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PreprintCited by 15Genomics and Chromatin DynamicsNuclear Structure and FunctionDNA Repair Mechanisms

Dosage sensitivity of the loop extrusion rate confers tunability to genome folding while creating vulnerability to genetic disruption

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Shah, Rini, Tortora, Maxime M. C., Louafi, Nessim, Rahmaninejad, Hadi, Hansen, Karissa L., Anderson, Erika C., Wen, David, Giorgetti, Luca +2 more·2025·bioRxiv (Cold Spring Harbor Laboratory)
DOI 10.1101/2025.08.14.667581PMC PMC12485851
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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 discover 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 the molecular origin of haploinsufficiency in cohesinopathies, such as Cornelia de Lange syndrome.

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Sorted by citations

Authors
Shah, R., Tortora, M. M. C., Louafi, N., Rahmaninejad, H., Hansen, K. L., Anderson, E. C., Wen, D., Giorgetti, L., Fudenberg, G., & Nora, E. P.
Affiliations
  • University of California, San Francisco (US)
  • University of Southern California (US)
  • Friedrich Miescher Institute (CH)
Corresponding author
  • Fudenberg, Geoffrey
  • Nora, Elphège P.
ORCID
Venue
bioRxiv (Cold Spring Harbor Laboratory)
Publisher
openRxiv
Published
2025-08-15
DOI
10.1101/2025.08.14.667581
PMC
PMC12485851
OpenAlex
W4413348294
Cited by
15
References
12
Citations by year
2026: 12 · 2025: 3
Type
posted content
Language
en
Open access
Licence
Locations
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nd)
  • Europe PMC (PubMed Central) (submittedVersion, cc-by-nd)
Funders
  • National Science Foundation
  • California Institute for Regenerative Medicine (EDUC4-12812)
  • Hellman Foundation
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (192642)
  • National Institutes of Health (1s10od028511-01)
  • University of California, San Francisco (1R35GM142792-01)
  • National Institute of General Medical Sciences (R35GM142792, R35GM143116)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD007470)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Keywords
DNA loop extrusion, cohesin, extrusion speed, NIPBL, Pds5, dosage sensitivity, genome folding, chromosome organization, cohesinopathies, Cornelia de Lange syndrome, haploinsufficiency, transcription, chromatin organization

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