Skip to content
DraconiticResearch
Search Sources API
197,768 studies31 sourcesUpdated 33 min ago
Peer-reviewedCC BYNature communications

Quantitative changes in 3D contact predict changes in enhancer-promoter regulation upon cohesin depletion.

  • Philine Guckelberger1,2,3
  • Benjamin R. Doughty4
  • Glen Munson5
  • Suhas S.P. Rao6,7,8
  • Yingxuan Tan9,10,4
  • Xiangmeng Shawn Cai9,11,4
  • Charles P. Fulco1
  • Joseph Nasser1
  • Kristy S. Mualim4,12
  • Drew T. Bergman1
  • Judhajeet Ray5
  • Evelyn Jagoda5
17 more authors
  • Chad J. Munger9,4
  • Andreas R. Gschwind9,4
  • Maya U. Sheth9,11,4
  • Anthony S. Tan9,4
  • Saul Godinez Pulido13,8
  • Namita Mitra13,8
  • David Weisz13,8
  • Muhammad S. Shamim13,14,8
  • Neva C. Durand1,15,8
  • Ragini Mahajan13,16,8
  • Ruqayya Khan13,8
  • Lars Michael Steinmetz4,17,18
  • Masato T. Kanemaki19,20,21
  • Eric S. Lander1,22,23
  • Alexander Meissner1,2,3
  • Erez Lieberman Aiden13,15,8
  • Jesse M. Engreitz9,4,24,25,5
25 affiliations
  1. 1Broad Institute of MIT and Harvard, Cambridge, MA, USA
  2. 2Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin, Berlin, Germany
  3. 3Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany
  4. 4Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
  5. 5The Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA
  6. 6Department of Medicine, University of California San Francisco, San Francisco, CA, USA
  7. 7Department of Structural Biology, Stanford University, Stanford, CA, USA
  8. 8The Center for Genome Architecture, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
  9. 9Basic Sciences and Engineering Initiative, Betty Irene Moore Children’s Heart Center, Lucile Packard Children’s Hospital, Stanford, CA, USA
  10. 10Department of Computer Science, Stanford University, Stanford, CA, USA
  11. 11Department of Bioengineering, Stanford University, Stanford, CA, USA
  12. 12Department of Plant Biology, Carnegie Institute of Science, Stanford, CA, USA
  13. 13Center for Theoretical Biological Physics, Rice University, Houston, TX, USA
  14. 14Medical Student Training Program, Baylor College of Medicine, Houston, TX, USA
  15. 15Department of Computer Science, Rice University, Houston, TX, USA
  16. 16Department of BioSciences, Rice University, Houston, TX, USA
  17. 17European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany
  18. 18Stanford Genome Technology Center, Palo Alto, CA, USA
  19. 19Department of Biological Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
  20. 20Department of Chromosome Science, National Institute of Genetics, Research Organization of Information and Systems (ROIS), Yata 1111, Shizuoka, Mishima 411-8540, Japan
  21. 21Graduate Institute for Advanced Studies, SOKENDAI, Yata 1111, Shizuoka, Mishima 411-8540, Japan
  22. 22Department of Biology, MIT, Cambridge, MA, USA
  23. 23Department of Systems Biology, Harvard Medical School, Boston, MA, US
  24. 24Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
  25. 25Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA
Read full textPDFDOICite

Abstract

Enhancers are key drivers of gene regulation thought to act via 3D physical interactions with the promoters of their target genes. However, genome-wide depletions of architectural proteins such as cohesin result in only limited changes in gene expression, despite a loss of contact domains and loops. Consequently, the role of cohesin and 3D contacts in enhancer function remains debated. Here, we developed CRISPRi of regulatory elements upon degron operation (CRUDO), a novel approach to measure how changes in contact frequency impact enhancer effects on target genes by perturbing enhancers with CRISPRi and measuring gene expression in the presence or absence of cohesin. We systematically perturbed all 1,039 candidate enhancers near five cohesin-dependent genes and identified 34 enhancer-gene regulatory interactions. Of 26 regulatory interactions with sufficient statistical power to evaluate cohesin dependence, 18 show cohesin-dependent effects. A decrease in enhancer-promoter contact frequency upon removal of cohesin is frequently accompanied by a decrease in the regulatory effect of the enhancer on gene expression, consistent with a contact-based model for enhancer function. However, changes in contact frequency and regulatory effects on gene expression vary as a function of distance, with distal enhancers (e.g., >50Kb) experiencing much larger changes than proximal ones (e.g., <50Kb). Because most enhancers are located close to their target genes, these observations can explain how only a small subset of genes - those with strong distal enhancers - are sensitive to cohesin. Together, our results illuminate how 3D contacts, influenced by both cohesin and genomic distance, tune enhancer effects on gene expression.

Related

  1. Dynamic merging of enhancer- and promoter-associated assemblies is coupled to transcriptional bursting
    Q. Lin, B. Wang, Y. Liu +9
    bioRxivPreprintAll rights reservedFull textMolecular biology & gene regulationbioRxiv
  2. Enhancer-promoter proximity predicts transcriptional competence but not transcriptional output in the Drosophila brain
    Olivier Messina, Loucif Remini, Christopher H. Bohrer +4
    arXivPreprintCC BY-NC-SA 4.0Full textBiophysicsGenetics & genomicsarXiv
  3. Insulators As Dynamic, Tunable Regulators of Enhancer-Promoter Coordination in Living Drosophila Embryos
    N. Buitrago, C. Nieto, A. Singh +1
    bioRxivPreprintCC BY-NC-NDFull textMolecular biology & gene regulationbioRxiv
  4. Epigenetic Rewiring of Enhancer–Promoter Interactions in Cancer: Mechanisms and Therapeutic Implications
    Lavanya Choppavarapu, Bakhtiyor Nosirov, Michael Kahn +1
    CancersPeer-reviewedCC BY 4.0Molecular biology & gene regulationCrossref
  5. Recurrent enhancer-promoter interactions across samples
    Matthew Weston, Satvik Gunjala, Haiyan Hu +1
    PLOS OnePeer-reviewedCC BYFull textMolecular biology & gene regulationBioinformatics & computational biologyPLOSEurope PMCPMC

Cite

BibTeXRIS
BibTeX
@article{guckelberger2026quantitative,
  title = {{Quantitative changes in 3D contact predict changes in enhancer-promoter regulation upon cohesin depletion.}},
  author = {Philine Guckelberger and Benjamin R. Doughty and Glen Munson and Suhas S.P. Rao and Yingxuan Tan and Xiangmeng Shawn Cai and Charles P. Fulco and Joseph Nasser and Kristy S. Mualim and Drew T. Bergman and Judhajeet Ray and Evelyn Jagoda and Chad J. Munger and Andreas R. Gschwind and Maya U. Sheth and Anthony S. Tan and Saul Godinez Pulido and Namita Mitra and David Weisz and Muhammad S. Shamim and Neva C. Durand and Ragini Mahajan and Ruqayya Khan and Lars Michael Steinmetz and Masato T. Kanemaki and Eric S. Lander and Alexander Meissner and Erez Lieberman Aiden and Jesse M. Engreitz},
  journal = {Nature communications},
  year = {2026},
  month = sep,
  doi = {10.1038/s41467-026-77582-1},
  url = {https://europepmc.org/article/MED/42957655},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Quantitative changes in 3D contact predict changes in enhancer-promoter regulation upon cohesin depletion.
AU  - Philine Guckelberger
AU  - Benjamin R. Doughty
AU  - Glen Munson
AU  - Suhas S.P. Rao
AU  - Yingxuan Tan
AU  - Xiangmeng Shawn Cai
AU  - Charles P. Fulco
AU  - Joseph Nasser
AU  - Kristy S. Mualim
AU  - Drew T. Bergman
AU  - Judhajeet Ray
AU  - Evelyn Jagoda
AU  - Chad J. Munger
AU  - Andreas R. Gschwind
AU  - Maya U. Sheth
AU  - Anthony S. Tan
AU  - Saul Godinez Pulido
AU  - Namita Mitra
AU  - David Weisz
AU  - Muhammad S. Shamim
AU  - Neva C. Durand
AU  - Ragini Mahajan
AU  - Ruqayya Khan
AU  - Lars Michael Steinmetz
AU  - Masato T. Kanemaki
AU  - Eric S. Lander
AU  - Alexander Meissner
AU  - Erez Lieberman Aiden
AU  - Jesse M. Engreitz
PY  - 2026
DA  - 2026/09/29
JO  - Nature communications
DO  - 10.1038/s41467-026-77582-1
UR  - https://europepmc.org/article/MED/42957655
AB  - Enhancers are key drivers of gene regulation thought to act via 3D physical interactions with the promoters of their target genes. However, genome-wide depletions of architectural proteins such as cohesin result in only limited changes in gene expression, despite a loss of contact domains and loops. Consequently, the role of cohesin and 3D contacts in enhancer function remains debated. Here, we developed CRISPRi of regulatory elements upon degron operation (CRUDO), a novel approach to measure how changes in contact frequency impact enhancer effects on target genes by perturbing enhancers with CRISPRi and measuring gene expression in the presence or absence of cohesin. We systematically perturbed all 1,039 candidate enhancers near five cohesin-dependent genes and identified 34 enhancer-gene regulatory interactions. Of 26 regulatory interactions with sufficient statistical power to evaluate cohesin dependence, 18 show cohesin-dependent effects. A decrease in enhancer-promoter contact frequency upon removal of cohesin is frequently accompanied by a decrease in the regulatory effect of the enhancer on gene expression, consistent with a contact-based model for enhancer function. However, changes in contact frequency and regulatory effects on gene expression vary as a function of distance, with distal enhancers (e.g., >50Kb) experiencing much larger changes than proximal ones (e.g., <50Kb). Because most enhancers are located close to their target genes, these observations can explain how only a small subset of genes - those with strong distal enhancers - are sensitive to cohesin. Together, our results illuminate how 3D contacts, influenced by both cohesin and genomic distance, tune enhancer effects on gene expression.
SN  - 2041-1723
ER  -