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Cohesin cofactor dosage sets the rate of loop extrusion, rendering genome folding tunable yet vulnerable to genetic disruption

ABSTRACT: Genome folding is not static, but emerges from dynamic processes that control transcription, replication, recombination, and repair. DNA loop extrusion by cohesin is central to genome organization, yet it remains unclear how cells can tune extrusion kinetics to achieve precise and functional chromosome folding patterns. Here we show that extrusion rate acts as a tunable biophysical parameter in cells, quantitatively dialed by the respective dosage of the cohesin cofactors NIPBL and PDS5. Modulation of extrusion rate can offset changes in cohesin lifetime to buffer steady-state chromosome structure and transcriptional states, even in the face of abnormal extrusion dynamics. These findings provide a long-sought mechanistic basis for the genetic interactions between cohesin cofactors and for the molecular origin of haploinsufficiency in cohesinopathies, such as Cornelia de Lange syndrome.

ORGANISM(S): Mus musculus

PROVIDER: GSE305208 | GEO | 2026/03/09

REPOSITORIES: GEO

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Cohesin cofactor dosage sets the rate of loop extrusion, rendering genome folding tunable yet vulnerable to genetic disruption

Project description:Genome folding is not static, but emerges from dynamic processes that control transcription, replication, recombination, and repair. DNA loop extrusion by cohesin is central to genome organization, yet it remains unclear how cells can tune extrusion kinetics to achieve precise and functional chromosome folding patterns. Here we show that extrusion rate acts as a tunable biophysical parameter in cells, quantitatively dialed by the respective dosage of the cohesin cofactors NIPBL and PDS5. Modulation of extrusion rate can offset changes in cohesin lifetime to buffer steady-state chromosome structure and transcriptional states, even in the face of abnormal extrusion dynamics. These findings provide a long-sought mechanistic basis for the genetic interactions between cohesin cofactors and for the molecular origin of haploinsufficiency in cohesinopathies, such as Cornelia de Lange syndrome.

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Regulation of cohesin-mediated chromosome structure by PDS5 in mammals [Hi-C]

Project description:Cohesin regulates sister chromatids cohesion but also contributes to chromosome folding by promoting the formation of chromatin loops, a process proposed to be mediated by loop extrusion. PDS5 plays a crucial role in regulating the cohesin dynamic on chromatin, mainly through WAPL-mediated release activity and the opponent ESCO1/2-sororin dependent pathway. However, the exact function of PDS5 on cohesin-mediated chromatin looping remains ambiguous. Two versions of PDS5 exist in vertebrates, PDS5A and PDS5B. Here, we construct cells for rapid PDS5A or PDS5B degradation in PLC/PRF/5 cell line with the FKBP12F36V-dTAG degron system to perform loss of function studies. Combining Hi-C, ChIP-seq for cohesin regulators, and RNA-seq data, we describe the redundant and discrete roles of PDS5A and PDS5B in three-dimensional genome organization and gene expression.

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Cohesin cofactor dosage sets the rate of loop extrusion, rendering genome folding tunable yet vulnerable to genetic disruption

Project description:Cohesin cofactor dosage sets the rate of loop extrusion, rendering genome folding tunable yet vulnerable to genetic disruption

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Cohesin cofactor dosage sets the rate of loop extrusion, rendering genome folding tunable yet vulnerable to genetic disruption

Project description:Cohesin cofactor dosage sets the rate of loop extrusion, rendering genome folding tunable yet vulnerable to genetic disruption

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Cohesin-dependent chromosome loop extrusion is limited by transcription and stalled replication forks [RNA-seq]

Project description:Genome function depends on regulated chromosome folding, and loop extrusion by the protein complex cohesin is essential for this multilayered organization. The chromosomal positioning of cohesin is controlled by transcription, and the complex also localizes to stalled replication forks. However, the role of transcription and replication in chromosome looping remains unclear. Here, we show that reduction of chromosome-bound RNA polymerase weakens normal cohesin loop extrusion boundaries, allowing cohesin to form new long-range chromosome cis interactions. Stress response genes activated by transcription inhibition are also shown to act as new loop extrusion boundaries. Furthermore, cohesin loop extrusion during early S-phase is jointly controlled by transcription and replication units. Together, the results reveal that replication and transcription machineries are chromosome folding regulators that block the progression of loop-extruding cohesin, opening for new perspectives on cohesin’s roles in genome function and stability.

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Cohesin-dependent chromosome loop extrusion is limited by transcription and stalled replication forks [Hi-C]

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BRD4 orchestrates genome folding to promote neural crest progenitor differentiation

Project description:Higher-order chromatin structure is critical for proper gene regulation, but the relationship between genome folding and cellular identity remains elusive. Here, we show that genetic deletion of the Bromodomain-containing protein 4 (BRD4) in murine neural crest cells recapitulates features of cohesinopathies. We demonstrate that BRD4 interacts with NIPBL, a positive cohesin regulator, and acute depletion of BRD4 or loss of the BRD4-NIPBL interaction reduces NIPBL-occupancy, elucidating the importance of BRD4 in stabilizing NIPBL on chromatin. Genome-wide chromatin interaction mapping and quantitative imaging studies demonstrate that BRD4-depletion results in aberrant genome folding, specifically loss of a subset of chromatin loops, weakening of TADs, and compromised loop extrusion. Finally, loss of BRD4 or the interaction with NIPBL impedes neural crest differentiation which, remarkably, is rescued by WAPL depletion, a negative cohesin regulator. Our data reveal that BRD4 choreographs genome folding, illustrating the importance of balancing cohesin activity on progenitor differentiation.

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