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Context-dependent perturbations in chromatin folding and the transcriptome by cohesin and related factors [RNA-seq]

ABSTRACT: Cohesin plays vital roles in chromatin folding and gene expression regulation, cooperating with such factors as cohesin loaders, unloaders, and the insulation factor CTCF. Although models of regulation have been proposed (e.g., loop extrusion), how cohesin and related factors collectively or individually regulate the hierarchical chromatin structure and gene expression remains unclear. We have depleted cohesin and related factors and then conducted a comprehensive evaluation of the resulting 3D genome, transcriptome and epigenome data. We observed substantial variation in depletion effects among factors at topologically associating domain (TAD) boundaries and on interTAD interactions, which were related to epigenomic status.

ORGANISM(S): Homo sapiens

PROVIDER: GSE196449 | GEO | 2023/07/28

REPOSITORIES: GEO

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Context-dependent perturbations in chromatin folding and the transcriptome by cohesin and related factors [ChIP-seq]

Project description:Cohesin plays vital roles in chromatin folding and gene expression regulation, cooperating with such factors as cohesin loaders, unloaders, and the insulation factor CTCF. Although models of regulation have been proposed (e.g., loop extrusion), how cohesin and related factors collectively or individually regulate the hierarchical chromatin structure and gene expression remains unclear. We have depleted cohesin and related factors and then conducted a comprehensive evaluation of the resulting 3D genome, transcriptome and epigenome data. We observed substantial variation in depletion effects among factors at topologically associating domain (TAD) boundaries and on interTAD interactions, which were related to epigenomic status.

2023-07-28 | GSE196727 | GEO

Context-dependent perturbations in chromatin folding and the transcriptome by cohesin and related factors [Hi-C]

2023-07-28 | GSE196034 | GEO

Interplay between CTCF boundaries and a super enhancer controls cohesin extrusion trajectories and gene expression

Project description:To understand how chromatin domains coordinate gene expression, we dissected select genetic elements organizing topology and transcription around the Prdm14 super enhancer in mouse embryonic stem cells. Taking advantage of allelic polymorphisms, we developed methods to sensitively analyze changes in chromatin topology, gene expression, and protein recruitment. We show that enhancer insulation does not strictly rely on loop formation between its flanking boundaries, that the enhancer activates the Slco5a1 gene beyond its prominent domain boundary, and that it recruits cohesin for loop extrusion. Upon boundary inversion, we find that oppositely-oriented CTCF terminates extrusion trajectories but does not stall cohesin, while deleted or mutated CTCF sites allow cohesin to extend its trajectory. Enhancer-mediated gene activation occurs independent of paused loop extrusion near the gene promoter. We expand upon the loop extrusion model to propose that cohesin loading and extrusion trajectories originating at an enhancer contribute to gene activation.

2021-06-30 | GSE173354 | GEO

MCM complexes are barriers that restrict cohesin-mediated loop extrusion [snHi-C]

2022-03-08 | GSE196300 | 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

Analysis of sub-kilobase chromatin topology reveals nano-scale regulatory interactions with variable dependence on cohesin and CTCF

Project description:Enhancers and promoters predominantly interact within large-scale topologically associating domains (TADs), which are formed by loop extrusion mediated by cohesin and CTCF. However, it is unclear whether complex chromatin structures exist at sub-kilobase-scale and to what extent fine-scale regulatory interactions depend on loop extrusion. To address these questions, we present an MNase-based chromosome conformation capture (3C) approach, which has enabled us to generate the most detailed local interaction data to date and precisely investigate the effects of cohesin and CTCF depletion on chromatin architecture. Our data reveal that cis-regulatory elements have distinct internal nano-scale structures, within which local insulation is dependent on CTCF, but which are independent of cohesin. In contrast, we find that depletion of cohesin causes a subtle reduction in longer-range enhancer-promoter interactions and that CTCF depletion can cause rewiring of regulatory contacts. Together, our data show that loop extrusion is not essential for enhancer-promoter interactions, but contributes to their robustness and specificity and to precise regulation of gene expression.

2021-09-10 | GSE181694 | GEO

Universal dynamics of cohesin-mediated loop extrusion

Project description:Most animal genomes are partitioned into Topologically Associating Domains (TADs), created by cohesin-mediated loop extrusion and defined by convergently oriented CTCF sites. The dynamics of loop extrusion and its regulation remains poorly characterized in vivo. Here, we tracked TAD anchors in living human cells to visualize and quantify cohesin-dependent loop extrusion across multiple endogenous genomic regions. We show that TADs are dynamic structures whose anchors are brought in proximity about once per hour and for 6-19 min (~16% of the time). TADs are continuously subjected to extrusion by multiple cohesin complexes, extruding loops at ~0.1 kb/s. Remarkably, despite strong differences of Hi-C patterns between the chromatin regions, their dynamics is consistent with the same density, residence time and speed of cohesin. Our results suggest that TAD dynamics is governed primarily by CTCF site location and affinity, which allows genome-wide predictive models of cohesin-dependent interactions.

2024-07-28 | GSE273257 | GEO

CRL4-DCAF15 control of cohesin dynamics sustains 1 cell proliferation

Project description:The CRL4-DCAF15 E3 ubiquitin ligase complex is targeted by the aryl-sulfonamide molecular glues, leading to neo-substrate recruitment, ubiquitination, and proteasomal degradation. However, the physiological function of DCAF15 remains unknown. Using a domain-focused genetic screening approach, we reveal DCAF15 as an acute myeloid leukemia (AML)-biased dependency. Loss of DCAF15 results in suppression of AML through compromised replication fork integrity and consequent accumulation of DNA damage. Accordingly, DCAF15 loss sensitizes AML to replication stress-inducing therapeutics. Mechanistically, we discover that DCAF15 directly interacts with the SMC1A protein of the cohesin complex and destabilizes the cohesin regulatory factors PDS5A and CDCA5. Loss of PDS5A and CDCA5 removal precludes cohesin acetylation on chromatin, resulting in uncontrolled chromatin loop extrusion, defective DNA replication, and apoptosis. Collectively, our findings uncover an endogenous, cell autonomous function of DCAF15 in sustaining AML proliferation through post-translational control of cohesin dynamics.

2023-08-19 | MSV000092697 | MassIVE

Large-scale multi-omics analysis suggests an important role of intragenic cohesin in tissue-specific transcription.

Project description:Cohesin is a protein complex that is essential for chromosome segregation. Cohesin regulates gene expression by insulation and chromatin domain formation with insulation factor CTCF. It was also reported that CTCF-independent cohesin-binding sites co-localize with transcription factors (TFs) for enhancer-promoter interaction. However, it is not a trivial task to assign whole-genome cohesin-binding regions into various functions. Also, the context-specific roles of cohesin-mediated interactions, especially on intragenic region, remains unsolved. To this end, we performed a comprehensive characterization of DNA-binding sites for cohesin and transcription factors (TFs) in MCF-7 cells with and without transcription stimulus. We integrated these epigenomic data with transcriptomic and chromatin interactions data to analyze context-specific cohesin function in genome-wide manner. As a result, we extracted a new subset of cohesin-binding sites named decreased intragenic cohesin sites (DICs), which were different from previous known functions of cohesin. DICs were negatively correlated with transcriptional regulation: a part of them were related to enhancer markers and “paused” RNA polymerase 2, while others contributed to chromatin architectures. The intron enriched DICs also showed chromatin de-compaction and special genomic bindings. Further conventional machine learning approach also captured similar DICs with distinguishable features. More importantly, DICs could be found in various tissues and cell lines, including cohesinopathy patient cells, to play a role in the disturbed transcription. These results suggested a novel function of cohesin on intragenic regions for gene transcription regulation.

2022-05-12 | GSE177045 | GEO

Computational prediction of CTCF/cohesin-based intra-TAD (sbTAD) loops that insulate chromatin contacts and gene expression in mouse liver

Project description:This SuperSeries is composed of the SubSeries listed below, and presents the high throuput sequencing datasets that were generated as part of a larger study that investigates the role of CTCF and cohesin as key drivers of 3D-nuclear organization, anchoring the megabase-scale Topologically Associating Domains (TADs) that segment the genome. This study presents and validates 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. The intra-TAD loops are proposed to be formed by the same loop extrusion mechanism as the larger TAD loops; 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.

2018-05-11 | GSE102999 | GEO

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