Quantitative changes in 3D contact predict changes in enhancer-promoter regulation upon cohesin depletion
Abstract Enhancers are drivers of gene regulation thought to act via 3D interactions with promoters. However, genome-wide cohesin depletion causes only limited changes in gene expression, despite widespread loss of contact domains, raising questions about how 3D contacts and cohesin influence enhancer function. Here, we introduce CRISPRi of regulatory elements upon degron operation (CRUDO), to quantitatively assess how changes in contact frequency affect enhancer-driven gene regulation. We analyzed 1039 candidate enhancers near five cohesin-dependent genes and identified 30 significant enhancer-gene pairs, 16 with cohesin-dependent effects. While all cohesin-dependent enhancers were distal (>50 Kb), not all distal enhancers were sensitive to cohesin. Instead, changes in enhancer effects correlated with changes in enhancer-promoter 3D contact frequency, which appeared to depend on both genomic distance and other locus-specific factors. Across the genome, most predicted enhancer-gene regulatory interactions do not show substantial contact changes upon cohesin depletion, explaining why only a small subset of genes are cohesin-sensitive. Together, our results illuminate how 3D contacts tune enhancer effects on endogenous gene expression.
Authors
- Kristy S. Mualim (ORCID: https://orcid.org/0000-0002-6898-3205)
- Suhas S.P. Rao (ORCID: https://orcid.org/0009-0002-2353-3371)
- Lars Michael Steinmetz (ORCID: https://orcid.org/0000-0002-3962-2865)
- Muhammad S. Shamim (ORCID: https://orcid.org/0000-0002-2600-5147)
- Erez Lieberman Aiden (ORCID: https://orcid.org/0000-0003-0634-6486)
- Ragini Mahajan (ORCID: https://orcid.org/0000-0002-1038-0698)
- Chad J. Munger (ORCID: https://orcid.org/0000-0003-1906-1164)
- Andreas R. Gschwind (ORCID: https://orcid.org/0000-0002-0769-6907)
- Masato T. Kanemaki (ORCID: https://orcid.org/0000-0002-7657-1649)
- Eric S. Lander (ORCID: https://orcid.org/0000-0003-2662-4631)
- Maya U. Sheth (ORCID: https://orcid.org/0000-0003-1466-8899)
- Namita Mitra (ORCID: https://orcid.org/0000-0003-0654-0043)
- Drew T. Bergman (ORCID: https://orcid.org/0000-0002-8314-7088)
- Neva C. Durand (ORCID: https://orcid.org/0009-0006-5647-2623)
- Evelyn Jagoda
- Judhajeet Ray (ORCID: https://orcid.org/0000-0003-1524-2603)
- David Weisz (ORCID: https://orcid.org/0000-0001-5868-6672)
- Philine Guckelberger (ORCID: https://orcid.org/0000-0002-1057-2518)
- Joseph Nasser (ORCID: https://orcid.org/0000-0001-5941-5751)
- Charles P. Fulco (ORCID: https://orcid.org/0000-0002-6592-1279)
- Glen Munson
- Yingxuan Tan (ORCID: https://orcid.org/0000-0001-6674-3219)
- Ruqayya Khan (ORCID: https://orcid.org/0000-0001-7549-8761)
- Benjamin R. Doughty (ORCID: https://orcid.org/0000-0003-0447-4468)
- Saul Godinez Pulido (ORCID: https://orcid.org/0000-0003-2111-5491)
- J Engreitz (ORCID: https://orcid.org/0000-0002-5754-1719)
- Anthony S. Tan
- Xiangmeng Shawn Cai (ORCID: https://orcid.org/0000-0002-2466-4210)
Institutions
- Broad Institute (US)
- National Institute of Genetics (JP)
- Lucile Packard Children's Hospital (US)
- Harvard University (US)
- University of California, San Francisco (US)
- Baylor College of Medicine (US)
- Carnegie Institution for Science (US)
- The Graduate University for Advanced Studies, SOKENDAI (JP)
- Carnegie Department of Plant Biology (US)
- Stanford Medicine (US)
- European Molecular Biology Laboratory (DE)
- Max Planck Institute for Molecular Genetics (DE)
- Center for Theoretical Biological Physics (US)
- European Molecular Biology Laboratory (DE)
- Stanford Cardiovascular Institute (US)
- The University of Texas Medical Branch at Galveston (US)
- Massachusetts Institute of Technology (US)
- Rice University (US)
- The University of Tokyo (JP)
- Freie Universität Berlin (DE)
- Stanford University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-09-29
- DOI
- https://doi.org/10.1038/s41467-026-77582-1
- Primary Topic
- Genomics and Chromatin Dynamics
- Type
- article
- Field-Weighted Citation Impact
- 0.00