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Cohesin mediates DNA loop extrusion and sister chromatid cohesion by distinct mechanisms [Hi-C]

ABSTRACT: Cohesin connects CTCF binding sites and other genomic loci in cis to form chromatin loops, and replicated DNA molecules in trans to mediate sister chromatid cohesion. Whether cohesin uses distinct or related mechanisms to perform these functions is unknown. Here we describe a cohesin hinge mutant, which can extrude DNA into loops but is unable to mediate cohesion. Our results suggest that the latter defect arises during cohesion establishment. The observation that cohesin’s cohesion and loop extrusion activities can be separated indicates that cohesin uses distinct mechanisms to perform these two functions. Unexpectedly, the same hinge mutant can also not be stopped by CTCF boundaries as well as wildtype cohesin. This suggests that cohesion establishment and cohesin’s interaction with CTCF boundaries depend on related mechanisms and raises the possibility that both require transient hinge opening to entrap DNA inside the cohesin ring.

ORGANISM(S): Homo sapiens

PROVIDER: GSE235771 | GEO | 2023/10/25

REPOSITORIES: GEO

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Cohesin mediates DNA loop extrusion and sister chromatid cohesion by distinct mechanisms [ChIP-seq]

Project description:Cohesin connects CTCF binding sites and other genomic loci in cis to form chromatin loops, and replicated DNA molecules in trans to mediate sister chromatid cohesion. Whether cohesin uses distinct or related mechanisms to perform these functions is unknown. Here we describe a cohesin hinge mutant, which can extrude DNA into loops but is unable to mediate cohesion. Our results suggest that the latter defect arises during cohesion establishment. The observation that cohesin’s cohesion and loop extrusion activities can be separated indicates that cohesin uses distinct mechanisms to perform these two functions. Unexpectedly, the same hinge mutant can also not be stopped by CTCF boundaries as well as wildtype cohesin. This suggests that cohesion establishment and cohesin’s interaction with CTCF boundaries depend on related mechanisms and raises the possibility that both require transient hinge opening to entrap DNA inside the cohesin ring.

2023-10-25 | GSE235770 | GEO

The cohesin ring uses its hinge to organize DNA using non-topological as well as topological mechanisms

Project description:As predicted by the notion that sister chromatid cohesion is mediated by entrapment of sister DNAs inside cohesin rings, there is a perfect correlation between co-entrapment of circular minichromosomes and sister chromatid cohesion. In most cells where cohesin loads onto chromosomes but fails to form cohesion, loading is accompanied by entrapment of individual DNAs. However, cohesin with a hinge whose positively charged lumen has been neutralized not only loads onto and translocates along chromatin but also organizes it into chromatid-like threads, despite largely failing to entrap DNAs inside its ring. Thus, cohesin engages chromatin in both a non-topological and a topological manner. Further, mutation of three highly conserved lysines within the Smc1 hinge abolishes all loading without affecting cohesin’s initial recruitment to centromers or its ability to hydrolyze ATP. We suggest that loading and translocation are mediated by conformational changes in cohesin’s hinge driven by cycles of ATP hydrolysis.

2018-04-23 | GSE105005 | GEO

Cohesin recruits the Esco1 acetyltransferase genomewide to repress transcription and promote cohesion in somatic cells

Project description:The cohesin complex links DNA molecules and plays key roles in the organization, expression, repair, and segregation of eukaryotic genomes. In vertebrates the Esco1 and Esco2 acetyltransferases both modify cohesin’s Smc3 subunit to establish sister chromatid cohesion during S phase, but differ in their N-terminal domains and expression during development and across the cell cycle. Here we show that Esco1 and Esco2 also differ dramatically in their interaction with chromatin, as Esco1 is recruited by cohesin to over 11,000 sites, whereas Esco2 is infrequently enriched at REST/NRSF target genes. Esco1’s colocalization with cohesin occurs throughout the cell cycle and depends on two short motifs (the A-box and B-box) present in and unique to all Esco1 orthologs. Deleting either motif led to the derepression of Esco1-proximal genes and functional uncoupling of cohesion from Smc3 acetylation. In contrast, other mutations that preserved Esco1’s recruitment separated its roles in cohesion establishment and gene silencing. We conclude that Esco1 uses cohesin as both a substrate and a scaffold for coordinating multiple chromatin-based transactions in somatic cells. Total RNA was isolated after treatment with indicated siRNAs, or transfection reagent only for control samples. Samples for each group in triplicate were processed for Illumina bead arrays (Illumina HT-12) by the MSKCC genomics core facility according to manufacturer instructions.

2015-08-25 | E-GEOD-71420 | biostudies-arrayexpress

Cohesin chromatin loop formation by an extrinsic motor (Micro-C)

Project description:The ring-shaped cohesin complex topologically entraps two DNAs to establish sister chromatid cohesion. Cohesin also shapes the interphase chromatin landscape, with wide-ranging implications for gene regulation, which cohesin is thought to achieve by actively extruding DNA loops without topologically entrapping DNA. The ‘loop extrusion’ model find motivation from in vitro observations - whether this process indeed underlies chromatin loop formation in vivo remains untested. Here, using the budding yeast S. cerevisiae, we generate cohesin variants that have lost their ability to extrude DNA loops but retain their ability to topologically entrap DNA. Analysis of these variants suggests that in vivo chromatin loops form independently of loop extrusion. Instead, we find that transcription promotes loop formation, likely by generating DNA substrates for topological loop capture. Transcription furthermore acts as an extrinsic motor that, by pushing cohesin along transcription units, extends chromatin loops and defines their ultimate positions. Our results necessitate a re-evaluation of the loop extrusion hypothesis and point to an alternative mechanism for cohesin-dependent chromatin organisation. Loop formation by DNA-DNA capture, akin to sister chromatid cohesion establishment at replication forks, unifies cohesin’s two roles in chromosome segregation and interphase genome organisation.

2024-08-04 | GSE248281 | GEO

Cohesin chromatin loop formation by an extrinsic motor (ChIP-Seq)

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Sensitivity of cohesin-chromatin association to high salt treatment corroborates non-topological mode of loop extrusion

Project description:Cohesin is a key organizer of chromatin folding in eukaryotic cells. Two basic activities of this ring-shaped protein complex are maintenance of sister chromatid cohesion and establishment of long-range DNA-DNA interactions through the process of loop extrusion. Though basic principles of both cohesion and loop extrusion have been described we still do not understand several crucial mechanistic details. One of such unresolved issues is the question of whether a cohesin ring topologically embraces DNA string(s) during loop extrusion. Here we show that cohesin complexes residing on CTCF-occupied genomic sites in mammalian cells do not interact with DNA topologically. We assessed stability of cohesin-dependent loops and cohesin association with chromatin in high ionic strength conditions in G1-synchronised HeLa cells. We found that increased salt concentration completely displaces cohesin from those genomic regions which correspond to CTCF-defined loop anchors. Unsurprisingly, CTCF-anchored cohesin loops also dissipate in these conditions. As topologically-engaged cohesin is considered to be salt-resistant, our data corroborate a non-topological model of loop extrusion.

2021-07-20 | GSE166387 | GEO

Cohesin recruits the Esco1 acetyltransferase genomewide to repress transcription and promote cohesion in somatic cells

2015-08-25 | GSE71420 | GEO

MCM complexes are barriers that restrict cohesin-mediated loop extrusion [RNA-Seq]

Project description:Eukaryotic genomes are compacted into loops and topologically associating domains (TADs), which contribute to transcription, recombination and genomic stability. Cohesin extrudes DNA into loops that are thought to lengthen until CTCF boundaries are encountered. Little is known about whether loop extrusion is impeded by DNA-bound machines. Here we show that the minichromosome maintenance (MCM) complex is a barrier that restricts loop extrusion in G1 phase. Single-nucleus Hi-C of mouse zygotes revealed that MCM loading reduces CTCF-anchored loops and decreases TAD boundary insulation, suggesting loop extrusion is impeded before reaching CTCF. This effect extends to HCT116 cells, where MCMs affect the number of CTCF-anchored loops and gene expression. Simulations suggest that MCMs are abundant, randomly positioned, partially permeable barriers. Single-molecule imaging shows that MCMs are physical barriers that frequently constrain cohesin translocation in vitro. Remarkably, chimaeric yeast MCMs harbouring a cohesin-interaction motif from human MCM3 induce cohesin pausing, suggesting that MCMs are “active” barriers with binding sites. These findings raise the possibility that cohesin can arrive by loop extrusion at MCMs, which determine the genomic sites at which sister chromatid cohesion is established. Based on in vivo, in silico and in vitro data, we conclude that distinct loop extrusion barriers shape the 3D genome.

2022-03-08 | GSE196496 | GEO

RB is a cell cycle-regulated repressor of cohesin-dependent loop formation

Project description:Chromatin organization and cell cycle are tightly intertwined in eukaryotes, but the underlying mechanisms remain unclear. We investigated how the retinoblastoma protein (RB), a key cell cycle regulator, influences chromatin architecture. Chromosome conformation capture assays reveal that RB loss increases the number and size of cohesin-dependent loops and strengthens topologically associating domains (TADs). RB shows extensive colocalization with cohesin in the human genome, and it impacts cohesin’s distribution on chromatin. Active RB evicted cohesin from RB-bound TAD boundaries, repressed insulator activity, and enhanced the expression of non-E2F target genes that are important for cell adhesion. We conclude that RB has a central role in the interplay between cell cycle and chromatin organization. This role safeguards chromatin architecture and controls transcription.

2024-11-01 | E-MTAB-13566 | biostudies-arrayexpress

The cohesin acetylation cycle controls chromatin loop length through a PDS5A brake mechanism

Project description:Cohesin structures the genome through the formation of chromatin loops and by holding together the sister chromatids. The acetylation of cohesin’s SMC3 subunit is a dynamic process that involves the acetyltransferase ESCO1 and deacetylase HDAC8. Here we show that this cohesin acetylation cycle controls the 3D genome. ESCO1 restricts the length of chromatin loops and architectural stripes, while HDAC8 promotes the extension of such loops and stripes. This role in controlling loop length turns out to be distinct from the canonical role of cohesin acetylation that protects against WAPL-mediated DNA release. We reveal that acetylation rather controls cohesin’s interaction with PDS5A to restrict chromatin loop length. Our data supports a model in which this PDS5A-bound state acts as a brake that enables the pausing and restart of loop enlargement. The cohesin acetylation cycle hereby provides punctuation in the process of genome folding.

2022-03-14 | PXD032185 | Pride

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