Cohesin Disrupts Polycomb-Dependent Chromosome Interactions in Embryonic Stem Cells

Rhodes, James; Feldmann, Angelika; Hernández-Rodríguez, Benjamín; Díaz, Noèlia; Brown, Jill M.; Fursova, Nadezda A.; Blackledge, Neil P.; Prathapan, Praveen; Dobrinić, Paula; Huseyin, Miles K.; Szczurek, Aleksander; Kruse, Kai; Nasmyth, K; Buckle, Veronica J.; Vaquerizas, Juan M.; Klose, Robert J.

doi:10.1016/j.celrep.2019.12.057

Cited by 138 publications

(181 citation statements)

References 97 publications

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“…Finally, an enrichment for H3K27me3 histone mark associated with Polycomb Repressive Complexes is consistent with the independent findings of a very recent study in ES cells (Rhodes et al, 2020). Notably, the enrichment of Polycomb at the PIRs of cohesin-independent interactions appears to be considerably more pronounced in ES cells compared with differentiated cells such as HeLa (Rhodes et al, 2020), in line with the prominent role of these complexes in stem cell genome architecture and transcriptional control (Mas and Di Croce, 2016;Schoenfelder et al, 2015b).…”

Section: Discussionsupporting

confidence: 90%

Cohesin-dependent and independent mechanisms support chromosomal contacts between promoters and enhancers

Thiecke

Wutz

Muhar

et al. 2020

Preprint

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It is currently assumed that 3D chromosomal organisation plays a central role in transcriptional control. However, recent evidence shows that steady-state transcription of only a minority of genes is affected by depletion of architectural proteins such as cohesin and CTCF. Here, we have used Capture Hi-C to interrogate the dynamics of chromosomal contacts of all human gene promoters upon rapid architectural protein degradation. We show that promoter contacts lost in these conditions tend to be long-range, with at least one interaction partner localising in the vicinity of topologically associated domain (TAD) boundaries. In contrast, many shorter-range chromosomal contacts, particularly those that connect active promoters with each other and with active enhancers remain unaffected by cohesin and CTCF depletion. We demonstrate that the effects of cohesin depletion on nascent transcription can be explained by changes in the connectivity of their enhancers. Jointly, these results provide a mechanistic explanation to the limited, but consistent effects of cohesin and CTCF on steady-state transcription and point towards the existence of alternative enhancer-promoter pairing mechanisms that are independent of these proteins.

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Section: Discussionsupporting

confidence: 90%

Cohesin-dependent and independent mechanisms support chromosomal contacts between promoters and enhancers

Thiecke

Wutz

Muhar

et al. 2020

Preprint

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“…S3 C). The former likely reflects loss of loops and TADs, whereas the latter might reflect long-range polycomb interactions, which have recently been observed in other cell types (Donaldson-Collier et al, 2019; Wang et al, 2018; Rhodes et al, 2020; Ogiyama et al, 2018; Du et al, 2020). The first maximum of the slope derivative reflects the average loop size, which increases from 390 kbp in Scc1 fl/fl to 1.6 Mbp in Scc1 Δ/Δ oocytes.…”

Section: Resultsmentioning

confidence: 85%

Wapl releases Scc1-cohesin and regulates chromosome structure and segregation in mouse oocytes

Silva

Powell

Ladstätter

et al. 2020

Journal of Cell Biology

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Cohesin is essential for genome folding and inheritance. In somatic cells, these functions are both mediated by Scc1-cohesin, which in mitosis is released from chromosomes by Wapl and separase. In mammalian oocytes, cohesion is mediated by Rec8-cohesin. Scc1 is expressed but neither required nor sufficient for cohesion, and its function remains unknown. Likewise, it is unknown whether Wapl regulates one or both cohesin complexes and chromosome segregation in mature oocytes. Here, we show that Wapl is required for accurate meiosis I chromosome segregation, predominantly releases Scc1-cohesin from chromosomes, and promotes production of euploid eggs. Using single-nucleus Hi-C, we found that Scc1 is essential for chromosome organization in oocytes. Increasing Scc1 residence time on chromosomes by Wapl depletion leads to vermicelli formation and intra-loop structures but, unlike in somatic cells, does not increase loop size. We conclude that distinct cohesin complexes generate loops and cohesion in oocytes and propose that the same principle applies to all cell types and species.

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“…Regulation of gene expression is crucial for a myriad of biological processes, including embryonic development, tissue homeostasis, and dosage compensation 2,9,10,[16][17][18] . Gene silencing mediated by Polycomb Repressive Complexes 1 and 2 (PRC1 and PRC2) allows for temporal and tissue-specific control of gene expression during development, with aberrant regulation leading to cancer and congenital disorders 19,20 .…”

Section: Introductionmentioning

confidence: 99%

Polycomb-mediated Genome Architecture Enables Long-range Spreading of H3K27 methylation

Kraft

Yost

Murphy

et al. 2020

Preprint

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SUMMARYPolycomb-group proteins play critical roles in gene silencing through the deposition of histone H3 lysine 27 trimethylation (H3K27me3) and chromatin compaction1-5. This process is essential for embryonic stem cell (ESCs) pluripotency, differentiation, and development. Polycomb repressive complex 2 (PRC2) can both read and write H3K27me3, enabling progressive spread of H3K27me3 on the linear genome6. Long-range Polycomb-associated DNA contacts have also been described, but their regulation and role in gene silencing remains unclear7-10. Here, we apply H3K27me3 HiChIP11-13, a protein-directed chromosome conformation method, and optical reconstruction of chromatin architecture14 to profile long-range Polycomb-associated DNA loops that span tens to hundreds of megabases across multiple topological associated domains in mouse ESCs and human induced pluripotent stem cells7-10. We find that H3K27me3 loop anchors are enriched for Polycomb nucleation points and coincide with key developmental genes, such as Hmx1, Wnt6 and Hoxa. Genetic deletion of H3K27me3 loop anchors revealed a coupling of Polycomb-associated genome architecture and H3K27me3 deposition evidenced by disruption of spatial contact between distant loci and altered H3K27me3 in cis, both locally and megabases away on the same chromosome. Further, we find that global alterations in PRC2 occupancy resulting from an EZH2 mutant15 selectively deficient in RNA binding is accompanied by loss of Polycomb-associated DNA looping. Together, these results suggest PRC2 acts as a “genomic wormhole”, using RNA binding to enhance long range chromosome folding and H3K27me3 spreading. Additionally, developmental gene loci have novel roles in Polycomb spreading, emerging as important architectural elements of the epigenome.

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Cohesin Disrupts Polycomb-Dependent Chromosome Interactions in Embryonic Stem Cells

Abstract: Highlights d Interaction between polycomb target genes in ESCs occurs independently of cohesin d Loop extrusion by cohesin disrupts interactions between polycomb target genes d Cohesin removal enhances repression at polycomb target genes with increased interactions

Cited by 138 publications

References 97 publications

Cohesin-dependent and independent mechanisms support chromosomal contacts between promoters and enhancers

Cohesin-dependent and independent mechanisms support chromosomal contacts between promoters and enhancers

Wapl releases Scc1-cohesin and regulates chromosome structure and segregation in mouse oocytes

Polycomb-mediated Genome Architecture Enables Long-range Spreading of H3K27 methylation

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