},
title = {Chromatin Architecture Emerges during Zygotic Genome Activation Independent of Transcription.},
journal = {Cell},
volume = {169},
number = {2},
pages = {216-228.e19},
doi = {10.1016/j.cell.2017.03.024},
pmid = {28388407},
issn = {1097-4172},
mesh = {Animals ; Chromatin/*metabolism ; Drosophila Proteins/metabolism ; Drosophila melanogaster/*embryology/*genetics ; Embryo, Nonmammalian/metabolism ; Genes, Essential ; *Genome, Insect ; RNA Polymerase II/metabolism ; Time Factors ; Transcription Factors/metabolism ; Transcription, Genetic ; *Transcriptional Activation ; Zygote/*metabolism ; },
abstract = {Chromatin architecture is fundamental in regulating gene expression. To investigate when spatial genome organization is first established during development, we examined chromatin conformation during Drosophila embryogenesis and observed the emergence of chromatin architecture within a tight time window that coincides with the onset of transcription activation in the zygote. Prior to zygotic genome activation, the genome is mostly unstructured. Early expressed genes serve as nucleation sites for topologically associating domain (TAD) boundaries. Activation of gene expression coincides with the establishment of TADs throughout the genome and co-localization of housekeeping gene clusters, which remain stable in subsequent stages of development. However, the appearance of TAD boundaries is independent of transcription and requires the transcription factor Zelda for locus-specific TAD boundary insulation. These results offer insight into when spatial organization of the genome emerges and identify a key factor that helps trigger this architecture.},
}
@article {pmid28359583,
year = {2017},
author = {Fanucchi, S and Mhlanga, MM},
title = {Enhancer-Derived lncRNAs Regulate Genome Architecture: Fact or Fiction?.},
journal = {Trends in genetics : TIG},
volume = {33},
number = {6},
pages = {375-377},
doi = {10.1016/j.tig.2017.03.004},
pmid = {28359583},
issn = {0168-9525},
mesh = {Chromosomes/*genetics ; *Enhancer Elements, Genetic ; Epigenesis, Genetic ; Genome, Human ; Genome-Wide Association Study ; Humans ; Promoter Regions, Genetic ; RNA, Long Noncoding/*genetics ; Regulatory Sequences, Nucleic Acid/genetics ; },
abstract = {How does the non-coding portion of the genome contribute to the regulation of genome architecture? A recent paper by Tan et al. focuses on the relationship between cis-acting complex-trait-associated lincRNAs and the formation of chromosomal contacts in topologically associating domains (TADs).},
}
@article {pmid28355537,
year = {2017},
author = {Brackley, CA and Liebchen, B and Michieletto, D and Mouvet, F and Cook, PR and Marenduzzo, D},
title = {Ephemeral Protein Binding to DNA Shapes Stable Nuclear Bodies and Chromatin Domains.},
journal = {Biophysical journal},
volume = {112},
number = {6},
pages = {1085-1093},
doi = {10.1016/j.bpj.2017.01.025},
pmid = {28355537},
issn = {1542-0086},
mesh = {Cell Nucleus/*metabolism ; Chromatin/*metabolism ; DNA/chemistry/*metabolism ; DNA-Binding Proteins/chemistry/*metabolism ; Microscopy, Fluorescence ; Models, Molecular ; Nucleic Acid Conformation ; Protein Binding ; Protein Conformation ; },
abstract = {Fluorescence microscopy reveals that the contents of many (membrane-free) nuclear bodies exchange rapidly with the soluble pool while the underlying structure persists; such observations await a satisfactory biophysical explanation. To shed light on this, we perform large-scale Brownian dynamics simulations of a chromatin fiber interacting with an ensemble of (multivalent) DNA-binding proteins able to switch between an &quot;on&quot; (binding) and an &quot;off&quot; (nonbinding) state. This system provides a model for any DNA-binding protein that can be posttranslationally modified to change its affinity for DNA (e.g., through phosphorylation). Protein switching is a nonequilibrium process, and it leads to the formation of clusters of self-limiting size, where individual proteins in a cluster exchange with the soluble pool with kinetics similar to those seen in photobleaching experiments. This behavior contrasts sharply with that exhibited by nonswitching proteins, which are permanently in the on-state; when these bind to DNA nonspecifically, they form clusters that grow indefinitely in size. To explain these findings, we propose a mean-field theory from which we obtain a scaling relation between the typical cluster size and the protein switching rate. Protein switching also reshapes intrachromatin contacts to give networks resembling those seen in topologically associating domains, as switching markedly favors local (short-range) contacts over distant ones. Our results point to posttranslational modification of chromatin-bridging proteins as a generic mechanism driving the self-assembly of highly dynamic, nonequilibrium, protein clusters with the properties of nuclear bodies.},
}
@article {pmid28355183,
year = {2017},
author = {Flyamer, IM and Gassler, J and Imakaev, M and Brandão, HB and Ulianov, SV and Abdennur, N and Razin, SV and Mirny, LA and Tachibana-Konwalski, K},
title = {Single-nucleus Hi-C reveals unique chromatin reorganization at oocyte-to-zygote transition.},
journal = {Nature},
volume = {544},
number = {7648},
pages = {110-114},
doi = {10.1038/nature21711},
pmid = {28355183},
issn = {1476-4687},
support = {336460//European Research Council/International ; R01 GM114190/GM/NIGMS NIH HHS/United States ; U54 DK107980/DK/NIDDK NIH HHS/United States ; },
mesh = {Animals ; Cell Nucleus/genetics/*metabolism ; Cell Transdifferentiation ; Cellular Reprogramming ; Chromatin/chemistry/genetics/*metabolism ; *Chromosome Positioning ; Female ; Haploidy ; Interphase ; Maternal Inheritance/genetics ; Mice ; Nucleic Acid Conformation ; Oocytes/*cytology/metabolism ; Paternal Inheritance/genetics ; Single-Cell Analysis/*methods ; Stochastic Processes ; Totipotent Stem Cells/cytology/metabolism ; Zygote/*cytology/metabolism ; },
abstract = {Chromatin is reprogrammed after fertilization to produce a totipotent zygote with the potential to generate a new organism. The maternal genome inherited from the oocyte and the paternal genome provided by sperm coexist as separate haploid nuclei in the zygote. How these two epigenetically distinct genomes are spatially organized is poorly understood. Existing chromosome conformation capture-based methods are not applicable to oocytes and zygotes owing to a paucity of material. To study three-dimensional chromatin organization in rare cell types, we developed a single-nucleus Hi-C (high-resolution chromosome conformation capture) protocol that provides greater than tenfold more contacts per cell than the previous method. Here we show that chromatin architecture is uniquely reorganized during the oocyte-to-zygote transition in mice and is distinct in paternal and maternal nuclei within single-cell zygotes. Features of genomic organization including compartments, topologically associating domains (TADs) and loops are present in individual oocytes when averaged over the genome, but the presence of each feature at a locus varies between cells. At the sub-megabase level, we observed stochastic clusters of contacts that can occur across TAD boundaries but average into TADs. Notably, we found that TADs and loops, but not compartments, are present in zygotic maternal chromatin, suggesting that these are generated by different mechanisms. Our results demonstrate that the global chromatin organization of zygote nuclei is fundamentally different from that of other interphase cells. An understanding of this zygotic chromatin 'ground state' could potentially provide insights into reprogramming cells to a state of totipotency.},
}
@article {pmid28348222,
year = {2017},
author = {Eser, U and Chandler-Brown, D and Ay, F and Straight, AF and Duan, Z and Noble, WS and Skotheim, JM},
title = {Form and function of topologically associating genomic domains in budding yeast.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {114},
number = {15},
pages = {E3061-E3070},
doi = {10.1073/pnas.1612256114},
pmid = {28348222},
issn = {1091-6490},
support = {P50 GM107615/GM/NIGMS NIH HHS/United States ; R01 GM092925/GM/NIGMS NIH HHS/United States ; T32 GM007276/GM/NIGMS NIH HHS/United States ; U54 DK107979/DK/NIDDK NIH HHS/United States ; },
mesh = {Chromatin/*metabolism ; Chromatin Assembly and Disassembly ; Chromosomes, Fungal/genetics ; DNA Replication Timing ; *Genome, Fungal ; *Genomics ; Saccharomyces cerevisiae Proteins/genetics/*metabolism ; Saccharomycetales/*genetics ; Structure-Activity Relationship ; },
abstract = {The genome of metazoan cells is organized into topologically associating domains (TADs) that have similar histone modifications, transcription level, and DNA replication timing. Although similar structures appear to be conserved in fission yeast, computational modeling and analysis of high-throughput chromosome conformation capture (Hi-C) data have been used to argue that the small, highly constrained budding yeast chromosomes could not have these structures. In contrast, herein we analyze Hi-C data for budding yeast and identify 200-kb scale TADs, whose boundaries are enriched for transcriptional activity. Furthermore, these boundaries separate regions of similarly timed replication origins connecting the long-known effect of genomic context on replication timing to genome architecture. To investigate the molecular basis of TAD formation, we performed Hi-C experiments on cells depleted for the Forkhead transcription factors, Fkh1 and Fkh2, previously associated with replication timing. Forkhead factors do not regulate TAD formation, but do promote longer-range genomic interactions and control interactions between origins near the centromere. Thus, our work defines spatial organization within the budding yeast nucleus, demonstrates the conserved role of genome architecture in regulating DNA replication, and identifies a molecular mechanism specifically regulating interactions between pericentric origins.},
}
@article {pmid28334818,
year = {2017},
author = {Sauerwald, N and Zhang, S and Kingsford, C and Bahar, I},
title = {Chromosomal dynamics predicted by an elastic network model explains genome-wide accessibility and long-range couplings.},
journal = {Nucleic acids research},
volume = {45},
number = {7},
pages = {3663-3673},
doi = {10.1093/nar/gkx172},
pmid = {28334818},
issn = {1362-4962},
support = {R01 HG007104/HG/NHGRI NIH HHS/United States ; P30 DA035778/DA/NIDA NIH HHS/United States ; P41 GM103712/GM/NIGMS NIH HHS/United States ; R01 GM099738/GM/NIGMS NIH HHS/United States ; U54 HG008540/HG/NHGRI NIH HHS/United States ; },
mesh = {Cell Line ; Chromatin/*chemistry ; Gene Expression ; Genetic Loci ; Genome ; Genomics ; Humans ; *Models, Genetic ; Sequence Analysis, DNA ; },
abstract = {Understanding the three-dimensional (3D) architecture of chromatin and its relation to gene expression and regulation is fundamental to understanding how the genome functions. Advances in Hi-C technology now permit us to study 3D genome organization, but we still lack an understanding of the structural dynamics of chromosomes. The dynamic couplings between regions separated by large genomic distances (>50 Mb) have yet to be characterized. We adapted a well-established protein-modeling framework, the Gaussian Network Model (GNM), to model chromatin dynamics using Hi-C data. We show that the GNM can identify spatial couplings at multiple scales: it can quantify the correlated fluctuations in the positions of gene loci, find large genomic compartments and smaller topologically-associating domains (TADs) that undergo en bloc movements, and identify dynamically coupled distal regions along the chromosomes. We show that the predictions of the GNM correlate well with genome-wide experimental measurements. We use the GNM to identify novel cross-correlated distal domains (CCDDs) representing pairs of regions distinguished by their long-range dynamic coupling and show that CCDDs are associated with increased gene co-expression. Together, these results show that GNM provides a mathematically well-founded unified framework for modeling chromatin dynamics and assessing the structural basis of genome-wide observations.},
}
@article {pmid28334773,
year = {2017},
author = {Dali, R and Blanchette, M},
title = {A critical assessment of topologically associating domain prediction tools.},
journal = {Nucleic acids research},
volume = {45},
number = {6},
pages = {2994-3005},
doi = {10.1093/nar/gkx145},
pmid = {28334773},
issn = {1362-4962},
mesh = {Algorithms ; Binding Sites ; CCCTC-Binding Factor ; Chromosomes/*chemistry ; *High-Throughput Nucleotide Sequencing ; Humans ; Repressor Proteins/metabolism ; *Sequence Analysis, DNA ; *Software ; },
abstract = {Topologically associating domains (TADs) have been proposed to be the basic unit of chromosome folding and have been shown to play key roles in genome organization and gene regulation. Several different tools are available for TAD prediction, but their properties have never been thoroughly assessed. In this manuscript, we compare the output of seven different TAD prediction tools on two published Hi-C data sets. TAD predictions varied greatly between tools in number, size distribution and other biological properties. Assessed against a manual annotation of TADs, individual TAD boundary predictions were found to be quite reliable, but their assembly into complete TAD structures was much less so. In addition, many tools were sensitive to sequencing depth and resolution of the interaction frequency matrix. This manuscript provides users and designers of TAD prediction tools with information that will help guide the choice of tools and the interpretation of their predictions.},
}
@article {pmid28315703,
year = {2017},
author = {Carlberg, C},
title = {Molecular endocrinology of vitamin D on the epigenome level.},
journal = {Molecular and cellular endocrinology},
volume = {453},
number = {},
pages = {14-21},
doi = {10.1016/j.mce.2017.03.016},
pmid = {28315703},
issn = {1872-8057},
mesh = {Chromatin/genetics/metabolism ; Endocrine System/*metabolism ; *Epigenesis, Genetic ; Gene Expression Regulation ; Genome-Wide Association Study ; Humans ; Ligands ; Receptors, Calcitriol/*genetics/*metabolism ; Transcription Factors/genetics/metabolism ; Vitamin D/*genetics/*metabolism ; },
abstract = {The molecular endocrinology of vitamin D is based on the facts that i) its metabolite 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) is the high affinity ligand of the nuclear receptor vitamin D receptor (VDR) and ii) the transcription factor VDR is the unique target of 1,25(OH)2D3 in the nucleus. Short-term alterations of the epigenome are primarily changes in the post-translational modification status of nucleosome-forming histone proteins, the consequences of which are i) a local increase or decrease in chromatin accessibility and ii) the activation or repression of gene transcription. Vitamin D has via VDR a direct effect on the expression of several hundred primary target genes implying numerous effects on the epigenome. Next-generation sequencing methods, such as ChIP-seq and FAIRE-seq, were applied to cellular model systems of vitamin D signaling, such as THP-1 human monocytes, and provided data for a chromatin model of vitamin D signaling. Key points of this model are that i) in the absence of ligand VDR binds to a limited number of loci within accessible chromatin, ii) a stimulation with ligand increases the number of DNA-bound VDR molecules, iii) VDR's access to genomic DNA is supported by pioneer factors, such as PU.1 in monocytes, iv) VDR binding leads to local opening of chromatin and v) the binding strength of topologically associating domain anchor forming CCCTC-binding factor sites upstream and downstream of prominent VDR binding sites is changing in response to ligand stimulation. This model provides the present basis of the molecular endocrinology of vitamin D and will be in future refined by the integration of vitamin D-sensitive chromatin markers and other genome-wide data, such as the 1,25(OH)2D3-sensitive binding of co-factors, chromatin modifying enzymes and chromatin remodeling proteins.},
}
@article {pmid28252665,
year = {2017},
author = {Yoshida, J and Akagi, K and Misawa, R and Kokubu, C and Takeda, J and Horie, K},
title = {Chromatin states shape insertion profiles of the piggyBac, Tol2 and Sleeping Beauty transposons and murine leukemia virus.},
journal = {Scientific reports},
volume = {7},
number = {},
pages = {43613},
doi = {10.1038/srep43613},
pmid = {28252665},
issn = {2045-2322},
support = {R50 CA211533/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Chromatin/*genetics ; Chromatin Assembly and Disassembly ; *DNA Transposable Elements ; Gene Expression ; Gene Expression Regulation ; Gene Order ; Genetic Vectors/*genetics ; Genome ; Genomics/methods ; Histones/metabolism ; Leukemia Virus, Murine/*physiology ; Mice ; Models, Biological ; Mouse Embryonic Stem Cells/metabolism ; *Mutagenesis, Insertional ; Protein Binding ; Sequence Analysis, DNA ; Transcription Factors/metabolism ; Transcription Initiation Site ; *Virus Integration ; },
abstract = {DNA transposons and retroviruses are versatile tools in functional genomics and gene therapy. To facilitate their application, we conducted a genome-wide insertion site profiling of the piggyBac (PB), Tol2 and Sleeping Beauty (SB) transposons and the murine leukemia virus (MLV) in mouse embryonic stem cells (ESCs). PB and MLV preferred highly expressed genes, whereas Tol2 and SB preferred weakly expressed genes. However, correlations with DNase I hypersensitive sites were different for all vectors, indicating that chromatin accessibility is not the sole determinant. Therefore, we analysed various chromatin states. PB and MLV highly correlated with Cohesin, Mediator and ESC-specific transcription factors. Notably, CTCF sites were correlated with PB but not with MLV, suggesting MLV prefers smaller promoter-enhancer loops, whereas PB insertion encompasses larger chromatin loops termed topologically associating domains. Tol2 also correlated with Cohesin and CTCF. However, correlations with ESC-specific transcription factors were weaker, suggesting that Tol2 prefers transcriptionally weak chromatin loops. Consistently, Tol2 insertions were associated with bivalent histone modifications characteristic of silent and inducible loci. SB showed minimum preference to all chromatin states, suggesting the least adverse effect on adjacent genes. These results will be useful for vector selection for various applications.},
}
@article {pmid28167501,
year = {2017},
author = {Zhu, Y and Gong, K and Denholtz, M and Chandra, V and Kamps, MP and Alber, F and Murre, C},
title = {Comprehensive characterization of neutrophil genome topology.},
journal = {Genes &amp; development},
volume = {31},
number = {2},
pages = {141-153},
doi = {10.1101/gad.293910.116},
pmid = {28167501},
issn = {1549-5477},
support = {U54 DK107981/DK/NIDDK NIH HHS/United States ; P01 AI102853/AI/NIAID NIH HHS/United States ; P30 NS047101/NS/NINDS NIH HHS/United States ; U54 DK107977/DK/NIDDK NIH HHS/United States ; Z01 AI000880/AI/NIAID NIH HHS/United States ; P30 CA023100/CA/NCI NIH HHS/United States ; },
mesh = {Cell Differentiation/*genetics ; Chromosomes/genetics/metabolism ; DNA, Ribosomal/genetics/metabolism ; Epigenesis, Genetic ; Gene Expression Regulation, Developmental/genetics ; Genome, Human/*genetics ; HEK293 Cells ; Humans ; Long Interspersed Nucleotide Elements/genetics ; Neutrophils/*cytology ; Receptors, Cytoplasmic and Nuclear/metabolism ; },
abstract = {Neutrophils are responsible for the first line of defense against invading pathogens. Their nuclei are uniquely structured as multiple lobes that establish a highly constrained nuclear environment. Here we found that neutrophil differentiation was not associated with large-scale changes in the number and sizes of topologically associating domains (TADs). However, neutrophil genomes were enriched for long-range genomic interactions that spanned multiple TADs. Population-based simulation of spherical and toroid genomes revealed declining radii of gyration for neutrophil chromosomes. We found that neutrophil genomes were highly enriched for heterochromatic genomic interactions across vast genomic distances, a process named supercontraction. Supercontraction involved genomic regions located in the heterochromatic compartment in both progenitors and neutrophils or genomic regions that switched from the euchromatic to the heterochromatic compartment during neutrophil differentiation. Supercontraction was accompanied by the repositioning of centromeres, pericentromeres, and long interspersed nuclear elements (LINEs) to the neutrophil nuclear lamina. We found that Lamin B receptor expression was required to attach centromeric and pericentromeric repeats but not LINE-1 elements to the lamina. Differentiating neutrophils also repositioned ribosomal DNA and mininucleoli to the lamina-a process that was closely associated with sharply reduced ribosomal RNA expression. We propose that large-scale chromatin reorganization involving supercontraction and recruitment of heterochromatin and nucleoli to the nuclear lamina facilitates the folding of the neutrophil genome into a confined geometry imposed by a multilobed nuclear architecture.},
}
@article {pmid28157505,
year = {2017},
author = {Kundu, S and Ji, F and Sunwoo, H and Jain, G and Lee, JT and Sadreyev, RI and Dekker, J and Kingston, RE},
title = {Polycomb Repressive Complex 1 Generates Discrete Compacted Domains that Change during Differentiation.},
journal = {Molecular cell},
volume = {65},
number = {3},
pages = {432-446.e5},
doi = {10.1016/j.molcel.2017.01.009},
pmid = {28157505},
issn = {1097-4164},
support = {R01 GM043901/GM/NIGMS NIH HHS/United States ; P30 DK040561/DK/NIDDK NIH HHS/United States ; R01 HG003143/HG/NHGRI NIH HHS/United States ; R01 GM090278/GM/NIGMS NIH HHS/United States ; U54 DK107980/DK/NIDDK NIH HHS/United States ; },
mesh = {Animals ; Cell Differentiation ; Cells, Cultured ; Chromatin/chemistry/genetics/metabolism ; DNA/chemistry/genetics/*metabolism ; Embryonic Stem Cells/*cytology/metabolism ; Epigenesis, Genetic ; Gene Expression Regulation, Developmental ; Histones/metabolism ; Homeodomain Proteins/metabolism ; Humans ; Mice ; Neural Stem Cells/*cytology/metabolism ; Polycomb Repressive Complex 1/chemistry/*metabolism ; Protein Domains ; Ubiquitination ; },
abstract = {Master regulatory genes require stable silencing by the polycomb group (PcG) to prevent misexpression during differentiation and development. Some PcG proteins covalently modify histones, which contributes to heritable repression. The role for other effects on chromatin structure is less understood. We characterized the organization of PcG target genes in ESCs and neural progenitors using 5C and super-resolution microscopy. The genomic loci of repressed PcG targets formed discrete, small (20-140 Kb) domains of tight interaction that corresponded to locations bound by canonical polycomb repressive complex 1 (PRC1). These domains changed during differentiation as PRC1 binding changed. Their formation depended upon the Polyhomeotic component of canonical PRC1 and occurred independently of PRC1-catalyzed ubiquitylation. PRC1 domains differ from topologically associating domains in size and boundary characteristics. These domains have the potential to play a key role in transmitting epigenetic silencing of PcG targets by linking PRC1 to formation of a repressive higher-order structure.},
}
@article {pmid28154080,
year = {2017},
author = {Wang, X and Brandão, HB and Le, TB and Laub, MT and Rudner, DZ},
title = {Bacillus subtilis SMC complexes juxtapose chromosome arms as they travel from origin to terminus.},
journal = {Science (New York, N.Y.)},
volume = {355},
number = {6324},
pages = {524-527},
doi = {10.1126/science.aai8982},
pmid = {28154080},
issn = {1095-9203},
support = {R01 GM073831/GM/NIGMS NIH HHS/United States ; R01 GM082899/GM/NIGMS NIH HHS/United States ; R01 GM086466/GM/NIGMS NIH HHS/United States ; },
mesh = {Adenosine Triphosphatases/*metabolism ; Bacillus subtilis/*genetics/*metabolism ; Bacterial Proteins/*metabolism ; Cell Cycle Proteins/*metabolism ; Chromosome Segregation ; Chromosomes, Bacterial/chemistry/*metabolism ; DNA, Bacterial/chemistry/metabolism ; DNA-Binding Proteins/*metabolism ; Multiprotein Complexes/*metabolism ; },
abstract = {Structural maintenance of chromosomes (SMC) complexes play critical roles in chromosome dynamics in virtually all organisms, but how they function remains poorly understood. In the bacterium Bacillus subtilis, SMC-condensin complexes are topologically loaded at centromeric sites adjacent to the replication origin. Here we provide evidence that these ring-shaped assemblies tether the left and right chromosome arms together while traveling from the origin to the terminus (>2 megabases) at rates >50 kilobases per minute. Condensin movement scales linearly with time, providing evidence for an active transport mechanism. These data support a model in which SMC complexes function by processively enlarging DNA loops. Loop formation followed by processive enlargement provides a mechanism by which condensin complexes compact and resolve sister chromatids in mitosis and by which cohesin generates topologically associating domains during interphase.},
}
@article {pmid28129029,
year = {2017},
author = {Chen, H and Seaman, L and Liu, S and Ried, T and Rajapakse, I},
title = {Chromosome conformation and gene expression patterns differ profoundly in human fibroblasts grown in spheroids versus monolayers.},
journal = {Nucleus (Austin, Tex.)},
volume = {8},
number = {4},
pages = {383-391},
doi = {10.1080/19491034.2017.1280209},
pmid = {28129029},
issn = {1949-1042},
mesh = {*Cell Culture Techniques ; Chromosomes/*chemistry ; Fibroblasts/*chemistry/*metabolism ; Gene Expression Profiling ; *Gene Expression Regulation ; Humans ; Molecular Conformation ; Real-Time Polymerase Chain Reaction ; Spheroids, Cellular/physiology ; },
abstract = {Human cells derived for in vitro cultures are conventionally grown as adherent monolayers (2D) which do not resemble natural 3 dimensional (3D) tissue architecture. We examined genome structure with chromosome conformation capture (Hi-C) and gene expression with RNA-seq in fibroblasts derived from human foreskin grown in 2D and 3D conditions. Our combined analysis of Hi-C and RNA-seq data shows a large number of differentially expressed genes between 2D and 3D cells, and these changes are localized in genomic regions that displayed structural changes. We also find a trend of expression in a subset of skin-specific genes in fibroblast cells grown in 3D that resembles those in native tissue.},
}
@article {pmid28108933,
year = {2017},
author = {Zhan, Y and Giorgetti, L and Tiana, G},
title = {Modelling genome-wide topological associating domains in mouse embryonic stem cells.},
journal = {Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology},
volume = {25},
number = {1},
pages = {5-14},
doi = {10.1007/s10577-016-9544-6},
pmid = {28108933},
issn = {1573-6849},
mesh = {Animals ; Chromatin Assembly and Disassembly ; Chromosomes/chemistry/*ultrastructure ; *Genome ; Mice ; Models, Biological ; *Mouse Embryonic Stem Cells/ultrastructure ; Transcription, Genetic ; },
abstract = {Chromosome conformation capture (3C)-based techniques such as chromosome conformation capture carbon copy (5C) and Hi-C revealed that the folding of mammalian chromosomes is highly hierarchical. A fundamental structural unit in the hierarchy is represented by topologically associating domains (TADs), sub-megabase regions of the genome within which the chromatin fibre preferentially interacts. 3C-based methods provide the mean contact probabilities between chromosomal loci, averaged over a large number of cells, and do not give immediate access to the single-cell conformations of the chromatin fibre. However, coarse-grained polymer models based on 5C data can be used to extract the single-cell conformations of single TADs. Here, we extend this approach to analyse around 2500 TADs in murine embryonic stem cells based on high-resolution Hi-C data. This allowed to predict the cell-to-cell variability in single contacts within genome-wide TADs and correlations between them. Based on these results, we predict that TADs are more similar to ideal chains than to globules in terms of their physical size and three-dimensional shape distribution. Furthermore, we show that their physical size and the degree of structural anisotropy of single TADs are correlated with the level of transcriptional activity of the genes that it harbours. Finally, we show that a large number of multiplets of genomic loci co-localize more often than expected by random, and these loci are particularly enriched in promoters, enhancers and CTCF-bound sites. These results provide the first genome-wide structural reconstruction of TADs using polymeric models obeying the laws of thermodynamics and reveal important universal trends in the correlation between chromosome structure and transcription.},
}
@article {pmid28060840,
year = {2017},
author = {Jabbari, K and Bernardi, G},
title = {An Isochore Framework Underlies Chromatin Architecture.},
journal = {PloS one},
volume = {12},
number = {1},
pages = {e0168023},
doi = {10.1371/journal.pone.0168023},
pmid = {28060840},
issn = {1932-6203},
mesh = {Animals ; Base Composition ; *Chromatin ; Chromosomes, Mammalian ; Cluster Analysis ; Evolution, Molecular ; GC Rich Sequence ; Humans ; *Isochores ; Mice ; Synteny ; },
abstract = {A recent investigation showed the existence of correlations between the architectural features of mammalian interphase chromosomes and the compositional properties of isochores. This result prompted us to compare maps of the Topologically Associating Domains (TADs) and of the Lamina Associated Domains (LADs) with the corresponding isochore maps of mouse and human chromosomes. This approach revealed that: 1) TADs and LADs correspond to isochores, i.e., isochores are the genomic units that underlie chromatin domains; 2) the conservation of TADs and LADs in mammalian genomes is explained by the evolutionary conservation of isochores; 3) chromatin domains corresponding to GC-poor isochores (e.g., LADs) show not only self-interactions but also intrachromosomal interactions with other domains also corresponding to GC-poor isochores even if located far away; in contrast, chromatin domains corresponding to GC-rich isochores (e.g., TADs) show more localized chromosomal interactions, many of which are inter-chromosomal. In conclusion, this investigation establishes a link between DNA sequences and chromatin architecture, explains the evolutionary conservation of TADs and LADs and provides new information on the spatial distribution of GC-poor/gene-poor and GC-rich/gene-rich chromosomal regions in the interphase nucleus.},
}
@article {pmid28060558,
year = {2017},
author = {Barutcu, AR and Lian, JB and Stein, JL and Stein, GS and Imbalzano, AN},
title = {The connection between BRG1, CTCF and topoisomerases at TAD boundaries.},
journal = {Nucleus (Austin, Tex.)},
volume = {8},
number = {2},
pages = {150-155},
doi = {10.1080/19491034.2016.1276145},
pmid = {28060558},
issn = {1949-1042},
support = {P01 CA082834/CA/NCI NIH HHS/United States ; R37 DE012528/DE/NIDCR NIH HHS/United States ; },
mesh = {Adenosine Triphosphatases/*metabolism ; Animals ; CCCTC-Binding Factor ; DNA Topoisomerases/*metabolism ; *Genomics ; Humans ; Nucleosomes/metabolism ; Repressor Proteins/*metabolism ; },
abstract = {The eukaryotic genome is partitioned into topologically associating domains (TADs). Despite recent advances characterizing TADs and TAD boundaries, the organization of these structures is an important dimension of genome architecture and function that is not well understood. Recently, we demonstrated that knockdown of BRG1, an ATPase driving the chromatin remodeling activity of mammalian SWI/SNF enzymes, globally alters long-range genomic interactions and results in a reduction of TAD boundary strength. We provided evidence suggesting that this effect may be due to BRG1 affecting nucleosome occupancy around CTCF sites present at TAD boundaries. In this review, we elaborate on our findings and speculate that BRG1 may contribute to the regulation of the structural and functional properties of chromatin at TAD boundaries by affecting the function or the recruitment of CTCF and DNA topoisomerase complexes.},
}
@article {pmid28057745,
year = {2017},
author = {Zhan, Y and Mariani, L and Barozzi, I and Schulz, EG and Blüthgen, N and Stadler, M and Tiana, G and Giorgetti, L},
title = {Reciprocal insulation analysis of Hi-C data shows that TADs represent a functionally but not structurally privileged scale in the hierarchical folding of chromosomes.},
journal = {Genome research},
volume = {27},
number = {3},
pages = {479-490},
doi = {10.1101/gr.212803.116},
pmid = {28057745},
issn = {1549-5469},
mesh = {*Algorithms ; Animals ; Cells, Cultured ; *Chromatin Assembly and Disassembly ; Chromosomes/*chemistry/genetics/metabolism ; Embryonic Stem Cells/metabolism ; Female ; Gene Expression Regulation, Developmental ; *Insulator Elements ; Mice ; Models, Theoretical ; Neural Stem Cells/metabolism ; },
abstract = {Understanding how regulatory sequences interact in the context of chromosomal architecture is a central challenge in biology. Chromosome conformation capture revealed that mammalian chromosomes possess a rich hierarchy of structural layers, from multi-megabase compartments to sub-megabase topologically associating domains (TADs) and sub-TAD contact domains. TADs appear to act as regulatory microenvironments by constraining and segregating regulatory interactions across discrete chromosomal regions. However, it is unclear whether other (or all) folding layers share similar properties, or rather TADs constitute a privileged folding scale with maximal impact on the organization of regulatory interactions. Here, we present a novel algorithm named CaTCH that identifies hierarchical trees of chromosomal domains in Hi-C maps, stratified through their reciprocal physical insulation, which is a single and biologically relevant parameter. By applying CaTCH to published Hi-C data sets, we show that previously reported folding layers appear at different insulation levels. We demonstrate that although no structurally privileged folding level exists, TADs emerge as a functionally privileged scale defined by maximal boundary enrichment in CTCF and maximal cell-type conservation. By measuring transcriptional output in embryonic stem cells and neural precursor cells, we show that the likelihood that genes in a domain are coregulated during differentiation is also maximized at the scale of TADs. Finally, we observe that regulatory sequences occur at genomic locations corresponding to optimized mutual interactions at the same scale. Our analysis suggests that the architectural functionality of TADs arises from the interplay between their ability to partition interactions and the specific genomic position of regulatory sequences.},
}
@article {pmid28035241,
year = {2016},
author = {Wachsmuth, M and Knoch, TA and Rippe, K},
title = {Dynamic properties of independent chromatin domains measured by correlation spectroscopy in living cells.},
journal = {Epigenetics &amp; chromatin},
volume = {9},
number = {},
pages = {57},
doi = {10.1186/s13072-016-0093-1},
pmid = {28035241},
issn = {1756-8935},
abstract = {BACKGROUND: Genome organization into subchromosomal topologically associating domains (TADs) is linked to cell-type-specific gene expression programs. However, dynamic properties of such domains remain elusive, and it is unclear how domain plasticity modulates genomic accessibility for soluble factors.<br><br>RESULTS: Here, we combine and compare a high-resolution topology analysis of interacting chromatin loci with fluorescence correlation spectroscopy measurements of domain dynamics in single living cells. We identify topologically and dynamically independent chromatin domains of ~1 Mb in size that are best described by a loop-cluster polymer model. Hydrodynamic relaxation times and gyration radii of domains are larger for open (161 ± 15 ms, 297 ± 9 nm) than for dense chromatin (88 ± 7 ms, 243 ± 6 nm) and increase globally upon chromatin hyperacetylation or ATP depletion.<br><br>CONCLUSIONS: Based on the domain structure and dynamics measurements, we propose a loop-cluster model for chromatin domains. It suggests that the regulation of chromatin accessibility for soluble factors displays a significantly stronger dependence on factor concentration than search processes within a static network.},
}
@article {pmid27974201,
year = {2016},
author = {Poulos, RC and Thoms, JAI and Guan, YF and Unnikrishnan, A and Pimanda, JE and Wong, JWH},
title = {Functional Mutations Form at CTCF-Cohesin Binding Sites in Melanoma Due to Uneven Nucleotide Excision Repair across the Motif.},
journal = {Cell reports},
volume = {17},
number = {11},
pages = {2865-2872},
doi = {10.1016/j.celrep.2016.11.055},
pmid = {27974201},
issn = {2211-1247},
mesh = {Binding Sites ; CCCTC-Binding Factor/*genetics/metabolism ; Cell Cycle Proteins/*genetics/metabolism ; Cell Line, Tumor ; Chromatin/genetics ; Chromosomal Proteins, Non-Histone/*genetics/metabolism ; DNA Repair/genetics ; Humans ; Melanoma/*genetics/pathology ; Mutation ; *Transcription, Genetic ; },
abstract = {CTCF binding sites are frequently mutated in cancer, but how these mutations accumulate and whether they broadly perturb CTCF binding are not well understood. Here, we report that skin cancers exhibit a highly specific asymmetric mutation pattern within CTCF motifs attributable to ultraviolet irradiation and differential nucleotide excision repair (NER). CTCF binding site mutations form independently of replication timing and are enriched at sites of CTCF/cohesin complex binding, suggesting a role for cohesin in stabilizing CTCF-DNA binding and impairing NER. Performing CTCF ChIP-seq in a melanoma cell line, we show CTCF binding site mutations to be functional by demonstrating allele-specific reduction of CTCF binding to mutant alleles. While topologically associating domains with mutated CTCF anchors in melanoma contain differentially expressed cancer-associated genes, CTCF motif mutations appear generally under neutral selection. However, the frequency and potential functional impact of such mutations in melanoma highlights the need to consider their impact on cellular phenotype in individual genomes.},
}
@article {pmid27940490,
year = {2016},
author = {Brant, L and Georgomanolis, T and Nikolic, M and Brackley, CA and Kolovos, P and van Ijcken, W and Grosveld, FG and Marenduzzo, D and Papantonis, A},
title = {Exploiting native forces to capture chromosome conformation in mammalian cell nuclei.},
journal = {Molecular systems biology},
volume = {12},
number = {12},
pages = {891},
doi = {10.15252/msb.20167311},
pmid = {27940490},
issn = {1744-4292},
mesh = {Animals ; Cell Nucleus/*genetics ; Chromosomes, Human/*chemistry/*genetics ; High-Throughput Nucleotide Sequencing/methods ; Human Umbilical Vein Endothelial Cells ; Humans ; Interphase ; K562 Cells ; Mammals/genetics ; Models, Genetic ; Nucleic Acid Conformation ; Oligonucleotide Array Sequence Analysis ; Sequence Analysis, DNA/methods ; },
abstract = {Mammalian interphase chromosomes fold into a multitude of loops to fit the confines of cell nuclei, and looping is tightly linked to regulated function. Chromosome conformation capture (3C) technology has significantly advanced our understanding of this structure-to-function relationship. However, all 3C-based methods rely on chemical cross-linking to stabilize spatial interactions. This step remains a &quot;black box&quot; as regards the biases it may introduce, and some discrepancies between microscopy and 3C studies have now been reported. To address these concerns, we developed &quot;i3C&quot;, a novel approach for capturing spatial interactions without a need for cross-linking. We apply i3C to intact nuclei of living cells and exploit native forces that stabilize chromatin folding. Using different cell types and loci, computational modeling, and a methylation-based orthogonal validation method, &quot;TALE-iD&quot;, we show that native interactions resemble cross-linked ones, but display improved signal-to-noise ratios and are more focal on regulatory elements and CTCF sites, while strictly abiding to topologically associating domain restrictions.},
}
@article {pmid27936932,
year = {2017},
author = {Achinger-Kawecka, J and Clark, SJ},
title = {Disruption of the 3D cancer genome blueprint.},
journal = {Epigenomics},
volume = {9},
number = {1},
pages = {47-55},
doi = {10.2217/epi-2016-0111},
pmid = {27936932},
issn = {1750-192X},
mesh = {Animals ; CCCTC-Binding Factor ; Chromatin Assembly and Disassembly ; *Epigenesis, Genetic ; *Gene Expression Regulation, Neoplastic ; *Genome, Human ; Humans ; Neoplasms/*genetics ; Repressor Proteins/genetics/metabolism ; },
abstract = {Recent advances in chromosome conformation capture technologies are improving the current appreciation of how 3D genome architecture affects its function in different cell types and disease. Long-range chromatin interactions are organized into topologically associated domains, which are known to play a role in constraining gene expression patterns. However, in cancer cells there are alterations in the 3D genome structure, which impacts on gene regulation. Disruption of topologically associated domains architecture can result in alterations in chromatin interactions that bring new regulatory elements and genes together, leading to altered expression of oncogenes and tumor suppressor genes. Here, we discuss the impact of genetic and epigenetic changes in cancer and how this affects the spatial organization of chromatin. Understanding how disruptions to the 3D architecture contribute to the cancer genome will provide novel insights into the principles of epigenetic gene regulation in cancer and mechanisms responsible for cancer associated mutations and rearrangements.},
}
@article {pmid27899590,
year = {2017},
author = {Cubeñas-Potts, C and Rowley, MJ and Lyu, X and Li, G and Lei, EP and Corces, VG},
title = {Different enhancer classes in Drosophila bind distinct architectural proteins and mediate unique chromatin interactions and 3D architecture.},
journal = {Nucleic acids research},
volume = {45},
number = {4},
pages = {1714-1730},
doi = {10.1093/nar/gkw1114},
pmid = {27899590},
issn = {1362-4962},
support = {R01 GM035463/GM/NIGMS NIH HHS/United States ; F32 GM113570/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Biomarkers ; Cell Line ; Chromatin/chemistry/*genetics/*metabolism ; Chromatin Immunoprecipitation ; Computational Biology/methods ; *DNA-Binding Proteins ; Drosophila/*genetics/*metabolism ; *Enhancer Elements, Genetic ; High-Throughput Nucleotide Sequencing ; Histones/metabolism ; Promoter Regions, Genetic ; Protein Binding ; },
abstract = {Eukaryotic gene expression is regulated by enhancer-promoter interactions but the molecular mechanisms that govern specificity have remained elusive. Genome-wide studies utilizing STARR-seq identified two enhancer classes in Drosophila that interact with different core promoters: housekeeping enhancers (hkCP) and developmental enhancers (dCP). We hypothesized that the two enhancer classes are occupied by distinct architectural proteins, affecting their enhancer-promoter contacts. By evaluating ChIP-seq occupancy of architectural proteins, typical enhancer-associated proteins, and histone modifications, we determine that both enhancer classes are enriched for RNA Polymerase II, CBP, and architectural proteins but there are also distinctions. hkCP enhancers contain H3K4me3 and exclusively bind Cap-H2, Chromator, DREF and Z4, whereas dCP enhancers contain H3K4me1 and are more enriched for Rad21 and Fs(1)h-L. Additionally, we map the interactions of each enhancer class utilizing a Hi-C dataset with <1 kb resolution. Results suggest that hkCP enhancers are more likely to form multi-TSS interaction networks and be associated with topologically associating domain (TAD) borders, while dCP enhancers are more often bound to one or two TSSs and are enriched at chromatin loop anchors. The data support a model suggesting that the unique architectural protein occupancy within enhancers is one contributor to enhancer-promoter interaction specificity.},
}
@article {pmid27869826,
year = {2017},
author = {Weischenfeldt, J and Dubash, T and Drainas, AP and Mardin, BR and Chen, Y and Stütz, AM and Waszak, SM and Bosco, G and Halvorsen, AR and Raeder, B and Efthymiopoulos, T and Erkek, S and Siegl, C and Brenner, H and Brustugun, OT and Dieter, SM and Northcott, PA and Petersen, I and Pfister, SM and Schneider, M and Solberg, SK and Thunissen, E and Weichert, W and Zichner, T and Thomas, R and Peifer, M and Helland, A and Ball, CR and Jechlinger, M and Sotillo, R and Glimm, H and Korbel, JO},
title = {Pan-cancer analysis of somatic copy-number alterations implicates IRS4 and IGF2 in enhancer hijacking.},
journal = {Nature genetics},
volume = {49},
number = {1},
pages = {65-74},
doi = {10.1038/ng.3722},
pmid = {27869826},
issn = {1546-1718},
mesh = {DNA Copy Number Variations/*genetics ; Enhancer Elements, Genetic/*genetics ; *Gene Expression Regulation, Neoplastic ; Genetic Association Studies ; Genetic Predisposition to Disease ; Humans ; Insulin Receptor Substrate Proteins/*genetics ; Insulin-Like Growth Factor II/*genetics ; Neoplasms/*genetics ; Promoter Regions, Genetic ; },
abstract = {Extensive prior research focused on somatic copy-number alterations (SCNAs) affecting cancer genes, yet the extent to which recurrent SCNAs exert their influence through rearrangement of cis-regulatory elements (CREs) remains unclear. Here we present a framework for inferring cancer-related gene overexpression resulting from CRE reorganization (e.g., enhancer hijacking) by integrating SCNAs, gene expression data and information on topologically associating domains (TADs). Analysis of 7,416 cancer genomes uncovered several pan-cancer candidate genes, including IRS4, SMARCA1 and TERT. We demonstrate that IRS4 overexpression in lung cancer is associated with recurrent deletions in cis, and we present evidence supporting a tumor-promoting role. We additionally pursued cancer-type-specific analyses and uncovered IGF2 as a target for enhancer hijacking in colorectal cancer. Recurrent tandem duplications intersecting with a TAD boundary mediate de novo formation of a 3D contact domain comprising IGF2 and a lineage-specific super-enhancer, resulting in high-level gene activation. Our framework enables systematic inference of CRE rearrangements mediating dysregulation in cancer.},
}
@article {pmid27867070,
year = {2016},
author = {Symmons, O and Pan, L and Remeseiro, S and Aktas, T and Klein, F and Huber, W and Spitz, F},
title = {The Shh Topological Domain Facilitates the Action of Remote Enhancers by Reducing the Effects of Genomic Distances.},
journal = {Developmental cell},
volume = {39},
number = {5},
pages = {529-543},
doi = {10.1016/j.devcel.2016.10.015},
pmid = {27867070},
issn = {1878-1551},
mesh = {Animals ; Congenital Abnormalities/embryology/genetics ; *Enhancer Elements, Genetic ; Gene Expression Regulation, Developmental ; Gene Regulatory Networks ; Hedgehog Proteins/*genetics ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Promoter Regions, Genetic ; },
abstract = {Gene expression often requires interaction between promoters and distant enhancers, which occur within the context of highly organized topologically associating domains (TADs). Using a series of engineered chromosomal rearrangements at the Shh locus, we carried out an extensive fine-scale characterization of the factors that govern the long-range regulatory interactions controlling Shh expression. We show that Shh enhancers act pervasively, yet not uniformly, throughout the TAD. Importantly, changing intra-TAD distances had no impact on Shh expression. In contrast, inversions disrupting the TAD altered global folding of the region and prevented regulatory contacts in a distance-dependent manner. Our data indicate that the Shh TAD promotes distance-independent contacts between distant regions that would otherwise interact only sporadically, enabling functional communication between them. In large genomes where genomic distances per se can limit regulatory interactions, this function of TADs could be as essential for gene expression as the formation of insulated neighborhoods.},
}
@article {pmid27851967,
year = {2016},
author = {Schmitt, AD and Hu, M and Jung, I and Xu, Z and Qiu, Y and Tan, CL and Li, Y and Lin, S and Lin, Y and Barr, CL and Ren, B},
title = {A Compendium of Chromatin Contact Maps Reveals Spatially Active Regions in the Human Genome.},
journal = {Cell reports},
volume = {17},
number = {8},
pages = {2042-2059},
doi = {10.1016/j.celrep.2016.10.061},
pmid = {27851967},
issn = {2211-1247},
support = {R01 HG006292/HG/NHGRI NIH HHS/United States ; R01 ES024984/ES/NIEHS NIH HHS/United States ; U54 DK107977/DK/NIDDK NIH HHS/United States ; R01 HL129132/HL/NHLBI NIH HHS/United States ; T32 GM008666/GM/NIGMS NIH HHS/United States ; P50 GM085764/GM/NIGMS NIH HHS/United States ; },
mesh = {Adult ; Animals ; Cell Cycle Proteins/metabolism ; Cell Line ; Chromatin/*metabolism ; Chromosomal Proteins, Non-Histone/metabolism ; Conserved Sequence ; Disease/genetics ; Enhancer Elements, Genetic/genetics ; Gene Expression Regulation ; *Genome, Human ; Genome-Wide Association Study ; Humans ; Insulator Elements/genetics ; Mice ; Nucleic Acid Conformation ; Organ Specificity ; Polymorphism, Single Nucleotide/genetics ; },
abstract = {The three-dimensional configuration of DNA is integral to all nuclear processes in eukaryotes, yet our knowledge of the chromosome architecture is still limited. Genome-wide chromosome conformation capture studies have uncovered features of chromatin organization in cultured cells, but genome architecture in human tissues has yet to be explored. Here, we report the most comprehensive survey to date of chromatin organization in human tissues. Through integrative analysis of chromatin contact maps in 21 primary human tissues and cell types, we find topologically associating domains highly conserved in different tissues. We also discover genomic regions that exhibit unusually high levels of local chromatin interactions. These frequently interacting regions (FIREs) are enriched for super-enhancers and are near tissue-specifically expressed genes. They display strong tissue-specificity in local chromatin interactions. Additionally, FIRE formation is partially dependent on CTCF and the Cohesin complex. We further show that FIREs can help annotate the function of non-coding sequence variants.},
}
@article {pmid27841970,
year = {2016},
author = {Brackley, CA and Michieletto, D and Mouvet, F and Johnson, J and Kelly, S and Cook, PR and Marenduzzo, D},
title = {Simulating topological domains in human chromosomes with a fitting-free model.},
journal = {Nucleus (Austin, Tex.)},
volume = {7},
number = {5},
pages = {453-461},
doi = {10.1080/19491034.2016.1239684},
pmid = {27841970},
issn = {1949-1042},
mesh = {Chromosomes, Human/*chemistry/metabolism ; Humans ; *Models, Molecular ; Molecular Conformation ; },
abstract = {We discuss a polymer model for the 3D organization of human chromosomes. A chromosome is represented by a string of beads, with each bead being &quot;colored&quot; according to 1D bioinformatic data (e.g., chromatin state, histone modification, GC content). Individual spheres (representing bi- and multi-valent transcription factors) can bind reversibly and selectively to beads with the appropriate color. During molecular dynamics simulations, the factors bind, and the string spontaneously folds into loops, rosettes, and topologically-associating domains (TADs). This organization occurs in the absence of any specified interactions between distant DNA segments, or between transcription factors. A comparison with Hi-C data shows that simulations predict the location of most boundaries between TADs correctly. The model is &quot;fitting-free&quot; in the sense that it does not use Hi-C data as an input; consequently, one of its strengths is that it can - in principle - be used to predict the 3D organization of any region of interest, or whole chromosome, in a given organism, or cell line, in the absence of existing Hi-C data. We discuss how this simple model might be refined to include more transcription factors and binding sites, and to correctly predict contacts between convergent CTCF binding sites.},
}
@article {pmid27764097,
year = {2016},
author = {Shinkai, S and Nozaki, T and Maeshima, K and Togashi, Y},
title = {Dynamic Nucleosome Movement Provides Structural Information of Topological Chromatin Domains in Living Human Cells.},
journal = {PLoS computational biology},
volume = {12},
number = {10},
pages = {e1005136},
doi = {10.1371/journal.pcbi.1005136},
pmid = {27764097},
issn = {1553-7358},
mesh = {Binding Sites ; Chromatin/*chemistry/*genetics/ultrastructure ; Chromatin Assembly and Disassembly/genetics ; Computer Simulation ; HeLa Cells ; Humans ; *Models, Chemical ; Models, Genetic ; Models, Molecular ; Molecular Conformation ; Molecular Imaging/*methods ; Motion ; Nucleosomes/*chemistry/*genetics/ultrastructure ; },
abstract = {The mammalian genome is organized into submegabase-sized chromatin domains (CDs) including topologically associating domains, which have been identified using chromosome conformation capture-based methods. Single-nucleosome imaging in living mammalian cells has revealed subdiffusively dynamic nucleosome movement. It is unclear how single nucleosomes within CDs fluctuate and how the CD structure reflects the nucleosome movement. Here, we present a polymer model wherein CDs are characterized by fractal dimensions and the nucleosome fibers fluctuate in a viscoelastic medium with memory. We analytically show that the mean-squared displacement (MSD) of nucleosome fluctuations within CDs is subdiffusive. The diffusion coefficient and the subdiffusive exponent depend on the structural information of CDs. This analytical result enabled us to extract information from the single-nucleosome imaging data for HeLa cells. Our observation that the MSD is lower at the nuclear periphery region than the interior region indicates that CDs in the heterochromatin-rich nuclear periphery region are more compact than those in the euchromatin-rich interior region with respect to the fractal dimensions as well as the size. Finally, we evaluated that the average size of CDs is in the range of 100-500 nm and that the relaxation time of nucleosome movement within CDs is a few seconds. Our results provide physical and dynamic insights into the genome architecture in living cells.},
}
@article {pmid27569350,
year = {2016},
author = {Neme, A and Seuter, S and Carlberg, C},
title = {Vitamin D-dependent chromatin association of CTCF in human monocytes.},
journal = {Biochimica et biophysica acta},
volume = {1859},
number = {11},
pages = {1380-1388},
doi = {10.1016/j.bbagrm.2016.08.008},
pmid = {27569350},
issn = {0006-3002},
mesh = {CCCTC-Binding Factor ; Cell Line ; Chromatin/*metabolism ; Gene Expression Regulation ; Humans ; Monocytes/*metabolism ; Receptors, Calcitriol/metabolism ; Repressor Proteins/genetics/*metabolism ; Vitamin D/*pharmacology ; },
abstract = {CCCTC-binding factor (CTCF) is a transcription factor being involved in 3D chromatin organization and displays a highly conserved genome-wide binding pattern. In this study, we report the cistrome of CTCF in THP-1 human monocytes and confirm that from the 40,078 CTCF binding sites nearly 85% are identical with those found in K562 monocytes. Quadruplicate chromatin immunoprecipitation sequencing (ChIP-seq) demonstrated that at 2130 loci the association strenght of CTCF with genomic DNA was significantly (p<0.05) modulated by stimulation with the natural vitamin D receptor (VDR) ligand 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3). Some 55% of these CTCF sites contribute to DNA looping and mark the anchors of 587 putative topologically associating domains (TADs) containing at least one VDR binding site and one 1,25(OH)2D3 target gene. These TADs can explain the regulatory scenarios of up to 70% of all 1,25(OH)2D3 target genes. A self-organizing map approach subdivided the vitamin D-sensitive CTCF sites into seven classes that can be distinguished by participation in DNA loop formation, binding to open chromatin, carrying binding motifs for CTCF or its relative BORIS, overlap with transcription start site (TSS) regions and binding of VDR. These variant molecular profiles suggest different mechanisms of the 1,25(OH)2D3-dependent action of CTCF. The co-location of VDR and 1,25(OH)2D3-dependent CTCF sites increases in the context of accessible chromatin and TSS regions but does not show any significant correlation with classical DNA binding mechanisms of CTCF. In conclusion, vitamin D-sensitive CTCF sites provide further mechanistic details to the epigenome-wide understanding of 1,25(OH)2D3-mediated gene regulation.},
}
@article {pmid27514584,
year = {2016},
author = {Barutcu, AR and Hong, D and Lajoie, BR and McCord, RP and van Wijnen, AJ and Lian, JB and Stein, JL and Dekker, J and Imbalzano, AN and Stein, GS},
title = {RUNX1 contributes to higher-order chromatin organization and gene regulation in breast cancer cells.},
journal = {Biochimica et biophysica acta},
volume = {1859},
number = {11},
pages = {1389-1397},
doi = {10.1016/j.bbagrm.2016.08.003},
pmid = {27514584},
issn = {0006-3002},
support = {//Howard Hughes Medical Institute/United States ; P01 CA082834/CA/NCI NIH HHS/United States ; R01 HG003143/HG/NHGRI NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; },
mesh = {Breast Neoplasms/*genetics/pathology ; Chromatin/*metabolism ; Chromatin Immunoprecipitation ; Extracellular Matrix/metabolism ; Female ; *Gene Expression Regulation, Neoplastic ; Humans ; MCF-7 Cells ; },
abstract = {RUNX1 is a transcription factor functioning both as an oncogene and a tumor suppressor in breast cancer. RUNX1 alters chromatin structure in cooperation with chromatin modifier and remodeling enzymes. In this study, we examined the relationship between RUNX1-mediated transcription and genome organization. We characterized genome-wide RUNX1 localization and performed RNA-seq and Hi-C in RUNX1-depleted and control MCF-7 breast cancer cells. RNA-seq analysis showed that RUNX1 depletion led to up-regulation of genes associated with chromatin structure and down-regulation of genes related to extracellular matrix biology, as well as NEAT1 and MALAT1 lncRNAs. Our ChIP-Seq analysis supports a prominent role for RUNX1 in transcriptional activation. About 30% of all RUNX1 binding sites were intergenic, indicating diverse roles in promoter and enhancer regulation and suggesting additional functions for RUNX1. Hi-C analysis of RUNX1-depleted cells demonstrated that overall three-dimensional genome organization is largely intact, but indicated enhanced association of RUNX1 near Topologically Associating Domain (TAD) boundaries and alterations in long-range interactions. These results suggest an architectural role for RUNX1 in fine-tuning local interactions rather than in global organization. Our results provide novel insight into RUNX1-mediated perturbations of higher-order genome organization that are functionally linked with RUNX1-dependent compromised gene expression in breast cancer cells.},
}
@article {pmid27669308,
year = {2016},
author = {Chung, IM and Ketharnathan, S and Kim, SH and Thiruvengadam, M and Rani, MK and Rajakumar, G},
title = {Making Sense of the Tangle: Insights into Chromatin Folding and Gene Regulation.},
journal = {Genes},
volume = {7},
number = {10},
pages = {},
doi = {10.3390/genes7100071},
pmid = {27669308},
issn = {2073-4425},
abstract = {Proximity ligation assays such as circularized chromosome conformation capture and high-throughput chromosome capture assays have shed light on the structural organization of the interphase genome. Functional topologically associating domains (TADs) that constitute the building blocks of genomic organization are disrupted and reconstructed during the cell cycle. Epigenetic memory, as well as the sequence of chromosomes, regulate TAD reconstitution. Sub-TAD domains that are invariant across cell types have been identified, and contacts between these domains, rather than looping, are speculated to drive chromatin folding. Replication domains are established simultaneously with TADs during the cell cycle and the two correlate well in terms of characteristic features, such as lamin association and histone modifications. CCCTC-binding factor (CTCF) and cohesin cooperate across different cell types to regulate genes and genome organization. CTCF elements that demarcate TAD boundaries are commonly disrupted in cancer and promote oncogene activation. Chromatin looping facilitates interactions between distant promoters and enhancers, and the resulting enhanceosome complex promotes gene expression. Deciphering the chromatin tangle requires comprehensive integrative analyses of DNA- and protein-dependent factors that regulate genomic organization.},
}
@article {pmid27634932,
year = {2017},
author = {Ibn-Salem, J and Muro, EM and Andrade-Navarro, MA},
title = {Co-regulation of paralog genes in the three-dimensional chromatin architecture.},
journal = {Nucleic acids research},
volume = {45},
number = {1},
pages = {81-91},
doi = {10.1093/nar/gkw813},
pmid = {27634932},
issn = {1362-4962},
mesh = {Animals ; Biological Evolution ; Chromatin/*chemistry/metabolism ; Chromatin Assembly and Disassembly ; Cluster Analysis ; Computational Biology ; Dogs ; Enhancer Elements, Genetic ; *Gene Duplication ; *Gene Expression Regulation ; *Genome ; Humans ; Mice ; Promoter Regions, Genetic ; },
abstract = {Paralog genes arise from gene duplication events during evolution, which often lead to similar proteins that cooperate in common pathways and in protein complexes. Consequently, paralogs show correlation in gene expression whereby the mechanisms of co-regulation remain unclear. In eukaryotes, genes are regulated in part by distal enhancer elements through looping interactions with gene promoters. These looping interactions can be measured by genome-wide chromatin conformation capture (Hi-C) experiments, which revealed self-interacting regions called topologically associating domains (TADs). We hypothesize that paralogs share common regulatory mechanisms to enable coordinated expression according to TADs. To test this hypothesis, we integrated paralogy annotations with human gene expression data in diverse tissues, genome-wide enhancer-promoter associations and Hi-C experiments in human, mouse and dog genomes. We show that paralog gene pairs are enriched for co-localization in the same TAD, share more often common enhancer elements than expected and have increased contact frequencies over large genomic distances. Combined, our results indicate that paralogs share common regulatory mechanisms and cluster not only in the linear genome but also in the three-dimensional chromatin architecture. This enables concerted expression of paralogs over diverse cell-types and indicate evolutionary constraints in functional genome organization.},
}
@article {pmid27582050,
year = {2016},
author = {Uusküla-Reimand, L and Hou, H and Samavarchi-Tehrani, P and Rudan, MV and Liang, M and Medina-Rivera, A and Mohammed, H and Schmidt, D and Schwalie, P and Young, EJ and Reimand, J and Hadjur, S and Gingras, AC and Wilson, MD},
title = {Topoisomerase II beta interacts with cohesin and CTCF at topological domain borders.},
journal = {Genome biology},
volume = {17},
number = {1},
pages = {182},
doi = {10.1186/s13059-016-1043-8},
pmid = {27582050},
issn = {1474-760X},
support = {//Wellcome Trust/United Kingdom ; //CIHR/Canada ; },
mesh = {Alleles ; Animals ; Binding Sites ; CCCTC-Binding Factor ; Cell Cycle Proteins/*genetics/metabolism ; Chromatin/genetics ; Chromatin Immunoprecipitation ; Chromosomal Proteins, Non-Histone/*genetics/metabolism ; Chromosomes ; DNA Topoisomerases, Type II/*genetics/metabolism ; DNA, Ribosomal/genetics ; DNA-Binding Proteins/*genetics/metabolism ; Genome ; Humans ; Mice ; Poly-ADP-Ribose Binding Proteins ; Promoter Regions, Genetic ; Protein Binding ; Protein Interaction Maps/*genetics ; Proteomics ; Repressor Proteins/*genetics/metabolism ; *Transcription, Genetic ; },
abstract = {BACKGROUND: Type II DNA topoisomerases (TOP2) regulate DNA topology by generating transient double stranded breaks during replication and transcription. Topoisomerase II beta (TOP2B) facilitates rapid gene expression and functions at the later stages of development and differentiation. To gain new insight into the genome biology of TOP2B, we used proteomics (BioID), chromatin immunoprecipitation, and high-throughput chromosome conformation capture (Hi-C) to identify novel proximal TOP2B protein interactions and characterize the genomic landscape of TOP2B binding at base pair resolution.<br><br>RESULTS: Our human TOP2B proximal protein interaction network included members of the cohesin complex and nucleolar proteins associated with rDNA biology. TOP2B associates with DNase I hypersensitivity sites, allele-specific transcription factor (TF) binding, and evolutionarily conserved TF binding sites on the mouse genome. Approximately half of all CTCF/cohesion-bound regions coincided with TOP2B binding. Base pair resolution ChIP-exo mapping of TOP2B, CTCF, and cohesin sites revealed a striking structural ordering of these proteins along the genome relative to the CTCF motif. These ordered TOP2B-CTCF-cohesin sites flank the boundaries of topologically associating domains (TADs) with TOP2B positioned externally and cohesin internally to the domain loop.<br><br>CONCLUSIONS: TOP2B is positioned to solve topological problems at diverse cis-regulatory elements and its occupancy is a highly ordered and prevalent feature of CTCF/cohesin binding sites that flank TADs.},
}
@article {pmid27539148,
year = {2016},
author = {Xia, Q and Chesi, A and Manduchi, E and Johnston, BT and Lu, S and Leonard, ME and Parlin, UW and Rappaport, EF and Huang, P and Wells, AD and Blobel, GA and Johnson, ME and Grant, SFA},
title = {The type 2 diabetes presumed causal variant within TCF7L2 resides in an element that controls the expression of ACSL5.},
journal = {Diabetologia},
volume = {59},
number = {11},
pages = {2360-2368},
doi = {10.1007/s00125-016-4077-2},
pmid = {27539148},
issn = {1432-0428},
mesh = {Blotting, Western ; CRISPR-Associated Proteins/metabolism ; Cell Line ; Chromatin/genetics/metabolism ; Coenzyme A Ligases/*genetics/*metabolism ; Colon/metabolism ; Diabetes Mellitus, Type 2/*genetics/*metabolism ; HCT116 Cells ; Humans ; Polymerase Chain Reaction ; Polymorphism, Single Nucleotide/genetics ; RNA, Small Interfering ; Reverse Transcriptase Polymerase Chain Reaction ; Transcription Factor 7-Like 2 Protein/*genetics/*metabolism ; },
abstract = {AIMS/HYPOTHESIS: One of the most strongly associated type 2 diabetes loci reported to date resides within the TCF7L2 gene. Previous studies point to the T allele of rs7903146 in intron 3 as the causal variant at this locus. We aimed to identify the actual gene(s) under the influence of this variant.<br><br>METHODS: Using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 nuclease, we generated a 1.4 kb deletion of the genomic region harbouring rs7903146 in the HCT116 cell line, followed by global gene expression analysis. We then carried out a combination of circularised chromosome conformation capture (4C) and Capture C in cell lines, HCT116 and NCM460 in order to ascertain which promoters of these perturbed genes made consistent physical contact with this genomic region.<br><br>RESULTS: We observed 99 genes with significant differential expression (false discovery rate [FDR] cut-off:10%) and an effect size of at least twofold. The subsequent promoter contact analyses revealed just one gene, ACSL5, which resides in the same topologically associating domain as TCF7L2. The generation of additional, smaller deletions (66 bp and 104 bp) comprising rs7903146 showed consistently reduced ACSL5 mRNA levels across all three deletions of up to 30-fold, with commensurate loss of acyl-CoA synthetase long-chain family member 5 (ACSL5) protein. Notably, the deletion of this single-nucleotide polymorphism region abolished significantly detectable chromatin contacts with the ACSL5 promoter. We went on to confirm that contacts between rs7903146 and the ACSL5 promoter regions were conserved in human colon tissue. ACSL5 encodes ACSL5, an enzyme with known roles in fatty acid metabolism.<br><br>CONCLUSIONS/INTERPRETATION: This 'variant to gene mapping' effort implicates the genomic location harbouring rs7903146 as a regulatory region for ACSL5.},
}
@article {pmid27503290,
year = {2016},
author = {Glinsky, GV},
title = {Mechanistically Distinct Pathways of Divergent Regulatory DNA Creation Contribute to Evolution of Human-Specific Genomic Regulatory Networks Driving Phenotypic Divergence of Homo sapiens.},
journal = {Genome biology and evolution},
volume = {8},
number = {9},
pages = {2774-2788},
doi = {10.1093/gbe/evw185},
pmid = {27503290},
issn = {1759-6653},
mesh = {Animals ; *Evolution, Molecular ; *Gene Regulatory Networks ; *Genome, Human ; Humans ; *Phenotype ; Prefrontal Cortex/metabolism ; Primates/genetics ; *Regulatory Sequences, Nucleic Acid ; },
abstract = {Thousands of candidate human-specific regulatory sequences (HSRS) have been identified, supporting the hypothesis that unique to human phenotypes result from human-specific alterations of genomic regulatory networks. Collectively, a compendium of multiple diverse families of HSRS that are functionally and structurally divergent from Great Apes could be defined as the backbone of human-specific genomic regulatory networks. Here, the conservation patterns analysis of 18,364 candidate HSRS was carried out requiring that 100% of bases must remap during the alignments of human, chimpanzee, and bonobo sequences. A total of 5,535 candidate HSRS were identified that are: (i) highly conserved in Great Apes; (ii) evolved by the exaptation of highly conserved ancestral DNA; (iii) defined by either the acceleration of mutation rates on the human lineage or the functional divergence from non-human primates. The exaptation of highly conserved ancestral DNA pathway seems mechanistically distinct from the evolution of regulatory DNA segments driven by the species-specific expansion of transposable elements. Genome-wide proximity placement analysis of HSRS revealed that a small fraction of topologically associating domains (TADs) contain more than half of HSRS from four distinct families. TADs that are enriched for HSRS and termed rapidly evolving in humans TADs (revTADs) comprise 0.8-10.3% of 3,127 TADs in the hESC genome. RevTADs manifest distinct correlation patterns between placements of human accelerated regions, human-specific transcription factor-binding sites, and recombination rates. There is a significant enrichment within revTAD boundaries of hESC-enhancers, primate-specific CTCF-binding sites, human-specific RNAPII-binding sites, hCONDELs, and H3K4me3 peaks with human-specific enrichment at TSS in prefrontal cortex neurons (P < 0.0001 in all instances). Present analysis supports the idea that phenotypic divergence of Homo sapiens is driven by the evolution of human-specific genomic regulatory networks via at least two mechanistically distinct pathways of creation of divergent sequences of regulatory DNA: (i) recombination-associated exaptation of the highly conserved ancestral regulatory DNA segments; (ii) human-specific insertions of transposable elements.},
}
@article {pmid27445307,
year = {2016},
author = {Wang, S and Su, JH and Beliveau, BJ and Bintu, B and Moffitt, JR and Wu, CT and Zhuang, X},
title = {Spatial organization of chromatin domains and compartments in single chromosomes.},
journal = {Science (New York, N.Y.)},
volume = {353},
number = {6299},
pages = {598-602},
doi = {10.1126/science.aaf8084},
pmid = {27445307},
issn = {1095-9203},
support = {DP1 GM106412/GM/NIGMS NIH HHS/United States ; R01 GM096450/GM/NIGMS NIH HHS/United States ; R01 GM105637/GM/NIGMS NIH HHS/United States ; //Howard Hughes Medical Institute/United States ; },
mesh = {Cell Line ; Chromatin/*chemistry ; Chromosomes, Human, Pair 20/chemistry ; Chromosomes, Human, Pair 22/chemistry ; Chromosomes, Human, X/*chemistry ; Gene Expression Regulation ; *Genome, Human ; Humans ; *Interphase ; Molecular Imaging/methods ; },
abstract = {The spatial organization of chromatin critically affects genome function. Recent chromosome-conformation-capture studies have revealed topologically associating domains (TADs) as a conserved feature of chromatin organization, but how TADs are spatially organized in individual chromosomes remains unknown. Here, we developed an imaging method for mapping the spatial positions of numerous genomic regions along individual chromosomes and traced the positions of TADs in human interphase autosomes and X chromosomes. We observed that chromosome folding deviates from the ideal fractal-globule model at large length scales and that TADs are largely organized into two compartments spatially arranged in a polarized manner in individual chromosomes. Active and inactive X chromosomes adopt different folding and compartmentalization configurations. These results suggest that the spatial organization of chromatin domains can change in response to regulation.},
}
@article {pmid27437574,
year = {2016},
author = {Giorgetti, L and Lajoie, BR and Carter, AC and Attia, M and Zhan, Y and Xu, J and Chen, CJ and Kaplan, N and Chang, HY and Heard, E and Dekker, J},
title = {Structural organization of the inactive X chromosome in the mouse.},
journal = {Nature},
volume = {535},
number = {7613},
pages = {575-579},
doi = {10.1038/nature18589},
pmid = {27437574},
issn = {1476-4687},
support = {P50-HG007735/HG/NHGRI NIH HHS/United States ; R01 HG003143/HG/NHGRI NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; U54 DK107980/DK/NIDDK NIH HHS/United States ; P50 HG007735/HG/NHGRI NIH HHS/United States ; T32 AG047126/AG/NIA NIH HHS/United States ; },
mesh = {Alleles ; Animals ; Binding Sites ; CCCTC-Binding Factor ; Chromatin/chemistry/genetics/metabolism ; Chromosomes, Mammalian/chemistry/genetics/*metabolism ; Embryonic Stem Cells/metabolism ; Female ; Gene Silencing ; Male ; Mice ; Neural Stem Cells/metabolism ; Promoter Regions, Genetic/genetics ; RNA, Long Noncoding/genetics/metabolism ; Repressor Proteins/metabolism ; Sequence Analysis ; Transcription, Genetic ; X Chromosome/chemistry/genetics/*metabolism ; *X Chromosome Inactivation/genetics ; },
abstract = {X-chromosome inactivation (XCI) involves major reorganization of the X chromosome as it becomes silent and heterochromatic. During female mammalian development, XCI is triggered by upregulation of the non-coding Xist RNA from one of the two X chromosomes. Xist coats the chromosome in cis and induces silencing of almost all genes via its A-repeat region, although some genes (constitutive escapees) avoid silencing in most cell types, and others (facultative escapees) escape XCI only in specific contexts. A role for Xist in organizing the inactive X (Xi) chromosome has been proposed. Recent chromosome conformation capture approaches have revealed global loss of local structure on the Xi chromosome and formation of large mega-domains, separated by a region containing the DXZ4 macrosatellite. However, the molecular architecture of the Xi chromosome, in both the silent and expressed regions,remains unclear. Here we investigate the structure, chromatin accessibility and expression status of the mouse Xi chromosome in highly polymorphic clonal neural progenitors (NPCs) and embryonic stem cells. We demonstrate a crucial role for Xist and the DXZ4-containing boundary in shaping Xi chromosome structure using allele-specific genome-wide chromosome conformation capture (Hi-C) analysis, an assay for transposase-accessible chromatin with high throughput sequencing (ATAC-seq) and RNA sequencing. Deletion of the boundary disrupts mega-domain formation, and induction of Xist RNA initiates formation of the boundary and the loss of DNA accessibility. We also show that in NPCs, the Xi chromosome lacks active/inactive compartments and topologically associating domains (TADs), except around genes that escape XCI. Escapee gene clusters display TAD-like structures and retain DNA accessibility at promoter-proximal and CTCF-binding sites. Furthermore, altered patterns of facultative escape genes indifferent neural progenitor clones are associated with the presence of different TAD-like structures after XCI. These findings suggest a key role for transcription and CTCF in the formation of TADs in the context of the Xi chromosome in neural progenitors.},
}
@article {pmid27435934,
year = {2016},
author = {Barutcu, AR and Lajoie, BR and Fritz, AJ and McCord, RP and Nickerson, JA and van Wijnen, AJ and Lian, JB and Stein, JL and Dekker, J and Stein, GS and Imbalzano, AN},
title = {SMARCA4 regulates gene expression and higher-order chromatin structure in proliferating mammary epithelial cells.},
journal = {Genome research},
volume = {26},
number = {9},
pages = {1188-1201},
doi = {10.1101/gr.201624.115},
pmid = {27435934},
issn = {1549-5469},
support = {P01 CA082834/CA/NCI NIH HHS/United States ; R01 HG003143/HG/NHGRI NIH HHS/United States ; },
mesh = {Cell Line, Tumor ; Cell Proliferation/*genetics ; Chromatin/*genetics ; Chromatin Assembly and Disassembly ; DNA Helicases/*genetics ; Epithelial Cells/metabolism ; Gene Expression Regulation/genetics ; Humans ; Nuclear Proteins/*genetics ; Nucleosomes/genetics ; Transcription Factors/*genetics ; },
abstract = {The packaging of DNA into chromatin plays an important role in transcriptional regulation and nuclear processes. Brahma-related gene-1 SMARCA4 (also known as BRG1), the essential ATPase subunit of the mammalian SWI/SNF chromatin remodeling complex, uses the energy from ATP hydrolysis to disrupt nucleosomes at target regions. Although the transcriptional role of SMARCA4 at gene promoters is well-studied, less is known about its role in higher-order genome organization. SMARCA4 knockdown in human mammary epithelial MCF-10A cells resulted in 176 up-regulated genes, including many related to lipid and calcium metabolism, and 1292 down-regulated genes, some of which encode extracellular matrix (ECM) components that can exert mechanical forces and affect nuclear structure. ChIP-seq analysis of SMARCA4 localization and SMARCA4-bound super-enhancers demonstrated extensive binding at intergenic regions. Furthermore, Hi-C analysis showed extensive SMARCA4-mediated alterations in higher-order genome organization at multiple resolutions. First, SMARCA4 knockdown resulted in clustering of intra- and inter-subtelomeric regions, demonstrating a novel role for SMARCA4 in telomere organization. SMARCA4 binding was enriched at topologically associating domain (TAD) boundaries, and SMARCA4 knockdown resulted in weakening of TAD boundary strength. Taken together, these findings provide a dynamic view of SMARCA4-dependent changes in higher-order chromatin organization and gene expression, identifying SMARCA4 as a novel component of chromatin organization.},
}
@article {pmid27423862,
year = {2016},
author = {Kim, KD and Iwasaki, O and Noma, K},
title = {An IF-FISH Approach for Covisualization of Gene Loci and Nuclear Architecture in Fission Yeast.},
journal = {Methods in enzymology},
volume = {574},
number = {},
pages = {167-180},
doi = {10.1016/bs.mie.2016.04.003},
pmid = {27423862},
issn = {1557-7988},
support = {DP2 OD004348/OD/NIH HHS/United States ; P30 CA010815/CA/NCI NIH HHS/United States ; },
mesh = {Centromere/genetics/ultrastructure ; *Chromosomes, Fungal/genetics/ultrastructure ; Fluorescent Antibody Technique/*methods ; *Genetic Loci ; Genome, Fungal ; In Situ Hybridization, Fluorescence/*methods ; Schizosaccharomyces/cytology/*genetics/*ultrastructure ; },
abstract = {Recent genomic studies have revealed that chromosomal structures are formed by a hierarchy of organizing processes ranging from gene associations, including interactions among enhancers and promoters, to topologically associating domain formations. Gene associations identified by these studies can be characterized by microscopic analyses. Fission yeast is a model organism, in which gene associations have been broadly mapped across the genome, although many of those associations have not been further examined by cell biological approaches. To address the technically challenging process of the visualization of associating gene loci in the fission yeast nuclei, we provide, in detail, an IF-FISH procedure that allows for covisualizing both gene loci and nuclear structural markers such as the nuclear membrane and nucleolus.},
}
@article {pmid27414788,
year = {2016},
author = {Ye, BY and Shen, WL and Wang, D and Li, P and Zhang, Z and Shi, ML and Zhang, Y and Zhang, FX and Zhao, ZH},
title = {[ZNF143 is involved in CTCF-mediated chromatin interactions by cooperation with cohesin and other partners].},
journal = {Molekuliarnaia biologiia},
volume = {50},
number = {3},
pages = {496-503},
doi = {10.7868/S0026898416030034},
pmid = {27414788},
issn = {0026-8984},
mesh = {Binding Sites ; CCCTC-Binding Factor ; Cell Cycle Proteins/genetics/*metabolism ; Chromatin/*chemistry/metabolism ; Chromatin Assembly and Disassembly ; Chromosomal Proteins, Non-Histone/genetics/*metabolism ; Databases, Genetic ; Gene Expression ; Humans ; K562 Cells ; Nucleotide Motifs ; Protein Binding ; Protein Interaction Mapping ; Repressor Proteins/genetics/*metabolism ; Trans-Activators/genetics/*metabolism ; },
abstract = {ZNF143 is a ubiquitously expressed transcription factor conserved in vertebrates and might regulate the expression of numerous genes. But its function in mediating chromatin interactions remains elusive. By integrated analysis of public datasets, we provided evidence that a majority of ZNF143 binding sites (BSs) were involved in CTCF-mediated chromatin interaction networks (CTCF-CINs) by overlapping with cohesin-BSs and CTCF-BSs. We further showed that only a very few CTCF-CINs were associated with ZNF143 alone, whereas those associated with ZNF143 and cohesin simultaneously were highly overlapped with constitutive, conserved CTCF-BSs and enriched at boundaries of chromatin topologically associating domains. These observations implicate that as an important partner of CTCF, ZNF143 helps it establish the conserved chromatin structure by cooperating with cohesin.},
}
@article {pmid27402708,
year = {2016},
author = {Williamson, I and Lettice, LA and Hill, RE and Bickmore, WA},
title = {Shh and ZRS enhancer colocalisation is specific to the zone of polarising activity.},
journal = {Development (Cambridge, England)},
volume = {143},
number = {16},
pages = {2994-3001},
doi = {10.1242/dev.139188},
pmid = {27402708},
issn = {1477-9129},
support = {MC_PC_U127527202//Medical Research Council/United Kingdom ; MC_PC_U127584494//Medical Research Council/United Kingdom ; MC_U127584494//Medical Research Council/United Kingdom ; MR/K01563X/1//Medical Research Council/United Kingdom ; },
mesh = {Animals ; Chromosomes/genetics/metabolism ; Enhancer Elements, Genetic/*genetics ; Gene Expression Regulation, Developmental ; Hedgehog Proteins/genetics/*metabolism ; In Situ Hybridization, Fluorescence ; Limb Buds/metabolism ; Mice ; },
abstract = {Limb-specific Shh expression is regulated by the (∼1 Mb distant) ZRS enhancer. In the mouse, limb bud-restricted spatiotemporal Shh expression occurs from ∼E10 to E11.5 at the distal posterior margin and is essential for correct autopod formation. Here, we have analysed the higher-order chromatin conformation of Shh in expressing and non-expressing tissues, both by fluorescence in situ hybridisation (FISH) and by chromosome conformation capture (5C). Conventional and super-resolution light microscopy identified significantly elevated frequencies of Shh/ZRS colocalisation only in the Shh-expressing regions of the limb bud, in a conformation consistent with enhancer-promoter loop formation. However, in all tissues and at all developmental stages analysed, Shh-ZRS spatial distances were still consistently shorter than those to a neural enhancer located between Shh and ZRS in the genome. 5C identified a topologically associating domain (TAD) over the Shh/ZRS genomic region and enriched interactions between Shh and ZRS throughout E11.5 embryos. Shh/ZRS colocalisation, therefore, correlates with the spatiotemporal domain of limb bud-specific Shh expression, but close Shh and ZRS proximity in the nucleus occurs regardless of whether the gene or enhancer is active. We suggest that this constrained chromatin configuration optimises the opportunity for the active enhancer to locate and instigate the expression of Shh.},
}
@article {pmid27367409,
year = {2016},
author = {Zhang, B and Wolynes, PG},
title = {Shape Transitions and Chiral Symmetry Breaking in the Energy Landscape of the Mitotic Chromosome.},
journal = {Physical review letters},
volume = {116},
number = {24},
pages = {248101},
doi = {10.1103/PhysRevLett.116.248101},
pmid = {27367409},
issn = {1079-7114},
mesh = {*Chromosomes ; *Entropy ; *Liquid Crystals ; *Mitosis ; Probability ; Stereoisomerism ; },
abstract = {We derive an unbiased information theoretic energy landscape for chromosomes at metaphase using a maximum entropy approach that accurately reproduces the details of the experimentally measured pairwise contact probabilities between genomic loci. Dynamical simulations using this landscape lead to cylindrical, helically twisted structures reflecting liquid crystalline order. These structures are similar to those arising from a generic ideal homogenized chromosome energy landscape. The helical twist can be either right or left handed so chiral symmetry is broken spontaneously. The ideal chromosome landscape when augmented by interactions like those leading to topologically associating domain formation in the interphase chromosome reproduces these behaviors. The phase diagram of this landscape shows that the helical fiber order and the cylindrical shape persist at temperatures above the onset of chiral symmetry breaking, which is limited by the topologically associating domain interaction strength.},
}
@article {pmid27318199,
year = {2016},
author = {Kruse, K and Hug, CB and Hernández-Rodríguez, B and Vaquerizas, JM},
title = {TADtool: visual parameter identification for TAD-calling algorithms.},
journal = {Bioinformatics (Oxford, England)},
volume = {32},
number = {20},
pages = {3190-3192},
doi = {10.1093/bioinformatics/btw368},
pmid = {27318199},
issn = {1367-4811},
mesh = {*Algorithms ; Animals ; *Genome ; Humans ; Software ; },
abstract = {Eukaryotic genomes are hierarchically organized into topologically associating domains (TADs). The computational identification of these domains and their associated properties critically depends on the choice of suitable parameters of TAD-calling algorithms. To reduce the element of trial-and-error in parameter selection, we have developed TADtool: an interactive plot to find robust TAD-calling parameters with immediate visual feedback. TADtool allows the direct export of TADs called with a chosen set of parameters for two of the most common TAD calling algorithms: directionality and insulation index. It can be used as an intuitive, standalone application or as a Python package for maximum flexibility.<br><br>TADtool is available as a Python package from GitHub (https://github.com/vaquerizaslab/tadtool) or can be installed directly via PyPI, the Python package index (tadtool).<br><br>CONTACT: kai.kruse@mpi-muenster.mpg.de, jmv@mpi-muenster.mpg.deSupplementary information: Supplementary data are available at Bioinformatics online.},
}
@article {pmid27307607,
year = {2016},
author = {Hu, X and Shi, CH and Yip, KY},
title = {A novel method for discovering local spatial clusters of genomic regions with functional relationships from DNA contact maps.},
journal = {Bioinformatics (Oxford, England)},
volume = {32},
number = {12},
pages = {i111-i120},
doi = {10.1093/bioinformatics/btw256},
pmid = {27307607},
issn = {1367-4811},
mesh = {DNA ; Genome ; *Genomics ; Programming Languages ; Software ; },
abstract = {MOTIVATION: The three-dimensional structure of genomes makes it possible for genomic regions not adjacent in the primary sequence to be spatially proximal. These DNA contacts have been found to be related to various molecular activities. Previous methods for analyzing DNA contact maps obtained from Hi-C experiments have largely focused on studying individual interactions, forming spatial clusters composed of contiguous blocks of genomic locations, or classifying these clusters into general categories based on some global properties of the contact maps.<br><br>RESULTS: Here, we describe a novel computational method that can flexibly identify small clusters of spatially proximal genomic regions based on their local contact patterns. Using simulated data that highly resemble Hi-C data obtained from real genome structures, we demonstrate that our method identifies spatial clusters that are more compact than methods previously used for clustering genomic regions based on DNA contact maps. The clusters identified by our method enable us to confirm functionally related genomic regions previously reported to be spatially proximal in different species. We further show that each genomic region can be assigned a numeric affinity value that indicates its degree of participation in each local cluster, and these affinity values correlate quantitatively with DNase I hypersensitivity, gene expression, super enhancer activities and replication timing in a cell type specific manner. We also show that these cluster affinity values can precisely define boundaries of reported topologically associating domains, and further define local sub-domains within each domain.<br><br>The source code of BNMF and tutorials on how to use the software to extract local clusters from contact maps are available at http://yiplab.cse.cuhk.edu.hk/bnmf/<br><br>CONTACT: kevinyip@cse.cuhk.edu.hk<br><br>SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},
}
@article {pmid27300486,
year = {2016},
author = {Khoroshko, VA and Levitsky, VG and Zykova, TY and Antonenko, OV and Belyaeva, ES and Zhimulev, IF},
title = {Chromatin Heterogeneity and Distribution of Regulatory Elements in the Late-Replicating Intercalary Heterochromatin Domains of Drosophila melanogaster Chromosomes.},
journal = {PloS one},
volume = {11},
number = {6},
pages = {e0157147},
doi = {10.1371/journal.pone.0157147},
pmid = {27300486},
issn = {1932-6203},
mesh = {Animals ; Chromosomes, Insect/chemistry/*genetics ; DNA Replication Timing ; Drosophila melanogaster/chemistry/*genetics ; Gene Expression Regulation ; Heterochromatin/chemistry/*genetics ; Regulatory Sequences, Nucleic Acid ; },
abstract = {Late-replicating domains (intercalary heterochromatin) in the Drosophila genome display a number of features suggesting their organization is quite unique. Typically, they are quite large and encompass clusters of functionally unrelated tissue-specific genes. They correspond to the topologically associating domains and conserved microsynteny blocks. Our study aims at exploring further details of molecular organization of intercalary heterochromatin and has uncovered surprising heterogeneity of chromatin composition in these regions. Using the 4HMM model developed in our group earlier, intercalary heterochromatin regions were found to host chromatin fragments with a particular epigenetic profile. Aquamarine chromatin fragments (spanning 0.67% of late-replicating regions) are characterized as a class of sequences that appear heterogeneous in terms of their decompactization. These fragments are enriched with enhancer sequences and binding sites for insulator proteins. They likely mark the chromatin state that is related to the binding of cis-regulatory proteins. Malachite chromatin fragments (11% of late-replicating regions) appear to function as universal transitional regions between two contrasting chromatin states. Namely, they invariably delimit intercalary heterochromatin regions from the adjacent active chromatin of interbands. Malachite fragments also flank aquamarine fragments embedded in the repressed chromatin of late-replicating regions. Significant enrichment of insulator proteins CP190, SU(HW), and MOD2.2 was observed in malachite chromatin. Neither aquamarine nor malachite chromatin types appear to correlate with the positions of highly conserved non-coding elements (HCNE) that are typically replete in intercalary heterochromatin. Malachite chromatin found on the flanks of intercalary heterochromatin regions tends to replicate earlier than the malachite chromatin embedded in intercalary heterochromatin. In other words, there exists a gradient of replication progressing from the flanks of intercalary heterochromatin regions center-wise. The peculiar organization and features of replication in large late-replicating regions are discussed as possible factors shaping the evolutionary stability of intercalary heterochromatin.},
}
@article {pmid27259200,
year = {2016},
author = {Dixon, JR and Gorkin, DU and Ren, B},
title = {Chromatin Domains: The Unit of Chromosome Organization.},
journal = {Molecular cell},
volume = {62},
number = {5},
pages = {668-680},
doi = {10.1016/j.molcel.2016.05.018},
pmid = {27259200},
issn = {1097-4164},
support = {R01 ES024984/ES/NIEHS NIH HHS/United States ; K12 GM068524/GM/NIGMS NIH HHS/United States ; U54 DK107977/DK/NIDDK NIH HHS/United States ; P50 GM085764/GM/NIGMS NIH HHS/United States ; U54 HG006997/HG/NHGRI NIH HHS/United States ; P30 CA014195/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cell Nucleus/*metabolism ; Chromatin/chemistry/genetics/*metabolism ; *Chromatin Assembly and Disassembly ; Chromosomes/chemistry/genetics/*metabolism ; Gene Expression Regulation ; *Genome ; Genomics/methods ; Humans ; *Interphase ; Nucleic Acid Conformation ; Protein Conformation ; Structure-Activity Relationship ; },
abstract = {How eukaryotic chromosomes fold inside the nucleus is an age-old question that remains unanswered today. Early biochemical and microscopic studies revealed the existence of chromatin domains and loops as a pervasive feature of interphase chromosomes, but the biological implications of such organizational features were obscure. Genome-wide analysis of pair-wise chromatin interactions using chromatin conformation capture (3C)-based techniques has shed new light on the organization of chromosomes in interphase nuclei. Particularly, the finding of cell-type invariant, evolutionarily conserved topologically associating domains (TADs) in a broad spectrum of cell types has provided a new molecular framework for the study of animal development and human diseases. Here, we review recent progress in characterization of such chromatin domains and delineation of mechanisms of their formation in animal cells.},
}
@article {pmid27257057,
year = {2016},
author = {Vasquez, PA and Hult, C and Adalsteinsson, D and Lawrimore, J and Forest, MG and Bloom, K},
title = {Entropy gives rise to topologically associating domains.},
journal = {Nucleic acids research},
volume = {44},
number = {12},
pages = {5540-5549},
doi = {10.1093/nar/gkw510},
pmid = {27257057},
issn = {1362-4962},
support = {F31 CA165891/CA/NCI NIH HHS/United States ; R37 GM032238/GM/NIGMS NIH HHS/United States ; T32 GM007092/GM/NIGMS NIH HHS/United States ; T32 CA201159/CA/NCI NIH HHS/United States ; },
mesh = {Cell Nucleus/genetics ; Chromatin/*genetics ; Chromosomes/*genetics ; Entropy ; *Models, Genetic ; Saccharomyces cerevisiae/genetics ; },
abstract = {We investigate chromosome organization within the nucleus using polymer models whose formulation is closely guided by experiments in live yeast cells. We employ bead-spring chromosome models together with loop formation within the chains and the presence of nuclear bodies to quantify the extent to which these mechanisms shape the topological landscape in the interphase nucleus. By investigating the genome as a dynamical system, we show that domains of high chromosomal interactions can arise solely from the polymeric nature of the chromosome arms due to entropic interactions and nuclear confinement. In this view, the role of bio-chemical related processes is to modulate and extend the duration of the interacting domains.},
}
@article {pmid27249516,
year = {2016},
author = {Gavrilov, AA and Shevelyov, YY and Ulianov, SV and Khrameeva, EE and Kos, P and Chertovich, A and Razin, SV},
title = {Unraveling the mechanisms of chromatin fibril packaging.},
journal = {Nucleus (Austin, Tex.)},
volume = {7},
number = {3},
pages = {319-324},
doi = {10.1080/19491034.2016.1190896},
pmid = {27249516},
issn = {1949-1042},
mesh = {Animals ; Chromatin/*chemistry/*metabolism ; Chromosomes, Insect/genetics ; Drosophila melanogaster/genetics ; Humans ; },
abstract = {Recent data indicate that eukaryotic chromosomes are organized into Topologically Associating Domains (TADs); however, the mechanisms underlying TAD formation remain obscure. Based on the results of Hi-C analysis performed on 4 Drosophila melanogaster cell lines, we have proposed that specific properties of nucleosomes in active and repressed chromatin play a key role in the formation of TADs. Our computer simulations showed that the ability of &quot;inactive&quot; nucleosomes to stick to each other and the lack of such ability in &quot;active&quot; nucleosomes is sufficient for spatial segregation of these types of chromatin, which is revealed in the Hi-C analysis as TAD/inter-TAD partitioning. However, some Drosophila and mammalian TADs contain both active and inactive chromatin, a fact that does not fit this model. Herein, we present additional arguments for the model by postulating that transcriptionally active chromatin is extruded on the surface of a TAD, and discuss the possible impact of this organization on the enhancer-promoter communication and on the segregation of TADs.},
}
@article {pmid27222515,
year = {2016},
author = {Ros, MA},
title = {HOX13 proteins: the molecular switcher in Hoxd bimodal regulation.},
journal = {Genes &amp; development},
volume = {30},
number = {10},
pages = {1135-1137},
doi = {10.1101/gad.283598.116},
pmid = {27222515},
issn = {1549-5477},
mesh = {Embryonic Development ; Extremities/*embryology ; *Gene Expression Regulation, Developmental ; Genes, Homeobox ; Homeodomain Proteins/genetics ; Transcription Factors/genetics ; },
abstract = {The striking correlation between the genomic arrangement of Hox genes and their temporal and spatial pattern of expression during embryonic development has been a source of fascination since its discovery. This correspondence has been used as a privileged example in the investigation of the connection between genomic architecture and function. In this issue of Genes &amp; Development, Beccari and colleagues (pp. 1172-1186) make a big step forward in understanding Hox gene regulation during limb development by showing the pivotal role of HOXA13 and HOXD13 proteins in the transition from a proximal to a distal type of Hoxd transcriptional regulation.},
}
@article {pmid27210764,
year = {2016},
author = {Fudenberg, G and Imakaev, M and Lu, C and Goloborodko, A and Abdennur, N and Mirny, LA},
title = {Formation of Chromosomal Domains by Loop Extrusion.},
journal = {Cell reports},
volume = {15},
number = {9},
pages = {2038-2049},
doi = {10.1016/j.celrep.2016.04.085},
pmid = {27210764},
issn = {2211-1247},
support = {R01 GM114190/GM/NIGMS NIH HHS/United States ; R01 HG003143/HG/NHGRI NIH HHS/United States ; U54 DK107980/DK/NIDDK NIH HHS/United States ; },
mesh = {CCCTC-Binding Factor/metabolism ; Cell Cycle Proteins/metabolism ; Chromosomal Proteins, Non-Histone/metabolism ; Chromosomes/*chemistry ; Insulator Elements/genetics ; Models, Molecular ; *Nucleic Acid Conformation ; Sequence Deletion ; },
abstract = {Topologically associating domains (TADs) are fundamental structural and functional building blocks of human interphase chromosomes, yet the mechanisms of TAD formation remain unclear. Here, we propose that loop extrusion underlies TAD formation. In this process, cis-acting loop-extruding factors, likely cohesins, form progressively larger loops but stall at TAD boundaries due to interactions with boundary proteins, including CTCF. Using polymer simulations, we show that this model produces TADs and finer-scale features of Hi-C data. Each TAD emerges from multiple loops dynamically formed through extrusion, contrary to typical illustrations of single static loops. Loop extrusion both explains diverse experimental observations-including the preferential orientation of CTCF motifs, enrichments of architectural proteins at TAD boundaries, and boundary deletion experiments-and makes specific predictions for the depletion of CTCF versus cohesin. Finally, loop extrusion has potentially far-ranging consequences for processes such as enhancer-promoter interactions, orientation-specific chromosomal looping, and compaction of mitotic chromosomes.},
}
@article {pmid27198226,
year = {2016},
author = {Beccari, L and Yakushiji-Kaminatsui, N and Woltering, JM and Necsulea, A and Lonfat, N and Rodríguez-Carballo, E and Mascrez, B and Yamamoto, S and Kuroiwa, A and Duboule, D},
title = {A role for HOX13 proteins in the regulatory switch between TADs at the HoxD locus.},
journal = {Genes &amp; development},
volume = {30},
number = {10},
pages = {1172-1186},
doi = {10.1101/gad.281055.116},
pmid = {27198226},
issn = {1549-5477},
mesh = {Animals ; Body Patterning/*genetics ; Chick Embryo ; Enhancer Elements, Genetic/genetics ; Extremities/*embryology ; Gene Expression Regulation, Developmental/*genetics ; Genes, Homeobox/*genetics ; Homeodomain Proteins/genetics/*metabolism ; Limb Deformities, Congenital/genetics ; Mice ; Mice, Transgenic ; Mutation ; Protein Binding/genetics ; Protein Domains/*genetics ; },
abstract = {During vertebrate limb development, Hoxd genes are regulated following a bimodal strategy involving two topologically associating domains (TADs) located on either side of the gene cluster. These regulatory landscapes alternatively control different subsets of Hoxd targets, first into the arm and subsequently into the digits. We studied the transition between these two global regulations, a switch that correlates with the positioning of the wrist, which articulates these two main limb segments. We show that the HOX13 proteins themselves help switch off the telomeric TAD, likely through a global repressive mechanism. At the same time, they directly interact with distal enhancers to sustain the activity of the centromeric TAD, thus explaining both the sequential and exclusive operating processes of these two regulatory domains. We propose a model in which the activation of Hox13 gene expression in distal limb cells both interrupts the proximal Hox gene regulation and re-enforces the distal regulation. In the absence of HOX13 proteins, a proximal limb structure grows without any sign of wrist articulation, likely related to an ancestral fish-like condition.},
}
@article {pmid27115331,
year = {2016},
author = {Rivera-Mulia, JC and Gilbert, DM},
title = {Replication timing and transcriptional control: beyond cause and effect-part III.},
journal = {Current opinion in cell biology},
volume = {40},
number = {},
pages = {168-178},
doi = {10.1016/j.ceb.2016.03.022},
pmid = {27115331},
issn = {1879-0410},
support = {P01 GM085354/GM/NIGMS NIH HHS/United States ; R01 GM083337/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Cell Cycle ; Cell Nucleus/genetics ; DNA Replication ; *DNA Replication Timing ; *Gene Expression Regulation ; Genome ; Humans ; *Transcription, Genetic ; },
abstract = {DNA replication is essential for faithful transmission of genetic information and is intimately tied to chromosome structure and function. Genome duplication occurs in a defined temporal order known as the replication-timing (RT) program, which is regulated during the cell cycle and development in discrete units referred to as replication domains (RDs). RDs correspond to topologically-associating domains (TADs) and are spatio-temporally compartmentalized in the nucleus. While improvements in experimental tools have begun to reveal glimpses of causality, they have also unveiled complex context-dependent relationships that challenge long recognized correlations of RT to chromatin organization and gene regulation. In particular, RDs/TADs that switch RT during development march to the beat of a different drummer.},
}
@article {pmid27111891,
year = {2016},
author = {Valton, AL and Dekker, J},
title = {TAD disruption as oncogenic driver.},
journal = {Current opinion in genetics &amp; development},
volume = {36},
number = {},
pages = {34-40},
doi = {10.1016/j.gde.2016.03.008},
pmid = {27111891},
issn = {1879-0380},
support = {R01 GM112720/GM/NIGMS NIH HHS/United States ; R01 HG003143/HG/NHGRI NIH HHS/United States ; U01 HG007910/HG/NHGRI NIH HHS/United States ; U54 DK107980/DK/NIDDK NIH HHS/United States ; R01 AI117839/AI/NIAID NIH HHS/United States ; U01 DA040588/DA/NIDA NIH HHS/United States ; U54 HG007010/HG/NHGRI NIH HHS/United States ; U54 CA193419/CA/NCI NIH HHS/United States ; /HHMI/Howard Hughes Medical Institute/United States ; },
mesh = {Carcinogenesis/*genetics ; Chromatin/genetics ; Gene Expression Regulation, Neoplastic/*genetics ; *Genome, Human ; Genomics ; Humans ; Oncogene Proteins, Fusion/*genetics ; Protein Domains/genetics ; },
abstract = {Topologically Associating Domains (TADs) are conserved during evolution and play roles in guiding and constraining long-range regulation of gene expression. Disruption of TAD boundaries results in aberrant gene expression by exposing genes to inappropriate regulatory elements. Recent studies have shown that TAD disruption is often found in cancer cells and contributes to oncogenesis through two mechanisms. One mechanism locally disrupts domains by deleting or mutating a TAD boundary leading to fusion of the two adjacent TADs. The other mechanism involves genomic rearrangements that break up TADs and creates new ones without directly affecting TAD boundaries. Understanding the mechanisms by which TADs form and control long-range chromatin interactions will therefore not only provide insights into the mechanism of gene regulation in general, but will also reveal how genomic rearrangements and mutations in cancer genomes can lead to misregulation of oncogenes and tumor suppressors.},
}
@article {pmid27111547,
year = {2016},
author = {Razin, SV and Gavrilov, AA and Vassetzky, YS and Ulianov, SV},
title = {Topologically-associating domains: gene warehouses adapted to serve transcriptional regulation.},
journal = {Transcription},
volume = {7},
number = {3},
pages = {84-90},
doi = {10.1080/21541264.2016.1181489},
pmid = {27111547},
issn = {2154-1272},
mesh = {Chromosomes/*chemistry/genetics ; *Gene Expression Regulation ; Genome ; Nucleic Acid Conformation ; Regulatory Sequences, Nucleic Acid ; *Transcription, Genetic ; },
abstract = {Structural-functional domains have long been hypothesized to occur in eukaryotic chromosomes, but their existence still remains controversial. Here, we discuss the current state of studies of 3D genome folding and the relation of this folding to the functional organization of the genome.},
}
@article {pmid27098512,
year = {2016},
author = {Yu, S and Yang, F and Shen, WH},
title = {Genome maintenance in the context of 4D chromatin condensation.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {73},
number = {16},
pages = {3137-3150},
doi = {10.1007/s00018-016-2221-2},
pmid = {27098512},
issn = {1420-9071},
support = {R01 GM100478/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Cell Cycle ; Chromatin/chemistry/*genetics/metabolism ; Chromatin Assembly and Disassembly ; Chromosome Segregation ; Epigenesis, Genetic ; *Genomic Instability ; Histone Code ; Histones/chemistry/genetics/metabolism ; Humans ; Neoplasms/genetics/metabolism ; },
abstract = {The eukaryotic genome is packaged in the three-dimensional nuclear space by forming loops, domains, and compartments in a hierarchical manner. However, when duplicated genomes prepare for segregation, mitotic cells eliminate topologically associating domains and abandon the compartmentalized structure. Alongside chromatin architecture reorganization during the transition from interphase to mitosis, cells halt most DNA-templated processes such as transcription and repair. The intrinsically condensed chromatin serves as a sophisticated signaling module subjected to selective relaxation for programmed genomic activities. To understand the elaborate genome-epigenome interplay during cell cycle progression, the steady three-dimensional genome requires a time scale to form a dynamic four-dimensional and a more comprehensive portrait. In this review, we will dissect the functions of critical chromatin architectural components in constructing and maintaining an orderly packaged chromatin environment. We will also highlight the importance of the spatially and temporally conscious orchestration of chromatin remodeling to ensure high-fidelity genetic transmission.},
}
@article {pmid27028634,
year = {2016},
author = {Tiana, G and Amitai, A and Pollex, T and Piolot, T and Holcman, D and Heard, E and Giorgetti, L},
title = {Structural Fluctuations of the Chromatin Fiber within Topologically Associating Domains.},
journal = {Biophysical journal},
volume = {110},
number = {6},
pages = {1234-1245},
doi = {10.1016/j.bpj.2016.02.003},
pmid = {27028634},
issn = {1542-0086},
support = {250367//European Research Council/International ; },
mesh = {Algorithms ; Animals ; Chromatin/*chemistry ; Cluster Analysis ; Genetic Loci ; Mice ; Nucleic Acid Conformation ; Probability ; },
abstract = {Experiments based on chromosome conformation capture have shown that mammalian genomes are partitioned into topologically associating domains (TADs), within which the chromatin fiber preferentially interacts. TADs may provide three-dimensional scaffolds allowing genes to contact their appropriate distal regulatory DNA sequences (e.g., enhancers) and thus to be properly regulated. Understanding the cell-to-cell and temporal variability of the chromatin fiber within TADs, and what determines them, is thus of great importance to better understand transcriptional regulation. We recently described an equilibrium polymer model that can accurately predict cell-to-cell variation of chromosome conformation within single TADs, from chromosome conformation capture-based data. Here we further analyze the conformational and energetic properties of our model. We show that the chromatin fiber within TADs can easily fluctuate between several conformational states, which are hierarchically organized and are not separated by important free energy barriers, and that this is facilitated by the fact that the chromatin fiber within TADs is close to the onset of the coil-globule transition. We further show that in this dynamic state the properties of the chromatin fiber, and its contact probabilities in particular, are determined in a nontrivial manner not only by site-specific interactions between strongly interacting loci along the fiber, but also by nonlocal correlations between pairs of contacts. Finally, we use live-cell experiments to measure the dynamics of the chromatin fiber in mouse embryonic stem cells, in combination with dynamical simulations, and predict that conformational changes within one TAD are likely to occur on timescales that are much shorter than the duration of one cell cycle. This suggests that genes and their regulatory elements may come together and disassociate several times during a cell cycle. These results have important implications for transcriptional regulation as they support the concept of highly dynamic interactions driven by a complex interplay between site-specific interactions and the intrinsic biophysical properties of the chromatin fiber.},
}
@article {pmid26970625,
year = {2016},
author = {Darbellay, F and Duboule, D},
title = {Topological Domains, Metagenes, and the Emergence of Pleiotropic Regulations at Hox Loci.},
journal = {Current topics in developmental biology},
volume = {116},
number = {},
pages = {299-314},
doi = {10.1016/bs.ctdb.2015.11.022},
pmid = {26970625},
issn = {1557-8933},
mesh = {Animals ; Biological Evolution ; Chromatin ; *Enhancer Elements, Genetic ; Gene Expression Regulation ; *Genes, Homeobox ; Genome ; Homeodomain Proteins/*chemistry/genetics ; Multigene Family ; Protein Domains ; Vertebrates ; },
abstract = {Hox gene clusters of jaw vertebrates display a tight genomic organization, which has no equivalent in any other bilateria genomes sequenced thus far. It was previously argued that such a topological consolidation toward a condensed, metagenic structure was due to the accumulation of long-range regulations flanking Hox loci, a phenomenon made possible by the successive genome duplications that occurred at the root of the vertebrate lineage, similar to gene neofunctionalization but applied to a coordinated multigenic system. Here, we propose that the emergence of such large vertebrate regulatory landscapes containing a range of global enhancers was greatly facilitated by the presence of topologically associating domains (TADs). These chromatin domains, mostly constitutive, may have been used as genomic niches where novel regulations could evolve due to both the preexistence of a structural backbone poised to integrate novel regulatory inputs, and a highly adaptive transcriptional readout. We propose a scenario for the coevolution of such TADs and the emergence of pleiotropy at ancestral vertebrate Hox loci.},
}
@article {pmid26960733,
year = {2016},
author = {Zhu, Y and Chen, Z and Zhang, K and Wang, M and Medovoy, D and Whitaker, JW and Ding, B and Li, N and Zheng, L and Wang, W},
title = {Constructing 3D interaction maps from 1D epigenomes.},
journal = {Nature communications},
volume = {7},
number = {},
pages = {10812},
doi = {10.1038/ncomms10812},
pmid = {26960733},
issn = {2041-1723},
support = {U01 ES017166/ES/NIEHS NIH HHS/United States ; U01ES017166/ES/NIEHS NIH HHS/United States ; },
mesh = {Chromatin/*metabolism ; Chromosome Mapping ; *Epigenomics ; *Gene Expression Regulation ; *Gene Regulatory Networks ; *Genome, Human ; Humans ; Promoter Regions, Genetic ; Transcriptional Activation ; },
abstract = {The human genome is tightly packaged into chromatin whose functional output depends on both one-dimensional (1D) local chromatin states and three-dimensional (3D) genome organization. Currently, chromatin modifications and 3D genome organization are measured by distinct assays. An emerging question is whether it is possible to deduce 3D interactions by integrative analysis of 1D epigenomic data and associate 3D contacts to functionality of the interacting loci. Here we present EpiTensor, an algorithm to identify 3D spatial associations within topologically associating domains (TADs) from 1D maps of histone modifications, chromatin accessibility and RNA-seq. We demonstrate that active promoter-promoter, promoter-enhancer and enhancer-enhancer associations identified by EpiTensor are highly concordant with those detected by Hi-C, ChIA-PET and eQTL analyses at 200 bp resolution. Moreover, EpiTensor has identified a set of interaction hotspots, characterized by higher chromatin and transcriptional activity as well as enriched TF and ncRNA binding across diverse cell types, which may be critical for stabilizing the local 3D interactions.},
}
@article {pmid26906681,
year = {2016},
author = {Deschamps, J},
title = {Birth and upgrowth of the Hox topological domains during evolution.},
journal = {Nature genetics},
volume = {48},
number = {3},
pages = {227-228},
doi = {10.1038/ng.3514},
pmid = {26906681},
issn = {1546-1718},
mesh = {Animals ; Body Patterning/*genetics ; *Evolution, Molecular ; Homeodomain Proteins/*biosynthesis ; Lancelets/*genetics ; },
abstract = {The recently discovered chromatin compartments called topologically associating domains (TADs) are essential for the three-dimensional organization of regulatory interactions driving gene expression. A new study documents the emergence of a TAD flanking the amphioxus Hox cluster, prefiguring the vertebrate anterior Hox TAD and preceding the appearance of the concurring posterior Hox TAD.},
}
@article {pmid26876719,
year = {2016},
author = {Ramani, V and Shendure, J and Duan, Z},
title = {Understanding Spatial Genome Organization: Methods and Insights.},
journal = {Genomics, proteomics &amp; bioinformatics},
volume = {14},
number = {1},
pages = {7-20},
doi = {10.1016/j.gpb.2016.01.002},
pmid = {26876719},
issn = {2210-3244},
support = {U54 DK107979/DK/NIDDK NIH HHS/United States ; 1U54DK107979/DK/NIDDK NIH HHS/United States ; },
mesh = {Chromatin/chemistry/metabolism ; Chromatin Immunoprecipitation ; DNA/chemistry/metabolism ; Gene Expression Regulation ; *Genome, Human ; Humans ; Microscopy, Electron ; Molecular Conformation ; Transcription Factors/chemistry/metabolism ; },
abstract = {The manner by which eukaryotic genomes are packaged into nuclei while maintaining crucial nuclear functions remains one of the fundamental mysteries in biology. Over the last ten years, we have witnessed rapid advances in both microscopic and nucleic acid-based approaches to map genome architecture, and the application of these approaches to the dissection of higher-order chromosomal structures has yielded much new information. It is becoming increasingly clear, for example, that interphase chromosomes form stable, multilevel hierarchical structures. Among them, self-associating domains like so-called topologically associating domains (TADs) appear to be building blocks for large-scale genomic organization. This review describes features of these broadly-defined hierarchical structures, insights into the mechanisms underlying their formation, our current understanding of how interactions in the nuclear space are linked to gene regulation, and important future directions for the field.},
}
@article {pmid26868017,
year = {2016},
author = {Sharmin, M and Bravo, HC and Hannenhalli, S},
title = {Distinct genomic and epigenomic features demarcate hypomethylated blocks in colon cancer.},
journal = {BMC cancer},
volume = {16},
number = {},
pages = {88},
doi = {10.1186/s12885-016-2128-1},
pmid = {26868017},
issn = {1471-2407},
support = {R01 GM100335/GM/NIGMS NIH HHS/United States ; R01 HG005220/HG/NHGRI NIH HHS/United States ; NIH R01GM100335/GM/NIGMS NIH HHS/United States ; NIH R01HG005220/HG/NHGRI NIH HHS/United States ; },
mesh = {Cell Line, Tumor ; Chromatin/genetics ; Colonic Neoplasms/*genetics/pathology ; CpG Islands/genetics ; DNA Methylation/*genetics ; *Epigenomics ; *Genome, Human ; Histones/genetics ; Humans ; Promoter Regions, Genetic ; },
abstract = {BACKGROUND: Large mega base-pair genomic regions show robust alterations in DNA methylation levels in multiple cancers. A vast majority of these regions are hypomethylated in cancers. These regions are generally enriched for CpG islands, Lamin Associated Domains and Large organized chromatin lysine modification domains, and are associated with stochastic variability in gene expression. Given the size and consistency of hypomethylated blocks (HMB) across cancer types, we hypothesized that the immediate causes of methylation instability are likely to be encoded in the genomic region near HMB boundaries, in terms of specific genomic or epigenomic signatures. However, a detailed characterization of the HMB boundaries has not been reported.<br><br>METHOD: Here, we focused on ~13 k HMBs, encompassing approximately half of the genome, identified in colon cancer. We modeled the genomic features of HMB boundaries by Random Forest to identify their salient features, in terms of transcription factor (TF) binding motifs. Additionally we analyzed various epigenomic marks, and chromatin structural features of HMB boundaries relative to the non-HMB genomic regions.<br><br>RESULT: We found that the classical promoter epigenomic mark--H3K4me3, is highly enriched at HMB boundaries, as are CTCF bound sites. HMB boundaries harbor distinct combinations of TF motifs. Our Random Forest model based on TF motifs can accurately distinguish boundaries not only from regions inside and outside HMBs, but surprisingly, from active promoters as well. Interestingly, the distinguishing TFs and their interacting proteins are involved in chromatin modification. Finally, HMB boundaries significantly coincide with the boundaries of Topologically Associating Domains of the chromatin.<br><br>CONCLUSION: Our analyses suggest that the overall architecture of HMBs is guided by pre-existing chromatin architecture, and are associated with aberrant activity of promoter-like sequences at the boundary.},
}
@article {pmid26862051,
year = {2016},
author = {Lupiáñez, DG and Spielmann, M and Mundlos, S},
title = {Breaking TADs: How Alterations of Chromatin Domains Result in Disease.},
journal = {Trends in genetics : TIG},
volume = {32},
number = {4},
pages = {225-237},
doi = {10.1016/j.tig.2016.01.003},
pmid = {26862051},
issn = {0168-9525},
mesh = {Chromatin/*chemistry/genetics ; *Genetic Predisposition to Disease ; Humans ; },
abstract = {Spatial organization is an inherent property of the vertebrate genome to accommodate the roughly 2m of DNA in the nucleus of a cell. In this nonrandom organization, topologically associating domains (TADs) emerge as a fundamental structural unit that is thought to guide regulatory elements to their cognate promoters. In this review we summarize the most recent findings about TADs and the boundary regions separating them. We discuss how the disruption of these structures by genomic rearrangements can result in gene misexpression and disease.},
}
@article {pmid26852111,
year = {2016},
author = {Rowley, MJ and Corces, VG},
title = {The three-dimensional genome: principles and roles of long-distance interactions.},
journal = {Current opinion in cell biology},
volume = {40},
number = {},
pages = {8-14},
doi = {10.1016/j.ceb.2016.01.009},
pmid = {26852111},
issn = {1879-0410},
support = {F32 GM113570/GM/NIGMS NIH HHS/United States ; R01 GM035463/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; CCCTC-Binding Factor ; Chromatin/metabolism ; Chromatin Assembly and Disassembly ; Eukaryota/classification/*genetics ; Gene Expression Regulation ; *Genome ; Humans ; Repressor Proteins/metabolism ; },
abstract = {The linear sequence of eukaryotic genomes is arranged in a specific manner within the three-dimensional nuclear space. Interactions between distant sites partition the genome into domains of highly associating chromatin. Interaction domains are found in many organisms, but their properties and the principles governing their establishment vary between different species. Topologically associating domains (TADs) extending over large genomic regions are found in mammals and Drosophila melanogaster, whereas other types of contact domains exist in lower eukaryotes. Here we review recent studies that explore the mechanisms by which long distance chromatin interactions determine the 3D organization of the genome and the relationship between this organization and the establishment of specific patterns of gene expression.},
}
@article {pmid26767994,
year = {2015},
author = {Fabre, PJ and Benke, A and Manley, S and Duboule, D},
title = {Visualizing the HoxD Gene Cluster at the Nanoscale Level.},
journal = {Cold Spring Harbor symposia on quantitative biology},
volume = {80},
number = {},
pages = {9-16},
doi = {10.1101/sqb.2015.80.027177},
pmid = {26767994},
issn = {1943-4456},
mesh = {Animals ; Chromatin/*metabolism ; Embryonic Stem Cells ; Extremities/embryology ; *Gene Expression Regulation, Developmental ; Genes, Homeobox/*genetics ; Microscopy ; *Multigene Family ; Optical Imaging ; },
abstract = {Transcription of HoxD cluster genes in limbs is coordinated by two topologically associating domains (TADs), neighboring the cluster and containing various enhancers. Here, we use a combination of microscopy approaches and chromosome conformation capture to assess the structural changes occurring in this global architecture in various functional states. We observed that despite their spatial juxtaposition, the TADs are consistently kept as distinct three-dimensional units. Hox genes located at their boundary can show significant spatial segregation over long distances, suggesting that physical elongation of the HoxD cluster occurs. The use of superresolution imaging (STORM [stochastic optical reconstruction microscopy]) revealed that the gene cluster can be in an either compact or elongated shape. The latter configuration is observed in transcriptionally active tissue and in embryonic stem cells, consistent with chromosome conformation capture results. Such morphological changes at HoxD in developing digits seem to be associated with its position at the boundary between two TADs and support the idea that chromatin dynamics is important in the establishment of transcriptional activity.},
}
@article {pmid26748519,
year = {2016},
author = {Smith, EM and Lajoie, BR and Jain, G and Dekker, J},
title = {Invariant TAD Boundaries Constrain Cell-Type-Specific Looping Interactions between Promoters and Distal Elements around the CFTR Locus.},
journal = {American journal of human genetics},
volume = {98},
number = {1},
pages = {185-201},
doi = {10.1016/j.ajhg.2015.12.002},
pmid = {26748519},
issn = {1537-6605},
support = {HG003143/HG/NHGRI NIH HHS/United States ; R01 HG003143/HG/NHGRI NIH HHS/United States ; //Howard Hughes Medical Institute/United States ; U54 HG007010/HG/NHGRI NIH HHS/United States ; HG007010/HG/NHGRI NIH HHS/United States ; },
mesh = {Cell Line ; Chromatin/metabolism ; Cystic Fibrosis Transmembrane Conductance Regulator/*genetics ; *Enhancer Elements, Genetic ; Humans ; *Promoter Regions, Genetic ; },
abstract = {Three-dimensional genome structure plays an important role in gene regulation. Globally, chromosomes are organized into active and inactive compartments while, at the gene level, looping interactions connect promoters to regulatory elements. Topologically associating domains (TADs), typically several hundred kilobases in size, form an intermediate level of organization. Major questions include how TADs are formed and how they are related to looping interactions between genes and regulatory elements. Here we performed a focused 5C analysis of a 2.8 Mb chromosome 7 region surrounding CFTR in a panel of cell types. We find that the same TAD boundaries are present in all cell types, indicating that TADs represent a universal chromosome architecture. Furthermore, we find that these TAD boundaries are present irrespective of the expression and looping of genes located between them. In contrast, looping interactions between promoters and regulatory elements are cell-type specific and occur mostly within TADs. This is exemplified by the CFTR promoter that in different cell types interacts with distinct sets of distal cell-type-specific regulatory elements that are all located within the same TAD. Finally, we find that long-range associations between loci located in different TADs are also detected, but these display much lower interaction frequencies than looping interactions within TADs. Interestingly, interactions between TADs are also highly cell-type-specific and often involve loci clustered around TAD boundaries. These data point to key roles of invariant TAD boundaries in constraining as well as mediating cell-type-specific long-range interactions and gene regulation.},
}
@article {pmid26700852,
year = {2015},
author = {Fraser, J and Ferrai, C and Chiariello, AM and Schueler, M and Rito, T and Laudanno, G and Barbieri, M and Moore, BL and Kraemer, DC and Aitken, S and Xie, SQ and Morris, KJ and Itoh, M and Kawaji, H and Jaeger, I and Hayashizaki, Y and Carninci, P and Forrest, AR and , and Semple, CA and Dostie, J and Pombo, A and Nicodemi, M},
title = {Hierarchical folding and reorganization of chromosomes are linked to transcriptional changes in cellular differentiation.},
journal = {Molecular systems biology},
volume = {11},
number = {12},
pages = {852},
doi = {10.15252/msb.20156492},
pmid = {26700852},
issn = {1744-4292},
support = {MC_U120061476//Medical Research Council/United Kingdom ; //Medical Research Council/United Kingdom ; //Biotechnology and Biological Sciences Research Council/United Kingdom ; CAP-120350//Canadian Institutes of Health Research/Canada ; MOP-86716//Canadian Institutes of Health Research/Canada ; BB/H008098/1//Biotechnology and Biological Sciences Research Council/United Kingdom ; },
mesh = {Animals ; Cell Differentiation ; Cells, Cultured ; Chromatin/*chemistry ; Chromatin Assembly and Disassembly ; Chromosomes/*chemistry ; Epigenesis, Genetic ; Gene Expression Regulation ; Mice ; Mouse Embryonic Stem Cells/*cytology ; Neurons/*cytology ; *Transcription, Genetic ; },
abstract = {Mammalian chromosomes fold into arrays of megabase-sized topologically associating domains (TADs), which are arranged into compartments spanning multiple megabases of genomic DNA. TADs have internal substructures that are often cell type specific, but their higher-order organization remains elusive. Here, we investigate TAD higher-order interactions with Hi-C through neuronal differentiation and show that they form a hierarchy of domains-within-domains (metaTADs) extending across genomic scales up to the range of entire chromosomes. We find that TAD interactions are well captured by tree-like, hierarchical structures irrespective of cell type. metaTAD tree structures correlate with genetic, epigenomic and expression features, and structural tree rearrangements during differentiation are linked to transcriptional state changes. Using polymer modelling, we demonstrate that hierarchical folding promotes efficient chromatin packaging without the loss of contact specificity, highlighting a role far beyond the simple need for packing efficiency.},
}
@article {pmid26700097,
year = {2015},
author = {Geeven, G and Zhu, Y and Kim, BJ and Bartholdy, BA and Yang, SM and Macfarlan, TS and Gifford, WD and Pfaff, SL and Verstegen, MJ and Pinto, H and Vermunt, MW and Creyghton, MP and Wijchers, PJ and Stamatoyannopoulos, JA and Skoultchi, AI and de Laat, W},
title = {Local compartment changes and regulatory landscape alterations in histone H1-depleted cells.},
journal = {Genome biology},
volume = {16},
number = {},
pages = {289},
doi = {10.1186/s13059-015-0857-0},
pmid = {26700097},
issn = {1474-760X},
support = {CA079057/CA/NCI NIH HHS/United States ; R01 CA079057/CA/NCI NIH HHS/United States ; GM116143/GM/NIGMS NIH HHS/United States ; R01 GM116143/GM/NIGMS NIH HHS/United States ; R56 CA079057/CA/NCI NIH HHS/United States ; P30 CA013330/CA/NCI NIH HHS/United States ; },
mesh = {Animals ; Cell Line ; Chromatin/genetics/metabolism ; *Chromatin Assembly and Disassembly ; *Epigenesis, Genetic ; Histones/genetics/*metabolism ; Mice ; },
abstract = {BACKGROUND: Linker histone H1 is a core chromatin component that binds to nucleosome core particles and the linker DNA between nucleosomes. It has been implicated in chromatin compaction and gene regulation and is anticipated to play a role in higher-order genome structure. Here we have used a combination of genome-wide approaches including DNA methylation, histone modification and DNase I hypersensitivity profiling as well as Hi-C to investigate the impact of reduced cellular levels of histone H1 in embryonic stem cells on chromatin folding and function.<br><br>RESULTS: We find that depletion of histone H1 changes the epigenetic signature of thousands of potential regulatory sites across the genome. Many of them show cooperative loss or gain of multiple chromatin marks. Epigenetic alterations cluster to gene-dense topologically associating domains (TADs) that already showed a high density of corresponding chromatin features. Genome organization at the three-dimensional level is largely intact, but we find changes in the structural segmentation of chromosomes specifically for the epigenetically most modified TADs.<br><br>CONCLUSIONS: Our data show that cells require normal histone H1 levels to expose their proper regulatory landscape. Reducing the levels of histone H1 results in massive epigenetic changes and altered topological organization particularly at the most active chromosomal domains. Changes in TAD configuration coincide with epigenetic landscape changes but not with transcriptional output changes, supporting the emerging concept that transcriptional control and nuclear positioning of TADs are not causally related but independently controlled by the locally associated trans-acting factors.},
}
@article {pmid26686465,
year = {2016},
author = {Ji, X and Dadon, DB and Powell, BE and Fan, ZP and Borges-Rivera, D and Shachar, S and Weintraub, AS and Hnisz, D and Pegoraro, G and Lee, TI and Misteli, T and Jaenisch, R and Young, RA},
title = {3D Chromosome Regulatory Landscape of Human Pluripotent Cells.},
journal = {Cell stem cell},
volume = {18},
number = {2},
pages = {262-275},
doi = {10.1016/j.stem.2015.11.007},
pmid = {26686465},
issn = {1875-9777},
support = {T32 GM007287/GM/NIGMS NIH HHS/United States ; R01 MH104610/MH/NIMH NIH HHS/United States ; R25 HG007631/HG/NHGRI NIH HHS/United States ; R01 NS088538/NS/NINDS NIH HHS/United States ; R37 HD045022/HD/NICHD NIH HHS/United States ; //Intramural NIH HHS/United States ; HD 045022/HD/NICHD NIH HHS/United States ; R01 HD045022/HD/NICHD NIH HHS/United States ; R01 HG002668/HG/NHGRI NIH HHS/United States ; HG002668/HG/NHGRI NIH HHS/United States ; },
mesh = {CCCTC-Binding Factor ; Cell Cycle Proteins/metabolism ; Cell Line ; Chromatin/metabolism ; Chromosomal Proteins, Non-Histone/metabolism ; Chromosomes, Human/*genetics ; DNA/chemistry/metabolism ; Disease/genetics ; Enhancer Elements, Genetic ; Gene Expression Regulation ; Human Embryonic Stem Cells/metabolism ; Humans ; Insulator Elements/genetics ; MicroRNAs/metabolism ; Nucleic Acid Conformation ; Pluripotent Stem Cells/*metabolism ; Repressor Proteins ; Transcription Factors/metabolism ; },
abstract = {In this study, we describe the 3D chromosome regulatory landscape of human naive and primed embryonic stem cells. To devise this map, we identified transcriptional enhancers and insulators in these cells and placed them within the context of cohesin-associated CTCF-CTCF loops using cohesin ChIA-PET data. The CTCF-CTCF loops we identified form a chromosomal framework of insulated neighborhoods, which in turn form topologically associating domains (TADs) that are largely preserved during the transition between the naive and primed states. Regulatory changes in enhancer-promoter interactions occur within insulated neighborhoods during cell state transition. The CTCF anchor regions we identified are conserved across species, influence gene expression, and are a frequent site of mutations in cancer cells, underscoring their functional importance in cellular regulation. These 3D regulatory maps of human pluripotent cells therefore provide a foundation for future interrogation of the relationships between chromosome structure and gene control in development and disease.},
}
@article {pmid26610607,
year = {2015},
author = {Nguyen, VT and Barozzi, I and Faronato, M and Lombardo, Y and Steel, JH and Patel, N and Darbre, P and Castellano, L and Győrffy, B and Woodley, L and Meira, A and Patten, DK and Vircillo, V and Periyasamy, M and Ali, S and Frige, G and Minucci, S and Coombes, RC and Magnani, L},
title = {Differential epigenetic reprogramming in response to specific endocrine therapies promotes cholesterol biosynthesis and cellular invasion.},
journal = {Nature communications},
volume = {6},
number = {},
pages = {10044},
doi = {10.1038/ncomms10044},
pmid = {26610607},
issn = {2041-1723},
support = {103034/Z/13/Z//Wellcome Trust/United Kingdom ; //Cancer Research UK/United Kingdom ; },
mesh = {Animals ; Antineoplastic Agents, Hormonal/pharmacology/therapeutic use ; Aromatase Inhibitors/pharmacology/therapeutic use ; Biosynthetic Pathways/drug effects/genetics ; Blotting, Western ; Breast Neoplasms/drug therapy/*genetics/pathology ; Cholesterol/*biosynthesis ; Chromatin Immunoprecipitation ; Drug Resistance, Neoplasm/drug effects/*genetics ; Epigenesis, Genetic/*genetics ; Estrogen Receptor alpha/*metabolism ; Female ; Humans ; Hydroxycholesterols ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology ; Immunohistochemistry ; In Vitro Techniques ; MCF-7 Cells ; Mice ; Mice, SCID ; Neoplasm Invasiveness ; Neoplasm Transplantation ; Real-Time Polymerase Chain Reaction ; Up-Regulation ; },
abstract = {Endocrine therapies target the activation of the oestrogen receptor alpha (ERα) via distinct mechanisms, but it is not clear whether breast cancer cells can adapt to treatment using drug-specific mechanisms. Here we demonstrate that resistance emerges via drug-specific epigenetic reprogramming. Resistant cells display a spectrum of phenotypical changes with invasive phenotypes evolving in lines resistant to the aromatase inhibitor (AI). Orthogonal genomics analysis of reprogrammed regulatory regions identifies individual drug-induced epigenetic states involving large topologically associating domains (TADs) and the activation of super-enhancers. AI-resistant cells activate endogenous cholesterol biosynthesis (CB) through stable epigenetic activation in vitro and in vivo. Mechanistically, CB sparks the constitutive activation of oestrogen receptors alpha (ERα) in AI-resistant cells, partly via the biosynthesis of 27-hydroxycholesterol. By targeting CB using statins, ERα binding is reduced and cell invasion is prevented. Epigenomic-led stratification can predict resistance to AI in a subset of ERα-positive patients.},
}
@article {pmid26590169,
year = {2015},
author = {Dileep, V and Rivera-Mulia, JC and Sima, J and Gilbert, DM},
title = {Large-Scale Chromatin Structure-Function Relationships during the Cell Cycle and Development: Insights from Replication Timing.},
journal = {Cold Spring Harbor symposia on quantitative biology},
volume = {80},
number = {},
pages = {53-63},
doi = {10.1101/sqb.2015.80.027284},
pmid = {26590169},
issn = {1943-4456},
support = {P01 GM085354/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; *Cell Cycle ; Chromatin/*metabolism ; Chromatin Assembly and Disassembly ; Chromosomes/*metabolism ; *DNA Replication ; Humans ; Structure-Activity Relationship ; },
abstract = {Chromosome architecture has received a lot of attention since the recent development of genome-scale methods to measure chromatin interactions (Hi-C), enabling the first sequence-based models of chromosome tertiary structure. A view has emerged of chromosomes as a string of structural units (topologically associating domains; TADs) whose boundaries persist through the cell cycle and development. TADs with similar chromatin states tend to aggregate, forming spatially segregated chromatin compartments. However, high-resolution Hi-C has revealed substructure within TADs (subTADs) that poses a challenge for models that attribute significance to structural units at any given scale. More than 20 years ago, the DNA replication field independently identified stable structural (and functional) units of chromosomes (replication foci) as well as spatially segregated chromatin compartments (early and late foci), but lacked the means to link these units to genomic map units. Genome-wide studies of replication timing (RT) have now merged these two disciplines by identifying individual units of replication regulation (replication domains; RDs) that correspond to TADs and are arranged in 3D to form spatiotemporally segregated subnuclear compartments. Furthermore, classifying RDs/TADs by their constitutive versus developmentally regulated RT has revealed distinct classes of chromatin organization, providing unexpected insight into the relationship between large-scale chromosome structure and function.},
}
@article {pmid26558551,
year = {2016},
author = {Remeseiro, S and Hörnblad, A and Spitz, F},
title = {Gene regulation during development in the light of topologically associating domains.},
journal = {Wiley interdisciplinary reviews. Developmental biology},
volume = {5},
number = {2},
pages = {169-185},
doi = {10.1002/wdev.218},
pmid = {26558551},
issn = {1759-7692},
mesh = {Animals ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Embryonic Development/*genetics ; Enhancer Elements, Genetic ; *Gene Expression Regulation, Developmental ; Promoter Regions, Genetic ; Protein Structure, Tertiary ; *Transcriptional Activation ; },
abstract = {During embryonic development, complex transcriptional programs govern the precision of gene expression. Many key developmental genes are regulated via cis-regulatory elements that are located far away in the linear genome. How sequences located hundreds of kilobases away from a promoter can influence its activity has been the subject of numerous speculations, which all underline the importance of the 3D-organization of the genome. The recent advent of chromosome conformation capture techniques has put into focus the subdivision of the genome into topologically associating domains (TADs). TADs may influence regulatory activities on multiple levels. The relative invariance of TAD limits across cell types suggests that they may form fixed structural domains that could facilitate and/or confine long-range regulatory interactions. However, most recent studies suggest that interactions within TADs are more variable and dynamic than initially described. Hence, different models are emerging regarding how TADs shape the complex 3D conformations, and thereafter influence the networks of cis-interactions that govern gene expression during development. For further resources related to this article, please visit the WIREs website.},
}
@article {pmid26544940,
year = {2015},
author = {Eagen, KP and Hartl, TA and Kornberg, RD},
title = {Stable Chromosome Condensation Revealed by Chromosome Conformation Capture.},
journal = {Cell},
volume = {163},
number = {4},
pages = {934-946},
doi = {10.1016/j.cell.2015.10.026},
pmid = {26544940},
issn = {1097-4172},
support = {T32 GM007365/GM/NIGMS NIH HHS/United States ; R01 GM036659/GM/NIGMS NIH HHS/United States ; U01AI090905/AI/NIAID NIH HHS/United States ; U01 AI090905/AI/NIAID NIH HHS/United States ; T32 GM008294/GM/NIGMS NIH HHS/United States ; R01 AI021144/AI/NIAID NIH HHS/United States ; R37 GM036659/GM/NIGMS NIH HHS/United States ; T32GM007365/GM/NIGMS NIH HHS/United States ; AI21144/AI/NIAID NIH HHS/United States ; GM36659/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Cell Nucleus/chemistry/genetics ; Chromosomal Puffs ; Diploidy ; Drosophila melanogaster/chemistry/cytology/*genetics/growth &amp; development ; Genetic Techniques ; Larva/chemistry ; Polytene Chromosomes/*chemistry ; },
abstract = {Chemical cross-linking and DNA sequencing have revealed regions of intra-chromosomal interaction, referred to as topologically associating domains (TADs), interspersed with regions of little or no interaction, in interphase nuclei. We find that TADs and the regions between them correspond with the bands and interbands of polytene chromosomes of Drosophila. We further establish the conservation of TADs between polytene and diploid cells of Drosophila. From direct measurements on light micrographs of polytene chromosomes, we then deduce the states of chromatin folding in the diploid cell nucleus. Two states of folding, fully extended fibers containing regulatory regions and promoters, and fibers condensed up to 10-fold containing coding regions of active genes, constitute the euchromatin of the nuclear interior. Chromatin fibers condensed up to 30-fold, containing coding regions of inactive genes, represent the heterochromatin of the nuclear periphery. A convergence of molecular analysis with direct observation thus reveals the architecture of interphase chromosomes.},
}
@article {pmid26518482,
year = {2016},
author = {Ulianov, SV and Khrameeva, EE and Gavrilov, AA and Flyamer, IM and Kos, P and Mikhaleva, EA and Penin, AA and Logacheva, MD and Imakaev, MV and Chertovich, A and Gelfand, MS and Shevelyov, YY and Razin, SV},
title = {Active chromatin and transcription play a key role in chromosome partitioning into topologically associating domains.},
journal = {Genome research},
volume = {26},
number = {1},
pages = {70-84},
doi = {10.1101/gr.196006.115},
pmid = {26518482},
issn = {1549-5469},
mesh = {Animals ; Cell Line ; Chromatin/*genetics ; Chromatin Assembly and Disassembly ; Chromosome Mapping ; Computer Simulation ; Drosophila melanogaster/*genetics ; *Genome, Insect ; Models, Molecular ; Nucleosomes/genetics/metabolism ; Polytene Chromosomes/genetics ; Sequence Analysis, RNA ; *Transcription, Genetic ; },
abstract = {Recent advances enabled by the Hi-C technique have unraveled many principles of chromosomal folding that were subsequently linked to disease and gene regulation. In particular, Hi-C revealed that chromosomes of animals are organized into topologically associating domains (TADs), evolutionary conserved compact chromatin domains that influence gene expression. Mechanisms that underlie partitioning of the genome into TADs remain poorly understood. To explore principles of TAD folding in Drosophila melanogaster, we performed Hi-C and poly(A)(+) RNA-seq in four cell lines of various origins (S2, Kc167, DmBG3-c2, and OSC). Contrary to previous studies, we find that regions between TADs (i.e., the inter-TADs and TAD boundaries) in Drosophila are only weakly enriched with the insulator protein dCTCF, while another insulator protein Su(Hw) is preferentially present within TADs. However, Drosophila inter-TADs harbor active chromatin and constitutively transcribed (housekeeping) genes. Accordingly, we find that binding of insulator proteins dCTCF and Su(Hw) predicts TAD boundaries much worse than active chromatin marks do. Interestingly, inter-TADs correspond to decompacted inter-bands of polytene chromosomes, whereas TADs mostly correspond to densely packed bands. Collectively, our results suggest that TADs are condensed chromatin domains depleted in active chromatin marks, separated by regions of active chromatin. We propose the mechanism of TAD self-assembly based on the ability of nucleosomes from inactive chromatin to aggregate, and lack of this ability in acetylated nucleosomal arrays. Finally, we test this hypothesis by polymer simulations and find that TAD partitioning may be explained by different modes of inter-nucleosomal interactions for active and inactive chromatin.},
}
@article {pmid26504220,
year = {2015},
author = {Fabre, PJ and Benke, A and Joye, E and Nguyen Huynh, TH and Manley, S and Duboule, D},
title = {Nanoscale spatial organization of the HoxD gene cluster in distinct transcriptional states.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {112},
number = {45},
pages = {13964-13969},
doi = {10.1073/pnas.1517972112},
pmid = {26504220},
issn = {1091-6490},
mesh = {Animals ; Chromatin/genetics/*ultrastructure ; Chromatin Assembly and Disassembly/genetics/*physiology ; Extremities/*embryology ; Gene Expression Regulation, Developmental/*genetics ; Genes, Homeobox/*genetics ; Image Processing, Computer-Assisted ; In Situ Hybridization, Fluorescence ; Mice ; Multigene Family/*genetics ; Protein Structure, Tertiary ; Statistics, Nonparametric ; Transcriptional Activation/*genetics ; },
abstract = {Chromatin condensation plays an important role in the regulation of gene expression. Recently, it was shown that the transcriptional activation of Hoxd genes during vertebrate digit development involves modifications in 3D interactions within and around the HoxD gene cluster. This reorganization follows a global transition from one set of regulatory contacts to another, between two topologically associating domains (TADs) located on either side of the HoxD locus. Here, we use 3D DNA FISH to assess the spatial organization of chromatin at and around the HoxD gene cluster and report that although the two TADs are tightly associated, they appear as spatially distinct units. We measured the relative position of genes within the cluster and found that they segregate over long distances, suggesting that a physical elongation of the HoxD cluster can occur. We analyzed this possibility by super-resolution imaging (STORM) and found that tissues with distinct transcriptional activity exhibit differing degrees of elongation. We also observed that the morphological change of the HoxD cluster in developing digits is associated with its position at the boundary between the two TADs. Such variations in the fine-scale architecture of the gene cluster suggest causal links among its spatial configuration, transcriptional activation, and the flanking chromatin context.},
}
@article {pmid26431028,
year = {2015},
author = {Ramírez, F and Lingg, T and Toscano, S and Lam, KC and Georgiev, P and Chung, HR and Lajoie, BR and de Wit, E and Zhan, Y and de Laat, W and Dekker, J and Manke, T and Akhtar, A},
title = {High-Affinity Sites Form an Interaction Network to Facilitate Spreading of the MSL Complex across the X Chromosome in Drosophila.},
journal = {Molecular cell},
volume = {60},
number = {1},
pages = {146-162},
doi = {10.1016/j.molcel.2015.08.024},
pmid = {26431028},
issn = {1097-4164},
support = {R01 HG003143/HG/NHGRI NIH HHS/United States ; //Howard Hughes Medical Institute/United States ; },
mesh = {Animals ; Binding Sites ; Cell Line ; Chromatin Assembly and Disassembly ; Cytogenetic Analysis ; DNA-Binding Proteins/*metabolism ; Dosage Compensation, Genetic ; Drosophila Proteins/genetics/*metabolism ; Drosophila melanogaster/*genetics/metabolism ; Female ; Male ; RNA-Binding Proteins/genetics/*metabolism ; Transcription Factors/genetics/*metabolism ; X Chromosome/genetics/*metabolism ; },
abstract = {Dosage compensation mechanisms provide a paradigm to study the contribution of chromosomal conformation toward targeting and spreading of epigenetic regulators over a specific chromosome. By using Hi-C and 4C analyses, we show that high-affinity sites (HAS), landing platforms of the male-specific lethal (MSL) complex, are enriched around topologically associating domain (TAD) boundaries on the X chromosome and harbor more long-range contacts in a sex-independent manner. Ectopically expressed roX1 and roX2 RNAs target HAS on the X chromosome in trans and, via spatial proximity, induce spreading of the MSL complex in cis, leading to increased expression of neighboring autosomal genes. We show that the MSL complex regulates nucleosome positioning at HAS, therefore acting locally rather than influencing the overall chromosomal architecture. We propose that the sex-independent, three-dimensional conformation of the X chromosome poises it for exploitation by the MSL complex, thereby facilitating spreading in males.},
}
@article {pmid26418477,
year = {2015},
author = {Cubeñas-Potts, C and Corces, VG},
title = {Topologically Associating Domains: An invariant framework or a dynamic scaffold?.},
journal = {Nucleus (Austin, Tex.)},
volume = {6},
number = {6},
pages = {430-434},
doi = {10.1080/19491034.2015.1096467},
pmid = {26418477},
issn = {1949-1042},
support = {R01 GM035463/GM/NIGMS NIH HHS/United States ; R01GM035463/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Binding Sites ; CCCTC-Binding Factor ; Cell Differentiation ; Chromatin/chemistry/*metabolism ; Enhancer Elements, Genetic ; Epigenesis, Genetic ; *Genome ; Promoter Regions, Genetic ; Protein Binding ; Proteins/chemistry/*metabolism ; Repressor Proteins/chemistry/metabolism ; Stress, Physiological ; Temperature ; },
abstract = {Metazoan genomes are organized into regions of topologically associating domains (TADs). TADs are demarcated by border elements, which are enriched for active genes and high occupancy architectural protein binding sites. We recently demonstrated that 3D chromatin architecture is dynamic in response to heat shock, a physiological stress that downregulates transcription and causes a global redistribution of architectural proteins. We utilized a quantitative measure of border strength after heat shock, transcriptional inhibition, and architectural protein knockdown to demonstrate that changes in both transcription and architectural protein occupancy contribute to heat shock-induced TAD dynamics. Notably, architectural proteins appear to play a more important role in altering 3D chromatin architecture. Here, we discuss the implications of our findings on previous studies evaluating the dynamics of TAD structure during cellular differentiation. We propose that the subset of variable TADs observed after differentiation are representative of cell-type specific gene expression and are biologically significant.},
}
@article {pmid26348399,
year = {2015},
author = {Dekker, J and Heard, E},
title = {Structural and functional diversity of Topologically Associating Domains.},
journal = {FEBS letters},
volume = {589},
number = {20 Pt A},
pages = {2877-2884},
doi = {10.1016/j.febslet.2015.08.044},
pmid = {26348399},
issn = {1873-3468},
support = {R01 HG003143/HG/NHGRI NIH HHS/United States ; },
mesh = {Animals ; Chromatin/genetics ; *Gene Expression Regulation ; Humans ; Nucleic Acid Conformation ; *Regulatory Sequences, Nucleic Acid ; },
abstract = {Recent studies have shown that chromosomes in a range of organisms are compartmentalized in different types of chromatin domains. In mammals, chromosomes form compartments that are composed of smaller Topologically Associating Domains (TADs). TADs are thought to represent functional domains of gene regulation but much is still unknown about the mechanisms of their formation and how they exert their regulatory effect on embedded genes. Further, similar domains have been detected in other organisms, including flies, worms, fungi and bacteria. Although in all these cases these domains appear similar as detected by 3C-based methods, their biology appears to be quite distinct with differences in the protein complexes involved in their formation and differences in their internal organization. Here we outline our current understanding of such domains in different organisms and their roles in gene regulation.},
}
@article {pmid26340055,
year = {2015},
author = {Higgins, GA and Allyn-Feuer, A and Athey, BD},
title = {Epigenomic mapping and effect sizes of noncoding variants associated with psychotropic drug response.},
journal = {Pharmacogenomics},
volume = {16},
number = {14},
pages = {1565-1583},
doi = {10.2217/pgs.15.105},
pmid = {26340055},
issn = {1744-8042},
support = {T32 GM0704490552/GM/NIGMS NIH HHS/United States ; },
mesh = {Cell Cycle Proteins/genetics ; Chromatin/genetics ; Chromosomal Proteins, Non-Histone/genetics ; Chromosome Mapping/*methods ; Computational Biology ; Computer Simulation ; DNA Methylation ; Deoxyribonuclease I/genetics ; Epigenomics/*methods ; European Continental Ancestry Group ; Genetic Variation ; Genome-Wide Association Study ; Humans ; Polymorphism, Single Nucleotide ; Psychotropic Drugs/*pharmacology ; Transcription Factors/genetics ; },
abstract = {AIM: To provide insight into potential regulatory mechanisms of gene expression underlying addiction, analgesia, psychotropic drug response and adverse drug events, genome-wide association studies searching for variants associated with these phenotypes has been undertaken with limited success. We undertook analysis of these results with the aim of applying epigenetic knowledge to aid variant discovery and interpretation.<br><br>METHODS: We applied conditional imputation to results from 26 genome-wide association studies and three candidate gene-association studies. The analysis workflow included data from chromatin conformation capture, chromatin state annotation, DNase I hypersensitivity, hypomethylation, anatomical localization and biochronicity. We also made use of chromatin state data from the epigenome roadmap, transcription factor-binding data, spatial maps from published Hi-C datasets and 'guilt by association' methods.<br><br>RESULTS: We identified 31 pharmacoepigenomic SNPs from a total of 2024 variants in linkage disequilibrium with lead SNPs, of which only 6% were coding variants. Interrogation of chromatin state using our workflow and the epigenome roadmap showed agreement on 34 of 35 tissue assignments to regulatory elements including enhancers and promoters. Loop boundary domains were inferred by association with CTCF (CCCTC-binding factor) and cohesin, suggesting proximity to topologically associating domain boundaries and enhancer clusters. Spatial interactions between enhancer-promoter pairs detected both known and previously unknown mechanisms. Addiction and analgesia SNPs were common in relevant populations and exhibited large effect sizes, whereas a SNP located in the promoter of the SLC1A2 gene exhibited a moderate effect size for lithium response in bipolar disorder in patients of European ancestry. SNPs associated with drug-induced organ injury were rare but exhibited the largest effect sizes, consistent with the published literature.<br><br>CONCLUSION: This work demonstrates that an in silico bioinformatics-based approach using integrative analysis of a diversity of molecular and morphological data types can discover pharmacoepigenomic variants that are suitable candidates for further validation in cell lines, animal models and human clinical trials.},
}
@article {pmid26315910,
year = {2016},
author = {Weinreb, C and Raphael, BJ},
title = {Identification of hierarchical chromatin domains.},
journal = {Bioinformatics (Oxford, England)},
volume = {32},
number = {11},
pages = {1601-1609},
doi = {10.1093/bioinformatics/btv485},
pmid = {26315910},
issn = {1367-4811},
support = {R01 HG005690/HG/NHGRI NIH HHS/United States ; },
mesh = {Cell Differentiation ; *Chromatin ; Gene Expression Regulation ; Genome ; },
abstract = {MOTIVATION: The three-dimensional structure of the genome is an important regulator of many cellular processes including differentiation and gene regulation. Recently, technologies such as Hi-C that combine proximity ligation with high-throughput sequencing have revealed domains of self-interacting chromatin, called topologically associating domains (TADs), in many organisms. Current methods for identifying TADs using Hi-C data assume that TADs are non-overlapping, despite evidence for a nested structure in which TADs and sub-TADs form a complex hierarchy.<br><br>RESULTS: We introduce a model for decomposition of contact frequencies into a hierarchy of nested TADs. This model is based on empirical distributions of contact frequencies within TADs, where positions that are far apart have a greater enrichment of contacts than positions that are close together. We find that the increase in contact enrichment with distance is stronger for the inner TAD than for the outer TAD in a TAD/sub-TAD pair. Using this model, we develop the TADtree algorithm for detecting hierarchies of nested TADs. TADtree compares favorably with previous methods, finding TADs with a greater enrichment of chromatin marks such as CTCF at their boundaries.<br><br>A python implementation of TADtree is available at http://compbio.cs.brown.edu/software/<br><br>CONTACT: braphael@cs.brown.edu<br><br>SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},
}
@article {pmid26271925,
year = {2015},
author = {Ea, V and Sexton, T and Gostan, T and Herviou, L and Baudement, MO and Zhang, Y and Berlivet, S and Le Lay-Taha, MN and Cathala, G and Lesne, A and Victor, JM and Fan, Y and Cavalli, G and Forné, T},
title = {Distinct polymer physics principles govern chromatin dynamics in mouse and Drosophila topological domains.},
journal = {BMC genomics},
volume = {16},
number = {},
pages = {607},
doi = {10.1186/s12864-015-1786-8},
pmid = {26271925},
issn = {1471-2164},
support = {R01 GM085261/GM/NIGMS NIH HHS/United States ; GM085261/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Chromatin/chemistry/genetics/*metabolism ; Chromatin Assembly and Disassembly ; DNA/*chemistry ; Drosophila melanogaster/*genetics ; Epigenesis, Genetic ; Liver/metabolism ; Mice ; *Models, Molecular ; *Models, Statistical ; Mouse Embryonic Stem Cells/cytology ; Nucleic Acid Conformation ; },
abstract = {BACKGROUND: In higher eukaryotes, the genome is partitioned into large &quot;Topologically Associating Domains&quot; (TADs) in which the chromatin displays favoured long-range contacts. While a crumpled/fractal globule organization has received experimental supports at higher-order levels, the organization principles that govern chromatin dynamics within these TADs remain unclear. Using simple polymer models, we previously showed that, in mouse liver cells, gene-rich domains tend to adopt a statistical helix shape when no significant locus-specific interaction takes place.<br><br>RESULTS: Here, we use data from diverse 3C-derived methods to explore chromatin dynamics within mouse and Drosophila TADs. In mouse Embryonic Stem Cells (mESC), that possess large TADs (median size of 840 kb), we show that the statistical helix model, but not globule models, is relevant not only in gene-rich TADs, but also in gene-poor and gene-desert TADs. Interestingly, this statistical helix organization is considerably relaxed in mESC compared to liver cells, indicating that the impact of the constraints responsible for this organization is weaker in pluripotent cells. Finally, depletion of histone H1 in mESC alters local chromatin flexibility but not the statistical helix organization. In Drosophila, which possesses TADs of smaller sizes (median size of 70 kb), we show that, while chromatin compaction and flexibility are finely tuned according to the epigenetic landscape, chromatin dynamics within TADs is generally compatible with an unconstrained polymer configuration.<br><br>CONCLUSIONS: Models issued from polymer physics can accurately describe the organization principles governing chromatin dynamics in both mouse and Drosophila TADs. However, constraints applied on this dynamics within mammalian TADs have a peculiar impact resulting in a statistical helix organization.},
}
@article {pmid26235224,
year = {2015},
author = {Marks, H and Kerstens, HH and Barakat, TS and Splinter, E and Dirks, RA and van Mierlo, G and Joshi, O and Wang, SY and Babak, T and Albers, CA and Kalkan, T and Smith, A and Jouneau, A and de Laat, W and Gribnau, J and Stunnenberg, HG},
title = {Dynamics of gene silencing during X inactivation using allele-specific RNA-seq.},
journal = {Genome biology},
volume = {16},
number = {},
pages = {149},
doi = {10.1186/s13059-015-0698-x},
pmid = {26235224},
issn = {1474-760X},
support = {G1100526//Medical Research Council/United Kingdom ; MC_PC_12009//Medical Research Council/United Kingdom ; },
mesh = {Alleles ; Animals ; Chromatin/chemistry ; Embryoid Bodies/metabolism ; Embryonic Stem Cells/metabolism ; Female ; *Gene Silencing ; Humans ; Mice ; Neural Stem Cells/metabolism ; Sequence Analysis, RNA ; *X Chromosome Inactivation ; },
abstract = {BACKGROUND: During early embryonic development, one of the two X chromosomes in mammalian female cells is inactivated to compensate for a potential imbalance in transcript levels with male cells, which contain a single X chromosome. Here, we use mouse female embryonic stem cells (ESCs) with non-random X chromosome inactivation (XCI) and polymorphic X chromosomes to study the dynamics of gene silencing over the inactive X chromosome by high-resolution allele-specific RNA-seq.<br><br>RESULTS: Induction of XCI by differentiation of female ESCs shows that genes proximal to the X-inactivation center are silenced earlier than distal genes, while lowly expressed genes show faster XCI dynamics than highly expressed genes. The active X chromosome shows a minor but significant increase in gene activity during differentiation, resulting in complete dosage compensation in differentiated cell types. Genes escaping XCI show little or no silencing during early propagation of XCI. Allele-specific RNA-seq of neural progenitor cells generated from the female ESCs identifies three regions distal to the X-inactivation center that escape XCI. These regions, which stably escape during propagation and maintenance of XCI, coincide with topologically associating domains (TADs) as present in the female ESCs. Also, the previously characterized gene clusters escaping XCI in human fibroblasts correlate with TADs.<br><br>CONCLUSIONS: The gene silencing observed during XCI provides further insight in the establishment of the repressive complex formed by the inactive X chromosome. The association of escape regions with TADs, in mouse and human, suggests that TADs are the primary targets during propagation of XCI over the X chromosome.},
}
@article {pmid26220994,
year = {2015},
author = {Alekseyenko, AA and Walsh, EM and Wang, X and Grayson, AR and Hsi, PT and Kharchenko, PV and Kuroda, MI and French, CA},
title = {The oncogenic BRD4-NUT chromatin regulator drives aberrant transcription within large topological domains.},
journal = {Genes &amp; development},
volume = {29},
number = {14},
pages = {1507-1523},
doi = {10.1101/gad.267583.115},
pmid = {26220994},
issn = {1549-5477},
support = {T32 HL007627/HL/NHLBI NIH HHS/United States ; 2R01CA124633/CA/NCI NIH HHS/United States ; R01 CA124633/CA/NCI NIH HHS/United States ; GM101958/GM/NIGMS NIH HHS/United States ; R01 GM101958/GM/NIGMS NIH HHS/United States ; },
mesh = {Carcinoma, Squamous Cell/*physiopathology ; Cell Line, Tumor ; Enhancer Elements, Genetic ; *Gene Expression Regulation, Neoplastic ; Humans ; Nuclear Proteins/genetics/*metabolism ; Oncogene Proteins/genetics/*metabolism ; Protein Structure, Tertiary ; Transcription Factors/genetics/*metabolism ; },
abstract = {NUT midline carcinoma (NMC), a subtype of squamous cell cancer, is one of the most aggressive human solid malignancies known. NMC is driven by the creation of a translocation oncoprotein, BRD4-NUT, which blocks differentiation and drives growth of NMC cells. BRD4-NUT forms distinctive nuclear foci in patient tumors, which we found correlate with ∼100 unprecedented, hyperacetylated expanses of chromatin that reach up to 2 Mb in size. These &quot;megadomains&quot; appear to be the result of aberrant, feed-forward loops of acetylation and binding of acetylated histones that drive transcription of underlying DNA in NMC patient cells and naïve cells induced to express BRD4-NUT. Megadomain locations are typically cell lineage-specific; however, the cMYC and TP63 regions are targeted in all NMCs tested and play functional roles in tumor growth. Megadomains appear to originate from select pre-existing enhancers that progressively broaden but are ultimately delimited by topologically associating domain (TAD) boundaries. Therefore, our findings establish a basis for understanding the powerful role played by large-scale chromatin organization in normal and aberrant lineage-specific gene transcription.},
}
@article {pmid26198462,
year = {2016},
author = {van Bemmel, JG and Mira-Bontenbal, H and Gribnau, J},
title = {Cis- and trans-regulation in X inactivation.},
journal = {Chromosoma},
volume = {125},
number = {1},
pages = {41-50},
doi = {10.1007/s00412-015-0525-x},
pmid = {26198462},
issn = {1432-0886},
mesh = {Animals ; Cell Differentiation ; Embryonic Stem Cells/*metabolism/physiology ; Female ; Gene Expression Regulation, Developmental ; Gene Silencing ; Genes, X-Linked/genetics ; Humans ; *RNA, Long Noncoding ; *X Chromosome Inactivation ; },
abstract = {Female mammalian cells compensate dosage of X-linked gene expression through the inactivation of one of their two X chromosomes. X chromosome inactivation (XCI) in eutherians is dependent on the non-coding RNA Xist that is up-regulated from the future inactive X chromosome, coating it and recruiting factors involved in silencing and altering its chromatin state. Xist lies within the X-inactivation center (Xic), a region on the X that is required for XCI, and is regulated in cis by elements on the X chromosome and in trans by diffusible factors. In this review, we summarize the latest results in cis- and trans-regulation of the Xic. We discuss how the organization of the Xic in topologically associating domains is important for XCI (cis-regulation) and how proteins in the pluripotent state and upon development or differentiation of embryonic stem cells control proper inactivation of one X chromosome (trans-regulation).},
}
@article {pmid26184319,
year = {2015},
author = {Del Prete, S and Mikulski, P and Schubert, D and Gaudin, V},
title = {One, Two, Three: Polycomb Proteins Hit All Dimensions of Gene Regulation.},
journal = {Genes},
volume = {6},
number = {3},
pages = {520-542},
doi = {10.3390/genes6030520},
pmid = {26184319},
issn = {2073-4425},
abstract = {Polycomb group (PcG) proteins contribute to the formation and maintenance of a specific repressive chromatin state that prevents the expression of genes in a particular space and time. Polycomb repressive complexes (PRCs) consist of several PcG proteins with specific regulatory or catalytic properties. PRCs are recruited to thousands of target genes, and various recruitment factors, including DNA-binding proteins and non-coding RNAs, are involved in the targeting. PcG proteins contribute to a multitude of biological processes by altering chromatin features at different scales. PcG proteins mediate both biochemical modifications of histone tails and biophysical modifications (e.g., chromatin fiber compaction and three-dimensional (3D) chromatin conformation). Here, we review the role of PcG proteins in nuclear architecture, describing their impact on the structure of the chromatin fiber, on chromatin interactions, and on the spatial organization of the genome in nuclei. Although little is known about the role of plant PcG proteins in nuclear organization, much is known in the animal field, and we highlight similarities and differences in the roles of PcG proteins in 3D gene regulation in plants and animals.},
}
@article {pmid26150425,
year = {2015},
author = {Wang, XT and Dong, PF and Zhang, HY and Peng, C},
title = {Structural heterogeneity and functional diversity of topologically associating domains in mammalian genomes.},
journal = {Nucleic acids research},
volume = {43},
number = {15},
pages = {7237-7246},
doi = {10.1093/nar/gkv684},
pmid = {26150425},
issn = {1362-4962},
mesh = {Animals ; Base Sequence ; Cell Line ; Chromatin/*chemistry ; DNA/chemistry ; Epigenesis, Genetic ; *Genome ; Genome, Human ; Humans ; Mice ; Transcription, Genetic ; },
abstract = {Recent chromosome conformation capture (3C) derived techniques have revealed that topologically associating domain (TAD) is a pervasive element in chromatin three-dimensional (3D) organization. However, there is currently no parameter to quantitatively measure the structural characteristics of TADs, thus obscuring our understanding on the structural and functional differences among TADs. Based on our finding that there exist intrinsic chromatin interaction patterns in TADs, we define a theoretical parameter, called aggregation preference (AP), to characterize TAD structures by capturing the interaction aggregation degree. Applying this defined parameter to 11 Hi-C data sets generated by both traditional and in situ Hi-C experimental pipelines, our analyses reveal that heterogeneous structures exist among TADs, and this structural heterogeneity is significantly correlated to DNA sequences, epigenomic signals and gene expressions. Although TADs can be stable in genomic positions across cell lines, structural comparisons show that a considerable number of stable TADs undergo significantly structural rearrangements during cell changes. Moreover, the structural change of TAD is tightly associated with its transcription remodeling. Altogether, the theoretical parameter defined in this work provides a quantitative method to link structural characteristics and biological functions of TADs, and this linkage implies that chromatin interaction pattern has the potential to mark transcription activity in TADs.},
}
@article {pmid26119342,
year = {2015},
author = {Hsieh, TH and Weiner, A and Lajoie, B and Dekker, J and Friedman, N and Rando, OJ},
title = {Mapping Nucleosome Resolution Chromosome Folding in Yeast by Micro-C.},
journal = {Cell},
volume = {162},
number = {1},
pages = {108-119},
doi = {10.1016/j.cell.2015.05.048},
pmid = {26119342},
issn = {1097-4172},
support = {HG003143/HG/NHGRI NIH HHS/United States ; R01 HG003143/HG/NHGRI NIH HHS/United States ; GM079205/GM/NIGMS NIH HHS/United States ; 340712//European Research Council/International ; //Howard Hughes Medical Institute/United States ; R01 GM079205/GM/NIGMS NIH HHS/United States ; },
mesh = {Biochemistry/*methods ; Chromosomes, Fungal/*chemistry ; Nucleosomes/*chemistry ; Saccharomyces cerevisiae/*chemistry/genetics ; },
abstract = {We describe a Hi-C-based method, Micro-C, in which micrococcal nuclease is used instead of restriction enzymes to fragment chromatin, enabling nucleosome resolution chromosome folding maps. Analysis of Micro-C maps for budding yeast reveals abundant self-associating domains similar to those reported in other species, but not previously observed in yeast. These structures, far shorter than topologically associating domains in mammals, typically encompass one to five genes in yeast. Strong boundaries between self-associating domains occur at promoters of highly transcribed genes and regions of rapid histone turnover that are typically bound by the RSC chromatin-remodeling complex. Investigation of chromosome folding in mutants confirms roles for RSC, &quot;gene looping&quot; factor Ssu72, Mediator, H3K56 acetyltransferase Rtt109, and the N-terminal tail of H4 in folding of the yeast genome. This approach provides detailed structural maps of a eukaryotic genome, and our findings provide insights into the machinery underlying chromosome compaction.},
}
@article {pmid26030525,
year = {2015},
author = {Crane, E and Bian, Q and McCord, RP and Lajoie, BR and Wheeler, BS and Ralston, EJ and Uzawa, S and Dekker, J and Meyer, BJ},
title = {Condensin-driven remodelling of X chromosome topology during dosage compensation.},
journal = {Nature},
volume = {523},
number = {7559},
pages = {240-244},
doi = {10.1038/nature14450},
pmid = {26030525},
issn = {1476-4687},
support = {R01 GM030702/GM/NIGMS NIH HHS/United States ; R01 HG003143/HG/NHGRI NIH HHS/United States ; F32 GM100647/GM/NIGMS NIH HHS/United States ; S10RR029668/RR/NCRR NIH HHS/United States ; S10 RR029668/RR/NCRR NIH HHS/United States ; //Howard Hughes Medical Institute/United States ; },
mesh = {Adenosine Triphosphatases/*metabolism ; Animals ; Caenorhabditis elegans/*genetics/*metabolism ; Caenorhabditis elegans Proteins/genetics/*metabolism ; DNA-Binding Proteins/*metabolism ; Dosage Compensation, Genetic/genetics/*physiology ; Female ; Gene Expression Regulation ; In Situ Hybridization, Fluorescence ; Male ; Multiprotein Complexes/*metabolism ; Protein Binding ; Sequence Analysis, RNA ; X Chromosome/genetics/*metabolism ; },
abstract = {The three-dimensional organization of a genome plays a critical role in regulating gene expression, yet little is known about the machinery and mechanisms that determine higher-order chromosome structure. Here we perform genome-wide chromosome conformation capture analysis, fluorescent in situ hybridization (FISH), and RNA-seq to obtain comprehensive three-dimensional (3D) maps of the Caenorhabditis elegans genome and to dissect X chromosome dosage compensation, which balances gene expression between XX hermaphrodites and XO males. The dosage compensation complex (DCC), a condensin complex, binds to both hermaphrodite X chromosomes via sequence-specific recruitment elements on X (rex sites) to reduce chromosome-wide gene expression by half. Most DCC condensin subunits also act in other condensin complexes to control the compaction and resolution of all mitotic and meiotic chromosomes. By comparing chromosome structure in wild-type and DCC-defective embryos, we show that the DCC remodels hermaphrodite X chromosomes into a sex-specific spatial conformation distinct from autosomes. Dosage-compensated X chromosomes consist of self-interacting domains (∼1 Mb) resembling mammalian topologically associating domains (TADs). TADs on X chromosomes have stronger boundaries and more regular spacing than on autosomes. Many TAD boundaries on X chromosomes coincide with the highest-affinity rex sites and become diminished or lost in DCC-defective mutants, thereby converting the topology of X to a conformation resembling autosomes. rex sites engage in DCC-dependent long-range interactions, with the most frequent interactions occurring between rex sites at DCC-dependent TAD boundaries. These results imply that the DCC reshapes the topology of X chromosomes by forming new TAD boundaries and reinforcing weak boundaries through interactions between its highest-affinity binding sites. As this model predicts, deletion of an endogenous rex site at a DCC-dependent TAD boundary using CRISPR/Cas9 greatly diminished the boundary. Thus, the DCC imposes a distinct higher-order structure onto X chromosomes while regulating gene expression chromosome-wide.},
}
@article {pmid26028501,
year = {2015},
author = {Cremer, T and Cremer, M and Hübner, B and Strickfaden, H and Smeets, D and Popken, J and Sterr, M and Markaki, Y and Rippe, K and Cremer, C},
title = {The 4D nucleome: Evidence for a dynamic nuclear landscape based on co-aligned active and inactive nuclear compartments.},
journal = {FEBS letters},
volume = {589},
number = {20 Pt A},
pages = {2931-2943},
doi = {10.1016/j.febslet.2015.05.037},
pmid = {26028501},
issn = {1873-3468},
mesh = {Animals ; Cell Nucleus/physiology/*ultrastructure ; Chromatin/*physiology/ultrastructure ; DNA Repair ; Gene Expression Regulation ; Humans ; Transcription, Genetic ; },
abstract = {Recent methodological advancements in microscopy and DNA sequencing-based methods provide unprecedented new insights into the spatio-temporal relationships between chromatin and nuclear machineries. We discuss a model of the underlying functional nuclear organization derived mostly from electron and super-resolved fluorescence microscopy studies. It is based on two spatially co-aligned, active and inactive nuclear compartments (ANC and INC). The INC comprises the compact, transcriptionally inactive core of chromatin domain clusters (CDCs). The ANC is formed by the transcriptionally active periphery of CDCs, called the perichromatin region (PR), and the interchromatin compartment (IC). The IC is connected to nuclear pores and serves nuclear import and export functions. The ANC is the major site of RNA synthesis. It is highly enriched in epigenetic marks for transcriptionally competent chromatin and RNA Polymerase II. Marks for silent chromatin are enriched in the INC. Multi-scale cross-correlation spectroscopy suggests that nuclear architecture resembles a random obstacle network for diffusing proteins. An increased dwell time of proteins and protein complexes within the ANC may help to limit genome scanning by factors or factor complexes to DNA exposed within the ANC.},
}
@article {pmid26013771,
year = {2015},
author = {Moore, BL and Aitken, S and Semple, CA},
title = {Integrative modeling reveals the principles of multi-scale chromatin boundary formation in human nuclear organization.},
journal = {Genome biology},
volume = {16},
number = {},
pages = {110},
doi = {10.1186/s13059-015-0661-x},
pmid = {26013771},
issn = {1474-760X},
support = {//Medical Research Council/United Kingdom ; },
mesh = {CCCTC-Binding Factor ; Cell Line ; Chromatin/*genetics ; DNA Replication Timing ; DNA-Binding Proteins/genetics ; Databases, Genetic ; Epigenesis, Genetic ; Genetic Loci ; Humans ; K562 Cells ; *Models, Molecular ; Multigene Family ; Repressor Proteins/genetics/metabolism ; },
abstract = {BACKGROUND: Interphase chromosomes adopt a hierarchical structure, and recent data have characterized their chromatin organization at very different scales, from sub-genic regions associated with DNA-binding proteins at the order of tens or hundreds of bases, through larger regions with active or repressed chromatin states, up to multi-megabase-scale domains associated with nuclear positioning, replication timing and other qualities. However, we have lacked detailed, quantitative models to understand the interactions between these different strata.<br><br>RESULTS: Here we collate large collections of matched locus-level chromatin features and Hi-C interaction data, representing higher-order organization, across three human cell types. We use quantitative modeling approaches to assess whether locus-level features are sufficient to explain higher-order structure, and identify the most influential underlying features. We identify structurally variable domains between cell types and examine the underlying features to discover a general association with cell-type-specific enhancer activity. We also identify the most prominent features marking the boundaries of two types of higher-order domains at different scales: topologically associating domains and nuclear compartments. We find parallel enrichments of particular chromatin features for both types, including features associated with active promoters and the architectural proteins CTCF and YY1.<br><br>CONCLUSIONS: We show that integrative modeling of large chromatin dataset collections using random forests can generate useful insights into chromosome structure. The models produced recapitulate known biological features of the cell types involved, allow exploration of the antecedents of higher-order structures and generate testable hypotheses for further experimental studies.},
}
@article {pmid26013116,
year = {2015},
author = {Shen, W and Wang, D and Ye, B and Shi, M and Zhang, Y and Zhao, Z},
title = {A possible role of Drosophila CTCF in mitotic bookmarking and maintaining chromatin domains during the cell cycle.},
journal = {Biological research},
volume = {48},
number = {},
pages = {27},
doi = {10.1186/s40659-015-0019-6},
pmid = {26013116},
issn = {0717-6287},
mesh = {Animals ; Base Sequence ; Binding Sites ; CCCTC-Binding Factor ; Cell Cycle/physiology ; Chromatin/*physiology ; Chromatin Assembly and Disassembly/physiology ; Computational Biology ; Conserved Sequence ; Datasets as Topic ; Drosophila Proteins/*physiology ; Drosophila melanogaster/*chemistry ; Genome, Insect/*genetics ; Interphase/physiology ; Mitosis/*physiology ; Molecular Sequence Annotation ; Repressor Proteins/*physiology ; Synteny ; },
abstract = {BACKGROUND: The CCCTC-binding factor (CTCF) is a highly conserved insulator protein that plays various roles in many cellular processes. CTCF is one of the main architecture proteins in higher eukaryotes, and in combination with other architecture proteins and regulators, also shapes the three-dimensional organization of a genome. Experiments show CTCF partially remains associated with chromatin during mitosis. However, the role of CTCF in the maintenance and propagation of genome architectures throughout the cell cycle remains elusive.<br><br>RESULTS: We performed a comprehensive bioinformatics analysis on public datasets of Drosophila CTCF (dCTCF). We characterized dCTCF-binding sites according to their occupancy status during the cell cycle, and identified three classes: interphase-mitosis-common (IM), interphase-only (IO) and mitosis-only (MO) sites. Integrated function analysis showed dCTCF-binding sites of different classes might be involved in different biological processes, and IM sites were more conserved and more intensely bound. dCTCF-binding sites of the same class preferentially localized closer to each other, and were highly enriched at chromatin syntenic and topologically associating domains boundaries.<br><br>CONCLUSIONS: Our results revealed different functions of dCTCF during the cell cycle and suggested that dCTCF might contribute to the establishment of the three-dimensional architecture of the Drosophila genome by maintaining local chromatin compartments throughout the whole cell cycle.},
}
@article {pmid26012375,
year = {2015},
author = {Le Dily, F and Beato, M},
title = {TADs as modular and dynamic units for gene regulation by hormones.},
journal = {FEBS letters},
volume = {589},
number = {20 Pt A},
pages = {2885-2892},
doi = {10.1016/j.febslet.2015.05.026},
pmid = {26012375},
issn = {1873-3468},
mesh = {Animals ; Chromatin/genetics ; *Gene Expression Regulation ; Hormones/*physiology ; Humans ; Nucleic Acid Conformation ; *Regulatory Sequences, Nucleic Acid ; },
abstract = {During cell differentiation epigenetic processes permit the establishment of a cell type specific transcriptome by limiting the fraction of the genome that will be expressed. Based upon steady-state requirements and transcription factor expression, differentiated cells respond transiently to external cues by modulating the expression levels of subsets of genes. Increasing evidence demonstrates that the genome is organized non-randomly in a hierarchy of structures within the nuclear space, where chromosome territories are segmented into Topologically Associating Domains (TADs) and sub-domains. It remains poorly understood how this three-dimensional organization of the genome participates in the acquisition of a cell-specific program of gene expression. Furthermore, it is unknown whether this spatial framework influences the dynamic changes of gene expression that accompany alterations in the cell environment. In this review, we will discuss the impact of genome topology on the response of breast cancer cells to steroid hormones. We will cover steroid nuclear receptor mechanisms of action and discuss how topological organization of the genome, including segmentation into TADs, acts as a combinatorial platform to integrate signals whilst ultimately ensuring coordinate regulation of gene expression.},
}
@article {pmid26008126,
year = {2015},
author = {Cubeñas-Potts, C and Corces, VG},
title = {Architectural proteins, transcription, and the three-dimensional organization of the genome.},
journal = {FEBS letters},
volume = {589},
number = {20 Pt A},
pages = {2923-2930},
doi = {10.1016/j.febslet.2015.05.025},
pmid = {26008126},
issn = {1873-3468},
support = {R01 GM035463/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Binding Sites ; Chromatin/physiology/ultrastructure ; DNA-Binding Proteins/physiology ; *Epigenesis, Genetic ; Genome, Human ; Humans ; Nucleic Acid Conformation ; Protein Binding ; Regulatory Sequences, Nucleic Acid ; *Transcription, Genetic ; },
abstract = {Architectural proteins mediate interactions between distant sequences in the genome. Two well-characterized functions of architectural protein interactions include the tethering of enhancers to promoters and bringing together Polycomb-containing sites to facilitate silencing. The nature of which sequences interact genome-wide appears to be determined by the orientation of the architectural protein binding sites as well as the number and identity of architectural proteins present. Ultimately, long range chromatin interactions result in the formation of loops within the chromatin fiber. In this review, we discuss data suggesting that architectural proteins mediate long range chromatin interactions that both facilitate and hinder neighboring interactions, compartmentalizing the genome into regions of highly interacting chromatin domains.},
}
@article {pmid25995270,
year = {2015},
author = {Dileep, V and Ay, F and Sima, J and Vera, DL and Noble, WS and Gilbert, DM},
title = {Topologically associating domains and their long-range contacts are established during early G1 coincident with the establishment of the replication-timing program.},
journal = {Genome research},
volume = {25},
number = {8},
pages = {1104-1113},
doi = {10.1101/gr.183699.114},
pmid = {25995270},
issn = {1549-5469},
support = {AI106775/AI/NIAID NIH HHS/United States ; R01 AI106775/AI/NIAID NIH HHS/United States ; HG00700/HG/NHGRI NIH HHS/United States ; P01 GM085354/GM/NIGMS NIH HHS/United States ; GM085354/GM/NIGMS NIH HHS/United States ; R01 GM083337/GM/NIGMS NIH HHS/United States ; GM083337/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Cell Line ; Chromatin/*chemistry/*genetics ; Chromatin Assembly and Disassembly ; *DNA Replication Timing ; Epithelial Cells/cytology ; *G1 Phase ; Gene Expression Regulation, Developmental ; Genome ; Mice ; Sequence Analysis, DNA/methods ; },
abstract = {Mammalian genomes are partitioned into domains that replicate in a defined temporal order. These domains can replicate at similar times in all cell types (constitutive) or at cell type-specific times (developmental). Genome-wide chromatin conformation capture (Hi-C) has revealed sub-megabase topologically associating domains (TADs), which are the structural counterparts of replication domains. Hi-C also segregates inter-TAD contacts into defined 3D spatial compartments that align precisely to genome-wide replication timing profiles. Determinants of the replication-timing program are re-established during early G1 phase of each cell cycle and lost in G2 phase, but it is not known when TAD structure and inter-TAD contacts are re-established after their elimination during mitosis. Here, we use multiplexed 4C-seq to study dynamic changes in chromatin organization during early G1. We find that both establishment of TADs and their compartmentalization occur during early G1, within the same time frame as establishment of the replication-timing program. Once established, this 3D organization is preserved either after withdrawal into quiescence or for the remainder of interphase including G2 phase, implying 3D structure is not sufficient to maintain replication timing. Finally, we find that developmental domains are less well compartmentalized than constitutive domains and display chromatin properties that distinguish them from early and late constitutive domains. Overall, this study uncovers a strong connection between chromatin re-organization during G1, establishment of replication timing, and its developmental control.},
}
@article {pmid25918364,
year = {2015},
author = {Zhang, B and Wolynes, PG},
title = {Topology, structures, and energy landscapes of human chromosomes.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {112},
number = {19},
pages = {6062-6067},
doi = {10.1073/pnas.1506257112},
pmid = {25918364},
issn = {1091-6490},
mesh = {Cell Differentiation ; Chromatin/chemistry ; Chromosomes/chemistry ; Chromosomes, Human/*chemistry ; DNA/chemistry ; Gene Expression Regulation ; Genome, Human ; Humans ; Interphase/genetics ; Models, Molecular ; Molecular Conformation ; Probability ; Thermodynamics ; },
abstract = {Chromosome conformation capture experiments provide a rich set of data concerning the spatial organization of the genome. We use these data along with a maximum entropy approach to derive a least-biased effective energy landscape for the chromosome. Simulations of the ensemble of chromosome conformations based on the resulting information theoretic landscape not only accurately reproduce experimental contact probabilities, but also provide a picture of chromosome dynamics and topology. The topology of the simulated chromosomes is probed by computing the distribution of their knot invariants. The simulated chromosome structures are largely free of knots. Topologically associating domains are shown to be crucial for establishing these knotless structures. The simulated chromosome conformations exhibit a tendency to form fibril-like structures like those observed via light microscopy. The topologically associating domains of the interphase chromosome exhibit multistability with varying liquid crystalline ordering that may allow discrete unfolding events and the landscape is locally funneled toward &quot;ideal&quot; chromosome structures that represent hierarchical fibrils of fibrils.},
}
@article {pmid25913784,
year = {2015},
author = {Lonfat, N and Duboule, D},
title = {Structure, function and evolution of topologically associating domains (TADs) at HOX loci.},
journal = {FEBS letters},
volume = {589},
number = {20 Pt A},
pages = {2869-2876},
doi = {10.1016/j.febslet.2015.04.024},
pmid = {25913784},
issn = {1873-3468},
mesh = {Animals ; Embryonic Development ; Evolution, Molecular ; Gene Expression Regulation, Developmental ; Genetic Loci ; Genetic Pleiotropy ; Homeodomain Proteins/*genetics ; Humans ; Multigene Family ; Organ Specificity ; },
abstract = {Hox genes encode transcription factors necessary for patterning the major developing anterior to posterior embryonic axis. In addition, during vertebrate evolution, various subsets of this gene family were co-opted along with the emergence of novel body structures, such as the limbs or the external genitalia. The morphogenesis of these axial structures thus relies in part upon the precisely controlled transcription of specific Hox genes, a mechanism involving multiple long-range enhancers. Recently, it was reported that such regulatory mechanisms were largely shared between different developing tissues, though with some specificities, suggesting the recruitment of ancestral regulatory modalities from one tissue to another. The analysis of chromatin architectures at HoxD and HoxA loci revealed the existence of two flanking topologically associating domains (TADs), precisely encompassing the adjacent regulatory landscapes. Here, we discuss the function of these TADs in the control of Hox gene regulation and we speculate about their capacity to serve as structural frameworks for the emergence of novel enhancers. In this view, TADs may have been used as genomic niches to evolve pleiotropic regulations found at many developmental loci.},
}
@article {pmid25855284,
year = {2015},
author = {Umlauf, D},
title = {[The intimate genome… in three dimensions].},
journal = {Medecine sciences : M/S},
volume = {31},
number = {3},
pages = {304-311},
doi = {10.1051/medsci/20153103016},
pmid = {25855284},
issn = {0767-0974},
mesh = {Animals ; Chromosomes/*chemistry ; *Genome ; Humans ; *Imaging, Three-Dimensional ; *Molecular Conformation ; Oligonucleotide Array Sequence Analysis/methods ; },
abstract = {Over the past decade, techniques based on chromosome conformation capture (3C) have accelerated our understanding of eukaryote's nuclear architecture. Coupled to high throughput sequencing and bioinformatics they have unveiled different organizational levels of the genome at an unprecedented scale. Initially performed using large populations of cells, a new variant of these techniques can be applied to single cell. Although it can be shown that chromosome folding varies from one cell to the other, their overall organization into topologically associating domains is conserved between cells of the same population. Interestingly, the predicted chromosome structures reveal that regions engaged in trans-chromosomal interactions are preferentially localized at the surface of the chromosome territory. These results confirm and extend previous observations on individual loci therefore highlighting the power of 3C based techniques.},
}
@article {pmid25818644,
year = {2015},
author = {Li, L and Lyu, X and Hou, C and Takenaka, N and Nguyen, HQ and Ong, CT and Cubeñas-Potts, C and Hu, M and Lei, EP and Bosco, G and Qin, ZS and Corces, VG},
title = {Widespread rearrangement of 3D chromatin organization underlies polycomb-mediated stress-induced silencing.},
journal = {Molecular cell},
volume = {58},
number = {2},
pages = {216-231},
doi = {10.1016/j.molcel.2015.02.023},
pmid = {25818644},
issn = {1097-4164},
support = {R01 GM035463/GM/NIGMS NIH HHS/United States ; R01 HG005119/HG/NHGRI NIH HHS/United States ; P30 CA023108/CA/NCI NIH HHS/United States ; //Intramural NIH HHS/United States ; DK015602/DK/NIDDK NIH HHS/United States ; R01 GM069462/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Cell Line ; Chromatin/*genetics ; Chromosomes/*genetics ; Drosophila Proteins/chemistry/*genetics/metabolism ; Drosophila melanogaster/*genetics/metabolism ; Enhancer Elements, Genetic ; Molecular Sequence Data ; Polycomb-Group Proteins/chemistry/genetics/*metabolism ; Promoter Regions, Genetic ; Regulatory Sequences, Nucleic Acid ; Stress, Physiological ; Temperature ; },
abstract = {Chromosomes of metazoan organisms are partitioned in the interphase nucleus into discrete topologically associating domains (TADs). Borders between TADs are formed in regions containing active genes and clusters of architectural protein binding sites. The transcription of most genes is repressed after temperature stress in Drosophila. Here we show that temperature stress induces relocalization of architectural proteins from TAD borders to inside TADs, and this is accompanied by a dramatic rearrangement in the 3D organization of the nucleus. TAD border strength declines, allowing for an increase in long-distance inter-TAD interactions. Similar but quantitatively weaker effects are observed upon inhibition of transcription or depletion of individual architectural proteins. Heat shock-induced inter-TAD interactions result in increased contacts among enhancers and promoters of silenced genes, which recruit Pc and form Pc bodies in the nucleolus. These results suggest that the TAD organization of metazoan genomes is plastic and can be reconfigured quickly.},
}
@article {pmid25800747,
year = {2015},
author = {Trussart, M and Serra, F and Baù, D and Junier, I and Serrano, L and Marti-Renom, MA},
title = {Assessing the limits of restraint-based 3D modeling of genomes and genomic domains.},
journal = {Nucleic acids research},
volume = {43},
number = {7},
pages = {3465-3477},
doi = {10.1093/nar/gkv221},
pmid = {25800747},
issn = {1362-4962},
support = {232913//European Research Council/International ; 609989//European Research Council/International ; },
mesh = {*Genome ; *Models, Genetic ; },
abstract = {Restraint-based modeling of genomes has been recently explored with the advent of Chromosome Conformation Capture (3C-based) experiments. We previously developed a reconstruction method to resolve the 3D architecture of both prokaryotic and eukaryotic genomes using 3C-based data. These models were congruent with fluorescent imaging validation. However, the limits of such methods have not systematically been assessed. Here we propose the first evaluation of a mean-field restraint-based reconstruction of genomes by considering diverse chromosome architectures and different levels of data noise and structural variability. The results show that: first, current scoring functions for 3D reconstruction correlate with the accuracy of the models; second, reconstructed models are robust to noise but sensitive to structural variability; third, the local structure organization of genomes, such as Topologically Associating Domains, results in more accurate models; fourth, to a certain extent, the models capture the intrinsic structural variability in the input matrices and fifth, the accuracy of the models can be a priori predicted by analyzing the properties of the interaction matrices. In summary, our work provides a systematic analysis of the limitations of a mean-field restrain-based method, which could be taken into consideration in further development of methods as well as their applications.},
}
@article {pmid25764331,
year = {2014},
author = {Shibayama, Y and Fanucchi, S and Magagula, L and Mhlanga, MM},
title = {lncRNA and gene looping: what's the connection?.},
journal = {Transcription},
volume = {5},
number = {3},
pages = {e28658},
doi = {10.4161/trns.28658},
pmid = {25764331},
issn = {2154-1272},
mesh = {CCCTC-Binding Factor ; Cell Cycle Proteins/metabolism ; Chromatin/*metabolism ; Chromosomal Proteins, Non-Histone/metabolism ; Enhancer Elements, Genetic ; *Gene Expression Regulation ; Humans ; RNA, Long Noncoding/*metabolism ; Repressor Proteins/metabolism ; Transcription Initiation, Genetic ; },
abstract = {Recent functional studies have unveiled the significant role chromatin topology plays in gene regulation. Several lines of evidence suggest genes access necessary factors for transcription by forming chromatin loops. A clearer picture of the players involved in chromatin organization, including lncRNA, is emerging.},
}
@article {pmid25563431,
year = {2015},
author = {Maeshima, K and Kaizu, K and Tamura, S and Nozaki, T and Kokubo, T and Takahashi, K},
title = {The physical size of transcription factors is key to transcriptional regulation in chromatin domains.},
journal = {Journal of physics. Condensed matter : an Institute of Physics journal},
volume = {27},
number = {6},
pages = {064116},
doi = {10.1088/0953-8984/27/6/064116},
pmid = {25563431},
issn = {1361-648X},
mesh = {Chromatin/*chemistry/genetics/*metabolism ; *Gene Expression Regulation ; Models, Molecular ; Molecular Weight ; *Monte Carlo Method ; Protein Structure, Tertiary ; Transcription Factors/*chemistry/*metabolism ; *Transcription, Genetic ; Transcriptional Activation ; },
abstract = {Genetic information, which is stored in the long strand of genomic DNA as chromatin, must be scanned and read out by various transcription factors. First, gene-specific transcription factors, which are relatively small (∼50 kDa), scan the genome and bind regulatory elements. Such factors then recruit general transcription factors, Mediators, RNA polymerases, nucleosome remodellers, and histone modifiers, most of which are large protein complexes of 1-3 MDa in size. Here, we propose a new model for the functional significance of the size of transcription factors (or complexes) for gene regulation of chromatin domains. Recent findings suggest that chromatin consists of irregularly folded nucleosome fibres (10 nm fibres) and forms numerous condensed domains (e.g., topologically associating domains). Although the flexibility and dynamics of chromatin allow repositioning of genes within the condensed domains, the size exclusion effect of the domain may limit accessibility of DNA sequences by transcription factors. We used Monte Carlo computer simulations to determine the physical size limit of transcription factors that can enter condensed chromatin domains. Small gene-specific transcription factors can penetrate into the chromatin domains and search their target sequences, whereas large transcription complexes cannot enter the domain. Due to this property, once a large complex binds its target site via gene-specific factors it can act as a 'buoy' to keep the target region on the surface of the condensed domain and maintain transcriptional competency. This size-dependent specialization of target-scanning and surface-tethering functions could provide novel insight into the mechanisms of various DNA transactions, such as DNA replication and repair/recombination.},
}
@article {pmid25555574,
year = {2015},
author = {Giorgetti, L and Piolot, T and Heard, E},
title = {High-resolution 3D DNA FISH using plasmid probes and computational correction of optical aberrations to study chromatin structure at the sub-megabase scale.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {1262},
number = {},
pages = {37-53},
doi = {10.1007/978-1-4939-2253-6_3},
pmid = {25555574},
issn = {1940-6029},
mesh = {Cells, Cultured ; Chromatin/*genetics ; DNA Probes ; Embryonic Stem Cells ; Humans ; Image Interpretation, Computer-Assisted/*methods ; Imaging, Three-Dimensional ; In Situ Hybridization, Fluorescence/*methods ; Plasmids/*genetics ; },
abstract = {Characterizing the three-dimensional organization of chromosomes is a fundamental goal in molecular biology and will be critical to understand how gene expression is regulated by distal regulatory sequences such as enhancers. Chromosome conformation capture (3C) techniques have recently revealed that the interactions between regulatory elements appear to occur in the context of topologically associating domains (TADs), each spanning few hundreds kilobases, within which the chromatin fiber preferentially interacts. However, 3C-based data represent average interaction probabilities of the chromatin fiber over millions of cells. To understand how variable chromatin conformation is within each TAD, one needs to employ single-cell techniques such as 3D DNA FISH. Given the small size of TADs however (typically <1 Mb), classical DNA FISH design needs to be adapted to achieve high genomic and spatial resolution. Here, we describe a high-resolution 3D DNA FISH approach we recently developed, based on a combination of short plasmid probes and computational correction of optical aberrations. We describe probe design and generation and the 3D DNA FISH procedure. We further discuss how to optimize microscope settings and to implement calibration-bead-assisted computational corrections in order to achieve 50 nm resolution in two-color distance measurements between probes that can be as close as 50 kb along the genome.},
}
@article {pmid25437046,
year = {2014},
author = {Duttke, SH},
title = {Meeting report: 11th EMBL conference on transcription and chromatin - August 23-26, 2014 - Heidelberg, Germany.},
journal = {Epigenetics},
volume = {9},
number = {10},
pages = {1317-1321},
doi = {10.4161/15592294.2014.967590},
pmid = {25437046},
issn = {1559-2308},
support = {R01GM041249/GM/NIGMS NIH HHS/United States ; },
mesh = {Animals ; Chromatin/*genetics ; Circadian Rhythm ; Congresses as Topic ; DNA Methylation ; Enhancer Elements, Genetic ; Germany ; Heterochromatin/genetics ; Histones/metabolism ; Humans ; Nucleosomes/metabolism ; Promoter Regions, Genetic ; *Transcription, Genetic ; },
}
@article {pmid25409831,
year = {2014},
author = {Pope, BD and Ryba, T and Dileep, V and Yue, F and Wu, W and Denas, O and Vera, DL and Wang, Y and Hansen, RS and Canfield, TK and Thurman, RE and Cheng, Y and Gülsoy, G and Dennis, JH and Snyder, MP and Stamatoyannopoulos, JA and Taylor, J and Hardison, RC and Kahveci, T and Ren, B and Gilbert, DM},
title = {Topologically associating domains are stable units of replication-timing regulation.},
journal = {Nature},
volume = {515},
number = {7527},
pages = {402-405},
doi = {10.1038/nature13986},
pmid = {25409831},
issn = {1476-4687},
support = {HG003991/HG/NHGRI NIH HHS/United States ; F31 CA165863/CA/NCI NIH HHS/United States ; DK065806/DK/NIDDK NIH HHS/United States ; RC2 HG005573/HG/NHGRI NIH HHS/United States ; R56 DK065806/DK/NIDDK NIH HHS/United States ; HG005573/HG/NHGRI NIH HHS/United States ; F31CA165863/CA/NCI NIH HHS/United States ; P01 GM085354/GM/NIGMS NIH HHS/United States ; R01 DA033775/DA/NIDA NIH HHS/United States ; GM085354/GM/NIGMS NIH HHS/United States ; HG005602/HG/NHGRI NIH HHS/United States ; R01 DK065806/DK/NIDDK NIH HHS/United States ; U54 HG006997/HG/NHGRI NIH HHS/United States ; R01 GM083337/GM/NIGMS NIH HHS/United States ; R01 HG003991/HG/NHGRI NIH HHS/United States ; GM083337/GM/NIGMS NIH HHS/United States ; RC2 HG005602/HG/NHGRI NIH HHS/United States ; },
mesh = {Animals ; Cell Compartmentation ; Chromatin/*chemistry/*genetics/metabolism ; Chromatin Assembly and Disassembly ; DNA/*biosynthesis/genetics ; *DNA Replication Timing ; Genome/genetics ; Heterochromatin/chemistry/genetics/metabolism ; Humans ; Mice ; Organ Specificity ; Time Factors ; },
abstract = {Eukaryotic chromosomes replicate in a temporal order known as the replication-timing program. In mammals, replication timing is cell-type-specific with at least half the genome switching replication timing during development, primarily in units of 400-800 kilobases ('replication domains'), whose positions are preserved in different cell types, conserved between species, and appear to confine long-range effects of chromosome rearrangements. Early and late replication correlate, respectively, with open and closed three-dimensional chromatin compartments identified by high-resolution chromosome conformation capture (Hi-C), and, to a lesser extent, late replication correlates with lamina-associated domains (LADs). Recent Hi-C mapping has unveiled substructure within chromatin compartments called topologically associating domains (TADs) that are largely conserved in their positions between cell types and are similar in size to replication domains. However, TADs can be further sub-stratified into smaller domains, challenging the significance of structures at any particular scale. Moreover, attempts to reconcile TADs and LADs to replication-timing data have not revealed a common, underlying domain structure. Here we localize boundaries of replication domains to the early-replicating border of replication-timing transitions and map their positions in 18 human and 13 mouse cell types. We demonstrate that, collectively, replication domain boundaries share a near one-to-one correlation with TAD boundaries, whereas within a cell type, adjacent TADs that replicate at similar times obscure replication domain boundaries, largely accounting for the previously reported lack of alignment. Moreover, cell-type-specific replication timing of TADs partitions the genome into two large-scale sub-nuclear compartments revealing that replication-timing transitions are indistinguishable from late-replicating regions in chromatin composition and lamina association and accounting for the reduced correlation of replication timing to LADs and heterochromatin. Our results reconcile cell-type-specific sub-nuclear compartmentalization and replication timing with developmentally stable structural domains and offer a unified model for large-scale chromosome structure and function.},
}
@article {pmid25367294,
year = {2015},
author = {Wang, C and Liu, C and Roqueiro, D and Grimm, D and Schwab, R and Becker, C and Lanz, C and Weigel, D},
title = {Genome-wide analysis of local chromatin packing in Arabidopsis thaliana.},
journal = {Genome research},
volume = {25},
number = {2},
pages = {246-256},
doi = {10.1101/gr.170332.113},
pmid = {25367294},
issn = {1549-5469},
mesh = {Arabidopsis/*genetics/*metabolism ; Chromatin/*metabolism ; *Chromatin Assembly and Disassembly ; Cluster Analysis ; Computational Biology/methods ; Epigenesis, Genetic ; Genome, Plant ; *Genomics/methods ; Histones/metabolism ; Insulator Elements ; },
abstract = {The spatial arrangement of interphase chromosomes in the nucleus is important for gene expression and genome function in animals and in plants. The recently developed Hi-C technology is an efficacious method to investigate genome packing. Here we present a detailed Hi-C map of the three-dimensional genome organization of the plant Arabidopsis thaliana. We find that local chromatin packing differs from the patterns seen in animals, with kilobasepair-sized segments that have much higher intrachromosome interaction rates than neighboring regions, representing a dominant local structural feature of genome conformation in A. thaliana. These regions, which appear as positive strips on two-dimensional representations of chromatin interaction, are enriched in epigenetic marks H3K27me3, H3.1, and H3.3. We also identify more than 400 insulator-like regions. Furthermore, although topologically associating domains (TADs), which are prominent in animals, are not an obvious feature of A. thaliana genome packing, we found more than 1000 regions that have properties of TAD boundaries, and a similar number of regions analogous to the interior of TADs. The insulator-like, TAD-boundary-like, and TAD-interior-like regions are each enriched for distinct epigenetic marks and are each correlated with different gene expression levels. We conclude that epigenetic modifications, gene density, and transcriptional activity combine to shape the local packing of the A. thaliana nuclear genome.},
}
@article {pmid25280896,
year = {2015},
author = {Ciabrelli, F and Cavalli, G},
title = {Chromatin-driven behavior of topologically associating domains.},
journal = {Journal of molecular biology},
volume = {427},
number = {3},
pages = {608-625},
doi = {10.1016/j.jmb.2014.09.013},
pmid = {25280896},
issn = {1089-8638},
mesh = {Animals ; Cell Nucleus/*genetics ; Chromatin/*genetics ; *Epigenomics ; *Genome ; Humans ; },
abstract = {Metazoan genomes are highly organized inside the cell nucleus. Topologically associating domains (TADs) represent the building blocks of genome organization, but their linear modularity does not explain alone their spatial organization. Indeed, the chromatin type adorning a TAD can shape its structure and drives its nuclear positioning and its function. Genome-wide association studies revealed mainly four chromatin types: active chromatin, Polycomb-repressed chromatin, null chromatin and constitutive heterochromatin. In this review, we will describe the main three-dimensional features of each chromatin type and finally their relationships with TAD organization and epigenetic memory.},
}
@article {pmid25274727,
year = {2014},
author = {Le Dily, F and Baù, D and Pohl, A and Vicent, GP and Serra, F and Soronellas, D and Castellano, G and Wright, RH and Ballare, C and Filion, G and Marti-Renom, MA and Beato, M},
title = {Distinct structural transitions of chromatin topological domains correlate with coordinated hormone-induced gene regulation.},
journal = {Genes &amp; development},
volume = {28},
number = {19},
pages = {2151-2162},
doi = {10.1101/gad.241422.114},
pmid = {25274727},
issn = {1549-5477},
mesh = {Cell Line, Tumor ; Chromatin/chemistry/*drug effects ; Chromatin Assembly and Disassembly/drug effects ; Gene Expression Regulation/*drug effects ; Hormones/pharmacology ; Humans ; Progestins/*pharmacology ; },
abstract = {The human genome is segmented into topologically associating domains (TADs), but the role of this conserved organization during transient changes in gene expression is not known. Here we describe the distribution of progestin-induced chromatin modifications and changes in transcriptional activity over TADs in T47D breast cancer cells. Using ChIP-seq (chromatin immunoprecipitation combined with high-throughput sequencing), Hi-C (chromosome capture followed by high-throughput sequencing), and three-dimensional (3D) modeling techniques, we found that the borders of the ∼ 2000 TADs in these cells are largely maintained after hormone treatment and that up to 20% of the TADs could be considered as discrete regulatory units where the majority of the genes are either transcriptionally activated or repressed in a coordinated fashion. The epigenetic signatures of the TADs are homogeneously modified by hormones in correlation with the transcriptional changes. Hormone-induced changes in gene activity and chromatin remodeling are accompanied by differential structural changes for activated and repressed TADs, as reflected by specific and opposite changes in the strength of intra-TAD interactions within responsive TADs. Indeed, 3D modeling of the Hi-C data suggested that the structure of TADs was modified upon treatment. The differential responses of TADs to progestins and estrogens suggest that TADs could function as &quot;regulons&quot; to enable spatially proximal genes to be coordinately transcribed in response to hormones.},
}
@article {pmid24981874,
year = {2014},
author = {Van Bortle, K and Nichols, MH and Li, L and Ong, CT and Takenaka, N and Qin, ZS and Corces, VG},
title = {Insulator function and topological domain border strength scale with architectural protein occupancy.},
journal = {Genome biology},
volume = {15},
number = {6},
pages = {R82},
doi = {10.1186/gb-2014-15-5-r82},
pmid = {24981874},
issn = {1474-760X},
support = {R01 GM035463/GM/NIGMS NIH HHS/United States ; T32 GM008367/GM/NIGMS NIH HHS/United States ; OD010949-10/OD/NIH HHS/United States ; R01GM035463/GM/NIGMS NIH HHS/United States ; T32 GM008490/GM/NIGMS NIH HHS/United States ; },
mesh = {Adenosine Triphosphatases/metabolism ; Animals ; Base Sequence ; Binding Sites ; CCCTC-Binding Factor ; Cell Cycle Proteins/metabolism ; Chromatin/genetics ; Chromatin Immunoprecipitation ; Chromosomal Proteins, Non-Histone/metabolism ; Chromosome Mapping ; Consensus Sequence ; DNA-Binding Proteins/metabolism ; Drosophila Proteins/physiology ; Drosophila melanogaster/*genetics ; *Genes, Insect ; Humans ; K562 Cells ; Mice ; Multigene Family ; Multiprotein Complexes/metabolism ; Protein Binding ; Repressor Proteins/genetics ; Transcription Factors, TFIII/physiology ; },
abstract = {BACKGROUND: Chromosome conformation capture studies suggest that eukaryotic genomes are organized into structures called topologically associating domains. The borders of these domains are highly enriched for architectural proteins with characterized roles in insulator function. However, a majority of architectural protein binding sites localize within topological domains, suggesting sites associated with domain borders represent a functionally different subclass of these regulatory elements. How topologically associating domains are established and what differentiates border-associated from non-border architectural protein binding sites remain unanswered questions.<br><br>RESULTS: By mapping the genome-wide target sites for several Drosophila architectural proteins, including previously uncharacterized profiles for TFIIIC and SMC-containing condensin complexes, we uncover an extensive pattern of colocalization in which architectural proteins establish dense clusters at the borders of topological domains. Reporter-based enhancer-blocking insulator activity as well as endogenous domain border strength scale with the occupancy level of architectural protein binding sites, suggesting co-binding by architectural proteins underlies the functional potential of these loci. Analyses in mouse and human stem cells suggest that clustering of architectural proteins is a general feature of genome organization, and conserved architectural protein binding sites may underlie the tissue-invariant nature of topologically associating domains observed in mammals.<br><br>CONCLUSIONS: We identify a spectrum of architectural protein occupancy that scales with the topological structure of chromosomes and the regulatory potential of these elements. Whereas high occupancy architectural protein binding sites associate with robust partitioning of topologically associating domains and robust insulator function, low occupancy sites appear reserved for gene-specific regulation within topological domains.},
}
@article {pmid24813616,
year = {2014},
author = {Giorgetti, L and Galupa, R and Nora, EP and Piolot, T and Lam, F and Dekker, J and Tiana, G and Heard, E},
title = {Predictive polymer modeling reveals coupled fluctuations in chromosome conformation and transcription.},
journal = {Cell},
volume = {157},
number = {4},
pages = {950-963},
doi = {10.1016/j.cell.2014.03.025},
pmid = {24813616},
issn = {1097-4172},
support = {R01 HG003143/HG/NHGRI NIH HHS/United States ; R01HG003143/HG/NHGRI NIH HHS/United States ; },
mesh = {Animals ; Chromatin/chemistry ; Chromosomes/*chemistry ; Female ; In Situ Hybridization, Fluorescence ; Male ; Mice ; Models, Biological ; Models, Molecular ; RNA, Long Noncoding/metabolism ; *Transcription, Genetic ; *X Chromosome Inactivation ; },
abstract = {A new level of chromosome organization, topologically associating domains (TADs), was recently uncovered by chromosome conformation capture (3C) techniques. To explore TAD structure and function, we developed a polymer model that can extract the full repertoire of chromatin conformations within TADs from population-based 3C data. This model predicts actual physical distances and to what extent chromosomal contacts vary between cells. It also identifies interactions within single TADs that stabilize boundaries between TADs and allows us to identify and genetically validate key structural elements within TADs. Combining the model's predictions with high-resolution DNA FISH and quantitative RNA FISH for TADs within the X-inactivation center (Xic), we dissect the relationship between transcription and spatial proximity to cis-regulatory elements. We demonstrate that contacts between potential regulatory elements occur in the context of fluctuating structures rather than stable loops and propose that such fluctuations may contribute to asymmetric expression in the Xic during X inactivation.},
}
@article {pmid24614316,
year = {2014},
author = {Ong, CT and Corces, VG},
title = {CTCF: an architectural protein bridging genome topology and function.},
journal = {Nature reviews. Genetics},
volume = {15},
number = {4},
pages = {234-246},
doi = {10.1038/nrg3663},
pmid = {24614316},
issn = {1471-0064},
support = {R01 GM035463/GM/NIGMS NIH HHS/United States ; },
mesh = {Alternative Splicing ; Animals ; Base Sequence ; CCCTC-Binding Factor ; Chromatin/metabolism ; Consensus Sequence ; Epigenesis, Genetic ; *Genome ; Humans ; Models, Molecular ; Multigene Family ; Nucleic Acid Conformation ; Promoter Regions, Genetic ; Protein Binding ; Recombination, Genetic ; Repressor Proteins/*physiology ; Transcription, Genetic ; },
abstract = {The eukaryotic genome is organized in the three-dimensional nuclear space in a specific manner that is both a cause and a consequence of its function. This organization is partly established by a special class of architectural proteins, of which CCCTC-binding factor (CTCF) is the best characterized. Although CTCF has been assigned various roles that are often contradictory, new results now help to draw a unifying model to explain the many functions of this protein. CTCF creates boundaries between topologically associating domains in chromosomes and, within these domains, facilitates interactions between transcription regulatory sequences. Thus, CTCF links the architecture of the genome to its function.},
}
@article {pmid24486021,
year = {2014},
author = {Liang, J and Lacroix, L and Gamot, A and Cuddapah, S and Queille, S and Lhoumaud, P and Lepetit, P and Martin, PG and Vogelmann, J and Court, F and Hennion, M and Micas, G and Urbach, S and Bouchez, O and Nöllmann, M and Zhao, K and Emberly, E and Cuvier, O},
title = {Chromatin immunoprecipitation indirect peaks highlight long-range interactions of insulator proteins and Pol II pausing.},
journal = {Molecular cell},
volume = {53},
number = {4},
pages = {672-681},
doi = {10.1016/j.molcel.2013.12.029},
pmid = {24486021},
issn = {1097-4164},
support = {260787//European Research Council/International ; R01 ES023174/ES/NIEHS NIH HHS/United States ; ZIA HL005801-07/NULL/Intramural NIH HHS/United States ; },
mesh = {Animals ; Binding Sites ; CCCTC-Binding Factor ; Chromatin Immunoprecipitation/*methods ; DNA-Binding Proteins/metabolism ; Drosophila Proteins/metabolism ; Drosophila melanogaster ; Eye Proteins/metabolism ; *Gene Expression Regulation ; Gene Regulatory Networks ; Insulator Elements/*physiology ; Mutation ; Promoter Regions, Genetic ; Protein Binding ; Protein Interaction Mapping ; RNA Interference ; RNA Polymerase II/*metabolism ; Repressor Proteins/metabolism ; Transcription Factors/metabolism ; },
abstract = {Eukaryotic chromosomes are partitioned into topologically associating domains (TADs) that are demarcated by distinct insulator-binding proteins (IBPs) in Drosophila. Whether IBPs regulate specific long-range contacts and how this may impact gene expression remains unclear. Here we identify &quot;indirect peaks&quot; of multiple IBPs that represent their distant sites of interactions through long-range contacts. Indirect peaks depend on protein-protein interactions among multiple IBPs and their common cofactors, including CP190, as confirmed by high-resolution analyses of long-range contacts. Mutant IBPs unable to interact with CP190 impair long-range contacts as well as the expression of hundreds of distant genes that are specifically flanked by indirect peaks. Regulation of distant genes strongly correlates with RNAPII pausing, highlighting how this key transcriptional stage may trap insulator-based long-range interactions. Our data illustrate how indirect peaks may decipher gene regulatory networks through specific long-range interactions.},
}
@article {pmid24434548,
year = {2014},
author = {Cheutin, T and Cavalli, G},
title = {Polycomb silencing: from linear chromatin domains to 3D chromosome folding.},
journal = {Current opinion in genetics &amp; development},
volume = {25},
number = {},
pages = {30-37},
doi = {10.1016/j.gde.2013.11.016},
pmid = {24434548},
issn = {1879-0380},
mesh = {Animals ; Chromatin/*chemistry ; Chromosomes/*chemistry ; Gene Expression Regulation ; Gene Silencing ; Histones/metabolism ; Humans ; Polycomb-Group Proteins/genetics/*metabolism ; },
abstract = {Polycomb group (PcG) proteins are conserved chromatin factors that regulate key developmental genes. Genome wide studies have shown that PcG proteins and their associated H3K27me3 histone mark cover long genomic domains. PcG proteins and H3K27me3 accumulate in Pc nuclear foci, which are the cellular counterparts of genomic domains silenced by PcG proteins. One explanation for how large genomic domains form nuclear foci may rely on loops occurring between specific elements located within domains. However, recent improvement of the chromosome conformation capture (3C) technology, which allowed monitoring genome wide contacts depicts a more complex picture in which chromosomes are composed of many topologically associating domains (TADs). Chromatin regions marked with H3K27me3 correspond to one class of TADs and PcG proteins participate in long-range interactions of H3K27me3 TADs, whereas insulator proteins seem to be important for separating TADs and may also participate in the regulation of intra TAD architecture. Recent data converge to suggest that this hierarchical organization of chromosome domains plays an important role in genome function during cell proliferation and differentiation.},
}
@article {pmid26054763,
year = {2015},
author = {Perkel, J},
title = {MAPPING CHROMOSOME NEIGHBORHOODS.},
journal = {BioTechniques},
volume = {58},
number = {6},
pages = {280-284},
doi = {10.2144/000114296},
pmid = {26054763},
issn = {1940-9818},
mesh = {Animals ; Chromosome Mapping/*methods ; Chromosomes/*chemistry/*genetics/metabolism ; Gene Expression Regulation ; Humans ; Models, Molecular ; },
abstract = {The discovery of topologically associating domains (TADs) changed the way researchers think about gene expression and chromosome structure. Jeffrey Perkel takes a closer look into these “chromosome neighborhoods.&quot;},
}
@article {pmid23832846,
year = {2013},
author = {Nora, EP and Dekker, J and Heard, E},
title = {Segmental folding of chromosomes: a basis for structural and regulatory chromosomal neighborhoods?.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {35},
number = {9},
pages = {818-828},
doi = {10.1002/bies.201300040},
pmid = {23832846},
issn = {1521-1878},
support = {R01 HG003143/HG/NHGRI NIH HHS/United States ; },
mesh = {Animals ; Chromatin/*chemistry/*genetics ; DNA/genetics ; DNA Replication Timing ; Evolution, Molecular ; *Gene Expression Regulation ; Genome ; Humans ; Promoter Regions, Genetic ; Transcriptional Activation ; },
abstract = {We discuss here a series of testable hypotheses concerning the role of chromosome folding into topologically associating domains (TADs). Several lines of evidence suggest that segmental packaging of chromosomal neighborhoods may underlie features of chromatin that span large domains, such as heterochromatin blocks, association with the nuclear lamina and replication timing. By defining which DNA elements preferentially contact each other, the segmentation of chromosomes into TADs may also underlie many properties of long-range transcriptional regulation. Several observations suggest that TADs can indeed provide a structural basis to regulatory landscapes, by controlling enhancer sharing and allocation. We also discuss how TADs may shape the evolution of chromosomes, by causing maintenance of synteny over large chromosomal segments. Finally we suggest a series of experiments to challenge these ideas and provide concrete examples illustrating how they could be practically applied.},
}
@article {pmid23473598,
year = {2013},
author = {Gibcus, JH and Dekker, J},
title = {The hierarchy of the 3D genome.},
journal = {Molecular cell},
volume = {49},
number = {5},
pages = {773-782},
doi = {10.1016/j.molcel.2013.02.011},
pmid = {23473598},
issn = {1097-4164},
support = {R01 HG003143/HG/NHGRI NIH HHS/United States ; U54 HG004592/HG/NHGRI NIH HHS/United States ; HG003143/HG/NHGRI NIH HHS/United States ; HG004592/HG/NHGRI NIH HHS/United States ; },
mesh = {Animals ; Cell Nucleus/metabolism ; Chromatin ; Chromosomes/genetics ; Gene Expression Regulation ; *Genome ; Humans ; Models, Biological ; },
abstract = {Mammalian genomes encode genetic information in their linear sequence, but appropriate expression of their genes requires chromosomes to fold into complex three-dimensional structures. Transcriptional control involves the establishment of physical connections among genes and regulatory elements, both along and between chromosomes. Recent technological innovations in probing the folding of chromosomes are providing new insights into the spatial organization of genomes and its role in gene regulation. It is emerging that folding of large complex chromosomes involves a hierarchy of structures, from chromatin loops that connect genes and enhancers to larger chromosomal domains and nuclear compartments. The larger these structures are along this hierarchy, the more stable they are within cells, while becoming more stochastic between cells. Here, we review the experimental and theoretical data on this hierarchy of structures and propose a key role for the recently discovered topologically associating domains.},
}
@article {pmid22495304,
year = {2012},
author = {Nora, EP and Lajoie, BR and Schulz, EG and Giorgetti, L and Okamoto, I and Servant, N and Piolot, T and van Berkum, NL and Meisig, J and Sedat, J and Gribnau, J and Barillot, E and Blüthgen, N and Dekker, J and Heard, E},
title = {Spatial partitioning of the regulatory landscape of the X-inactivation centre.},
journal = {Nature},
volume = {485},
number = {7398},
pages = {381-385},
doi = {10.1038/nature11049},
pmid = {22495304},
issn = {1476-4687},
support = {R01 HG003143/HG/NHGRI NIH HHS/United States ; },
mesh = {Animals ; Cell Differentiation ; DNA, Intergenic/genetics ; Embryonic Stem Cells/cytology/metabolism ; Epigenesis, Genetic ; Epigenomics ; Female ; Fibroblasts ; Gene Expression Regulation ; Histones/metabolism ; In Situ Hybridization, Fluorescence ; Male ; Methylation ; Mice ; Molecular Sequence Data ; Promoter Regions, Genetic/genetics ; RNA, Long Noncoding ; RNA, Untranslated/*genetics ; Transcriptome ; X Chromosome/chemistry/*genetics ; X Chromosome Inactivation/*genetics ; },
abstract = {In eukaryotes transcriptional regulation often involves multiple long-range elements and is influenced by the genomic environment. A prime example of this concerns the mouse X-inactivation centre (Xic), which orchestrates the initiation of X-chromosome inactivation (XCI) by controlling the expression of the non-protein-coding Xist transcript. The extent of Xic sequences required for the proper regulation of Xist remains unknown. Here we use chromosome conformation capture carbon-copy (5C) and super-resolution microscopy to analyse the spatial organization of a 4.5-megabases (Mb) region including Xist. We discover a series of discrete 200-kilobase to 1 Mb topologically associating domains (TADs), present both before and after cell differentiation and on the active and inactive X. TADs align with, but do not rely on, several domain-wide features of the epigenome, such as H3K27me3 or H3K9me2 blocks and lamina-associated domains. TADs also align with coordinately regulated gene clusters. Disruption of a TAD boundary causes ectopic chromosomal contacts and long-range transcriptional misregulation. The Xist/Tsix sense/antisense unit illustrates how TADs enable the spatial segregation of oppositely regulated chromosomal neighbourhoods, with the respective promoters of Xist and Tsix lying in adjacent TADs, each containing their known positive regulators. We identify a novel distal regulatory region of Tsix within its TAD, which produces a long intervening RNA, Linx. In addition to uncovering a new principle of cis-regulatory architecture of mammalian chromosomes, our study sets the stage for the full genetic dissection of the X-inactivation centre.},
}