Synergy between regulatory elements can render cohesin dispensable for distal enhancer function

Enhancers are critical genetic elements controlling transcription from promoters, yet how they convey regulatory information across large genomic distances remains unclear. In this study, we engineered pluripotent stem cells in which cohesin loop extrusion can be inducibly disrupted without confounding cell cycle defects. Transcriptional dysregulation is cell type specific, and not all loci with distal enhancers depend equally on cohesin extrusion. Using comparative genome editing, we demonstrated that enhancer-promoter communication over just 20 kb can require cohesin. However, promoter-proximal elements can support long-range, cohesin-independent enhancer action-even across strong CCCTC-binding factor (CTCF) insulators. Lastly, transcriptional dynamics and the emergence of embryonic cell types remain largely robust despite disrupted extrusion. Beyond establishing strategies to study cohesin in enhancer biology, our work provides mechanistic insight into cell type specificity and genomic context specificity.

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Publication Details

Journal
Science
Published
2025-11-27
DOI
https://doi.org/10.1126/science.adt4221
Citations
8
Primary Topic
Genomics and Chromatin Dynamics
Type
article
Field-Weighted Citation Impact
6.45
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article

Synergy between regulatory elements can render cohesin dispensable for distal enhancer function

Geoffrey Fudenberg, Kaite Zhang, Erika C. Anderson, Moreno Martinovic et al.
8 citations
Science
Genomics and Chromatin Dynamics
6.45
article

Synergy between regulatory elements can render cohesin dispensable for distal enhancer function

Geoffrey Fudenberg, Kaite Zhang, Erika C. Anderson, Moreno Martinovic, Karissa Hansen, Rini Shah, Luca Braccioli, Kenya Bonitto, Elphège P. Nora, Ryan M. Boileau, Elzo de Wit, Robert Blelloch, Irié Carel, Smit Kadvani, Bozhena Pokorny, Annie S. Adachi
article en
8 citations

Abstract

Enhancers are critical genetic elements controlling transcription from promoters, yet how they convey regulatory information across large genomic distances remains unclear. In this study, we engineered pluripotent stem cells in which cohesin loop extrusion can be inducibly disrupted without confounding cell cycle defects. Transcriptional dysregulation is cell type specific, and not all loci with distal enhancers depend equally on cohesin extrusion. Using comparative genome editing, we demonstrated that enhancer-promoter communication over just 20 kb can require cohesin. However, promoter-proximal elements can support long-range, cohesin-independent enhancer action-even across strong CCCTC-binding factor (CTCF) insulators. Lastly, transcriptional dynamics and the emergence of embryonic cell types remain largely robust despite disrupted extrusion. Beyond establishing strategies to study cohesin in enhancer biology, our work provides mechanistic insight into cell type specificity and genomic context specificity.

ScienceVol. 391(6785)
University of Southern California (US), University of California, San Francisco (US), The Netherlands Cancer Institute (NL), Oncode Institute (NL), Chan Zuckerberg Initiative (United States) (US), Broad Center (US), UCSF Helen Diller Family Comprehensive Cancer Center (US)
Openalex Percentile: Top 3%
Genomics and Chromatin Dynamics
6.45
DOISourceOpenAlex
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