Cohesin as an essential disruptor of chromosome organization.

Adrian Bird

doi:10.1016/j.molcel.2025.01.010

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Cohesin as an essential disruptor of chromosome organization.

Adrian Bird

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Abstract

Cohesin is a multi-subunit molecular machine that is able to create lateral chromatin loops within a linear chromosome fiber. Despite intense study, a consensus view of the functional significance of loop extrusion has remained elusive. This perspective proposes a rationale based on the need for continual disruption of spurious higher-order chromatin secondary structures. It is argued that cohesin-mediated chromosomal churn ensures broad accessibility to the diffusible factors on which genome function depends.

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Cohesins Chromosomal Proteins, Non-Histone Cell Cycle Proteins Humans Chromatin Chromosomes Animals Journal Article Review

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Adrian Bird. 2025-02-04. Cohesin as an essential disruptor of chromosome organization.. https://doi.org/10.1016/j.molcel.2025.01.010

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Nuclear exosome targeting complexes modulate cohesin binding and enhancer-promoter interactions in 3D.

Three-dimensional long-range contacts between enhancers and promoters are thought to be largely determined by loop extrusion driven by the cohesin complex and insulator factors. However, recent evidence also suggests a role for noncoding RNAs, such as enhancer-associated RNAs and promoter upstream transcripts, in shaping enhancer-promoter connectivity. While the nuclear RNA exosome, together with targeting complexes, poly(A) tail exosome targeting connection and nuclear exosome targeting complex, controls the decay of noncoding RNAs, it remains unclear whether these complexes regulate three-dimensional chromatin contacts. Chromatin recruitment maps of the nuclear exosome targeting complex subunit ZCCHC8, the poly(A) tail exosome targeting connection subunit ZFC3H1, and the RNA helicase MTR4 in human cells reveal that these factors associate with sites of enhancer-promoter interactions. Depletion of these factors leads to the accumulation of ncRNAs, notably enhancer-associated RNAs and promoter upstream transcripts, and increases cohesin occupancy at these sites. Chromatin conformation capture analysis reveals that MTR4 modulates long-range enhancer-promoter contacts. Upon loss of MTR4, enhancer-promoter contacts increase while intraloop contacts decrease, suggesting that MTR4 facilitates loop extrusion. These data highlight a key interplay between cohesin-mediated enhancer-promoter interactions and the regulation of noncoding RNAs by nuclear RNA exosome targeting complexes that is consistent with a role for RNA in genome folding.

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PubMed2026

Folding a broken genome: the versatile roles of cohesin in genome maintenance.

Cohesin is a protein complex that shapes 3D genome organization through two distinct mechanisms. First, cohesin tethers replicated chromatids from DNA replication until mitosis. This process, known as sister chromatid cohesion, ensures accurate chromosome segregation and enables high-fidelity DNA repair through homologous recombination between the sister chromatids. Second, cohesin organizes the genome during interphase by dynamically extruding chromatin loops, structures that have key roles in gene regulation. Recent work has shown that, in addition to the well-established repair functions of sister chromatid cohesion, cohesin-mediated chromatin looping is closely linked to the repair of DNA double-strand breaks - one of the most toxic DNA lesions. In this Review, we discuss the central roles of cohesin in maintaining genome stability, with emphasis on the cellular response to DNA double-strand breaks. We review how dynamic loop structures facilitate signalling of repair events and promote long-range chromatin motions that underpin the repair process. Overall, its dual mode of action - cohesion and loop extrusion - positions cohesin as a central regulator of chromatin architecture and genome maintenance.

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PubMed2025

Barrier effects on the kinetics of cohesin-mediated loop extrusion.

Chromosome organization mediated by structural maintenance of chromosome complexes is crucial in many organisms. Cohesin extrudes chromatin into loops that are thought to lengthen until it is obstructed by CTCF proteins. In complex cellular environments, the loop extrusion machinery may encounter other chromatin-binding proteins. How these proteins interfere with the cohesin-meditated extrusion process is largely unexplored, but recent experiments have shown that some proteins serve as physical barriers that block cohesin translocation. Other proteins containing a cohesin-interaction motif serve as chemical barriers to induce cohesin pausing through interactions with it. Here, we develop an analytically solvable approach for the loop extrusion model incorporating barriers to investigate the effect of the barrier on the passive extrusion process. To further quantify the impact of barriers, we calculate the mean looping time it takes for cohesin to translocate to form a stable loop before dissociation. Our finding reveals that the physical barrier can accelerate the loop formation, and the degree of acceleration is closely related to the impedance strength of the physical barrier. In particular, the synergy of the cohesin loading site and the physical barrier site accelerates loop formation more significantly. The proximity of the cohesin loading site to the barrier site facilitates the rapid formation of stable loops in long genomes, which implies loop extrusion and chromatin-binding proteins might shape functional genomic organization. Conversely, chemical barriers consistently impede loop formation, with increasing impedance strength of the chemical barrier leading to longer loop formation time. Our study contributes to a more comprehensive understanding of the complexity of the loop extrusion process, providing a new perspective on the potential mechanisms of gene regulation.

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