The pluripotent genome in three dimensions is shaped around pluripotency factors

Wit, Elzo de; Bouwman, Britta A. M.; Zhu, Yun; Klous, Petra; Splinter, Erik; Verstegen, Marjon J.A.M.; Krijger, Peter H.L.; Festuccia, Nicola; Nora, Elphège P.; Welling, Maaike; Heard, Edith; Geijsen, Niels; Poot, Raymond A.; Chambers, Ian; Laat, Wouter de

doi:10.1038/nature12420

Cited by 243 publications

(277 citation statements)

References 40 publications

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“…The undefined chromatin signature of PADs in ESCs fits well with previous observations that inactive chromatin is unusually disorganized in pluripotent stem cells (de Wit et al 2013) and that chromocenters appear more diffuse in ESCs under the microscope (Mayer et al 2005;Meshorer et al 2006). This is possibly the consequence of the unusual behavior of classic pericentromeric proteins in ESCs, which are either absent from chromocenters or bind more loosely (Meshorer et al 2006;Brown et al 2013).…”

Section: Association Between Inactive Chromatin and Chromocenters Is supporting

confidence: 73%

Characterization and dynamics of pericentromere-associated domains in mice

et al. 2015

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Despite recent progress in genome topology knowledge, the role of repeats, which make up the majority of mammalian genomes, remains elusive. Satellite repeats are highly abundant sequences that cluster around centromeres, attract pericentromeric heterochromatin, and aggregate into nuclear chromocenters. These nuclear landmark structures are assumed to form a repressive compartment in the nucleus to which genes are recruited for silencing. We have designed a strategy for genome-wide identification of pericentromere-associated domains (PADs) in different mouse cell types. The ∼1000 PADs and non-PADs have similar chromatin states in embryonic stem cells, but during lineage commitment, chromocenters progressively associate with constitutively inactive genomic regions at the nuclear periphery. This suggests that PADs are not actively recruited to chromocenters, but that chromocenters are themselves attracted to inactive chromatin compartments. However, we also found that experimentally induced proximity of an active locus to chromocenters was sufficient to cause gene repression. Collectively, our data suggest that rather than driving nuclear organization, pericentromeric satellite repeats mostly co-segregate with inactive genomic regions into nuclear compartments where they can contribute to stable maintenance of the repressed status of proximal chromosomal regions.[Supplemental material is available for this article.]One of the major challenges in genome biology is to understand how the genome is organized and what factors control the spatiotemporal expression patterns of genes in different cell types. It is well established that higher-order organization of chromatin within the three-dimensional space of the nucleus is an important contributor to regulation of gene expression. In particular, long-range physical interactions of genomic elements in the nuclear space enable functional communication between genes and their regulatory DNA elements that can be hundreds of kilobases apart on the linear

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Section: Association Between Inactive Chromatin and Chromocenters Is supporting

confidence: 73%

Characterization and dynamics of pericentromere-associated domains in mice

et al. 2015

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“…Using compartment size as a proxy for the length scale of interactions, cohesin-based interactions and the alternative interactions detected in cohesin-deficient cells appeared to differ in scale. Consistent with correlative data (de Wit et al 2013;Phillips-Cremins et al 2013), cohesin-dependent interactions within compartments were mostly confined to <1 Mb, i.e., the scale of topologically associated domains (TADs). In contrast, the alternative interactions detected in cohesin-deficient cells increased with compartment sizes >1 Mb.…”

Section: Cohesin-based Chromatin Interactionssupporting

confidence: 64%

Cohesin-based chromatin interactions enable regulated gene expression within preexisting architectural compartments

et al. 2013

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Chromosome conformation capture approaches have shown that interphase chromatin is partitioned into spatially segregated Mb-sized compartments and sub-Mb-sized topological domains. This compartmentalization is thought to facilitate the matching of genes and regulatory elements, but its precise function and mechanistic basis remain unknown. Cohesin controls chromosome topology to enable DNA repair and chromosome segregation in cycling cells. In addition, cohesin associates with active enhancers and promoters and with CTCF to form long-range interactions important for gene regulation. Although these findings suggest an important role for cohesin in genome organization, this role has not been assessed on a global scale. Unexpectedly, we find that architectural compartments are maintained in noncycling mouse thymocytes after genetic depletion of cohesin in vivo. Cohesin was, however, required for specific long-range interactions within compartments where cohesin-regulated genes reside. Cohesin depletion diminished interactions between cohesin-bound sites, whereas alternative interactions between chromatin features associated with transcriptional activation and repression became more prominent, with corresponding changes in gene expression. Our findings indicate that cohesin-mediated long-range interactions facilitate discrete gene expression states within preexisting chromosomal compartments.

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“…Although we know much about the general mechanisms involved in control of gene transcription (Roeder 2005;Rajapakse et al 2009;Bonasio et al 2010;Conaway and Conaway 2011;Novershtern et al 2011;Adelman and Lis 2012;Peter et al 2012;Spitz and Furlong 2012;Zhou et al 2012;de Wit et al 2013;Gifford et al 2013;Kumar et al 2014;Levine et al 2014;Ziller et al 2014;Dixon et al 2015;Tsankov et al 2015), the complex pathways involved in the control of each cell's gene expression program have yet to be mapped in most cells. For some cell types, it is evident that core transcription factors (TFs) regulate their own genes and many others, forming the central core of a definable pathway.…”

Section: [Supplemental Materials Is Available For This Article]mentioning

confidence: 99%

“…Cold Peter et al 2012;Spitz and Furlong 2012;Zhou et al 2012;de Wit et al 2013;Gifford et al 2013;Kumar et al 2014;Ziller et al 2014;Dixon et al 2015;Tsankov et al 2015), but the pathways by which a small set of core TFs control gene expression programs have yet to be mapped in most cells. We describe here models of core transcriptional regulatory circuitry for 75 human cell and tissue types.…”

Section: Wwwgenomeorgmentioning

confidence: 99%

Models of human core transcriptional regulatory circuitries

et al. 2016

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A small set of core transcription factors (TFs) dominates control of the gene expression program in embryonic stem cells and other well-studied cellular models. These core TFs collectively regulate their own gene expression, thus forming an interconnected auto-regulatory loop that can be considered the core transcriptional regulatory circuitry (CRC) for that cell type. There is limited knowledge of core TFs, and thus models of core regulatory circuitry, for most cell types. We recently discovered that genes encoding known core TFs forming CRCs are driven by super-enhancers, which provides an opportunity to systematically predict CRCs in poorly studied cell types through super-enhancer mapping. Here, we use super-enhancer maps to generate CRC models for 75 human cell and tissue types. These core circuitry models should prove valuable for further investigating cell-type–specific transcriptional regulation in healthy and diseased cells.

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The pluripotent genome in three dimensions is shaped around pluripotency factors

Cited by 243 publications

References 40 publications

Characterization and dynamics of pericentromere-associated domains in mice

Characterization and dynamics of pericentromere-associated domains in mice

Cohesin-based chromatin interactions enable regulated gene expression within preexisting architectural compartments

Models of human core transcriptional regulatory circuitries

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