Polycomb-mediated chromatin loops revealed by a subkilobase-resolution chromatin interaction map

Eagen, Kyle P.; Aiden, E; Kornberg, Roger D.

doi:10.1073/pnas.1701291114

Cited by 165 publications

(213 citation statements)

References 34 publications

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“…The stripes extending from microTAD boundaries connect promoters to promoters (P-P links) ( Fig other through "loop" structures (19,30). However, instead of forming focal contact enrichments, we found that H3K27me3-rich regions form nested sets of chromatin contacts in Micro-C maps, as one patch of repressive chromatin hooks-and-loops to another patch ( Fig.…”

mentioning

confidence: 79%

Resolving the 3D landscape of transcription-linked mammalian chromatin folding

Slobodyanyuk

Hansen

et al. 2019

Preprint

118

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Chromatin folding below the scale of topologically associating domains (TADs) remains largely unexplored in mammals. Here, we used a high-resolution 3C-based method, Micro-C, to probe links between 3D-genome organization and transcriptional regulation in mouse stem cells. 20Combinatorial binding of transcription factors, cofactors, and chromatin modifiers spatially segregate TAD regions into "microTADs" with distinct regulatory features. Enhancer-promoter and promoter-promoter interactions extending from the edge of these domains predominantly link co-regulated loci, often independently of CTCF/Cohesin. Acute inhibition of transcription disrupts the gene-related folding features without altering higher-order chromatin structures. 25Intriguingly, we detect "two-start" zig-zag 30-nanometer chromatin fibers. Our work uncovers the finer-scale genome organization that establishes novel functional links between chromatin folding and gene regulation. 30ONE SENTENCE SUMMARY Transcriptional regulatory elements shape 3D genome architecture of microTADs. MAIN TEXT 35Chromatin packages the eukaryotic genome via a hierarchical series of folding steps ranging from nucleosomes to chromosome territories (1). Structural analysis of chromosome folding has been revolutionized by the Chromosome Conformation Capture (3C) family of techniques, which uses proximity ligation of cross-linked genomic loci in vivo to estimate contact frequencies (2). Interphase chromosome structures such as compartments (3), topologically-40 associating domains (TADs) (4, 5), and CTCF/cohesin chromatin loops (6) have been characterized using 3C-based methods. Chromosome compartments correspond to large-scale active and inactive chromatin segments and appear as a plaid-like pattern in Hi-C contact maps at the megabase scale (3). At the intermediate scale of tens to hundreds of kilobases, topologically associating domains (TADs) spatially organize the mammalian genome into 45 continuous self-interacting domains. TADs are defined as local domains in which genomic loci contact each other more frequently within the domain than with loci outside. TADs appear as square boxes along the diagonal of 3D contact maps (4, 5). Mounting evidence suggests that CTCF and cohesin likely mediate TAD formation via a loop extrusion mechanism (7, 8) wherein the cohesin ring complex entraps chromatin loci and extrudes chromatin until blocked by CTCF 50 or other proteins. Stabilization of cohesin at CTCF sites result in sharp corner peaks in contact maps and are also referred to as CTCF/cohesin loops or loop domains. Various studies have

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confidence: 79%

Resolving the 3D landscape of transcription-linked mammalian chromatin folding

Slobodyanyuk

Hansen

et al. 2019

Preprint

118

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“…TADs were nearly identical in polytene and diploid DNA, confirming that polytene chromosomes are good models of diploid genome organization (Eagen et al 2015) and suggesting that TADs are bands (Eagen et al 2015;Ullanov et al 2016). Subsequent studies at higher resolution have revealed up to several thousand TAD boundaries (Eagen et al 2017;Hug et al 2017;Ramirez et al 2017;Stadler et al 2017). The idea that TADs correspond generally to bands remains attractive, but the boundaries identified by different groups often differ, and some recent studies may be resolving structures smaller than bands.…”

mentioning

confidence: 81%

“…TADs mapped to this region by the indicated publications (1-6) are mapped below (blue). (1) Sexton et al (2012); (2) Hou et al (2012); (3) Eagen et al (2015); (4) Eagen et al (2017); (5) Stadler et al (2017); (6) Ramirez et al (2017). Genes in the region are also plotted.…”

Section: Conclusion Bands Are Fundamental Genomic Units That May Coormentioning

confidence: 99%

Polytene Chromosome Structure and Somatic Genome Instability

Spradling

2017

Cold Spring Harb Symp Quant Biol

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Polytene chromosomes have for 80 years provided the highest resolution view of interphase genome structure in an animal cell nucleus. These chromosomes represent the normal genomic state of nearly all Drosophila larval and many adult cells, and a better understanding of their striking banded structure has been sought for decades. A more recently appreciated characteristic of Drosophila polytene cells is somatic genome instability caused by unfinished replication (UR). Repair of stalled forks generates enough deletions in polytene salivary gland cells to alter 10%-90% of the DNA strands within more than 100 UR regions comprising 20% of the euchromatic genome. We accurately map UR regions and show that most approximate large polytene bands, indicating that replication forks frequently stall near band boundaries in late S phase. Chromosome conformation capture has recently identified dense topologically associated domains (TADs) in many genomes and most UR bands are similar or slightly smaller than a cognate Drosophila TAD. We argue that bands serve the evolutionarily ancient function of coordinating genome replication with local gene activity. We also discuss the relatively recent evolution of polyteny and somatic instability in Diptera and propose that these processes helped propel the amazing success of two-winged flies in becoming the most ecologically diverse insect group, with 200 times the number of species as mammals.

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“…In particular, the interaction of active domains flanking inactive domains may lead to a loose loop topology based on chromatin state domains rather than on precise loop anchor elements. A small number of Drosophila domains with apical interaction hotspots have been identified, but these are found to relate not to CTCF but to interactions between Polycomb silencing complexes …”

Section: How Is Domain Architecture Established Across Different Orgamentioning

confidence: 99%

“…A small number of Drosophila domains with apical interaction hotspots have been identified, but these are found to relate not to CTCF but to interactions between Polycomb silencing complexes. [22] Further evidence against the conservation of CTCF/cohesin loop extrusion is that, although Drosophila contains homologues of CTCF and cohesin-complex components, the specific hallmark of this mechanism, the pairing of convergent CTCF sites at domain boundaries, is lacking. [21] Replication in Drosophila of the analysis demonstrating clear orientation pairing of CTCF sites in mammals shows no preferential orientation bias for CTCF at TAD boundaries ( Figure 2).…”

Section: Drosophila Lacks Evidence For Ctcf-mediated Loop/ Domain Formentioning

confidence: 99%

Chromatin Architecture in the Fly: Living without CTCF/Cohesin Loop Extrusion?

Matthews

White

2019

BioEssays

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The organization of the genome into topologically associated domains (TADs) appears to be a fundamental process occurring across a wide range of eukaryote organisms, and it likely plays an important role in providing an architectural foundation for gene regulation. Initial studies emphasized the remarkable parallels between TAD organization in organisms as diverse as Drosophila and mammals. However, whereas CCCTC‐binding factor (CTCF)/cohesin loop extrusion is emerging as a key mechanism for the formation of mammalian topological domains, the genome organization in Drosophila appears to depend primarily on the partitioning of chromatin state domains. Recent work suggesting a fundamental conserved role of chromatin state in building domain architecture is discussed and insights into genome organization from recent studies in Drosophila are considered.

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Polycomb-mediated chromatin loops revealed by a subkilobase-resolution chromatin interaction map

Cited by 165 publications

References 34 publications

Resolving the 3D landscape of transcription-linked mammalian chromatin folding

Resolving the 3D landscape of transcription-linked mammalian chromatin folding

Polytene Chromosome Structure and Somatic Genome Instability

Chromatin Architecture in the Fly: Living without CTCF/Cohesin Loop Extrusion?

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