Cohesin is required for long-range enhancer action at the Shh locus
Open accessAbstract
The regulatory landscapes of developmental genes in mammals can be complex, with enhancers spread over many hundreds of kilobases. It has been suggested that three-dimensional genome organization, particularly topologically associating domains formed by cohesin-mediated loop extrusion, is important for enhancers to act over such large genomic distances. By coupling acute protein degradation with synthetic activation by targeted transcription factor recruitment, here we show that cohesin, but not CTCF, is required for activation of the target gene Shh by distant enhancers in mouse embryonic stem cells. Cohesin is not required for activation directly at the promoter or by an enhancer located closer to the Shh gene. Our findings support the hypothesis that chromatin compaction via cohesin-mediated loop extrusion allows for genes to be activated by enhancers that are located many hundreds of kilobases away in the linear genome and suggests that cohesin is dispensable for enhancers located more proximally.
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Reliance on cohesin can arise at much shorter genomic separation than previously appreciated from synthetic loci or artificial enhancer activation systems.
“Our observations also clarify that reliance on cohesin can arise at much shorter genomic separation than previously appreciated from synthetic loci or artificial enhancer activation systems (19, 20).”
From Synergy between regulatory elements can render cohesin dispensable for distal enhancer function (2026) · cites this paper as [20]
The Discussion reports that cohesin is required for Shh activation from enhancers more than 400 kb away, but dispensable for an enhancer 100 kb away; the Introduction identifies the study as using synthetic transcriptional activators. The paper therefore supports an example of cohesin reliance at a specified separation, but does not establish the claim’s comparison that this is much shorter than previously appreciated from synthetic loci or artificial activation systems. (LLM, conf=0.83)
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Synergy between regulatory elements can render cohesin dispensable for distal enhancer function
Hansen, K. L., Adachi, A. S., Braccioli, L., Kadvani, S., Boileau, R. M., Martinovic, M., Pokorny, B., Shah, R., Anderson, E. C., Zhang, K., et al. (2026) · Science · doi:10.1126/science.adt4221 · Cited by 29 · see citing works
- Authors
- Kane, L., Williamson, I., Flyamer, I. M., Kumar, Y., Hill, R. E., Lettice, L. A., & Bickmore, W. A.
- Affiliations
- Institute of Genetics and Cancer (GB)
- Corresponding author
- Bickmore, Wendy A.
- ORCID
- Venue
- Nature Structural & Molecular Biology
- Published
- 2022-09
- Volume
- 29
- Issue
- 9
- Pages
- 891-897
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- PMC
- PMC7613721
- OpenAlex
- W4295509862
- Cited by
- 153
- References
- 15
- Citations by year
- 2026: 29 · 2025: 57 · 2024: 36 · 2023: 25 · 2022: 3 · 2021: 3
- FWCI
- 9.88
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Funders
- Medical Research Council (MC_UU_00007/8, MC_UU_00007/2)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Keywords
- cohesin, long-range enhancers, Sonic hedgehog, loop extrusion, topologically associating domains, 3D genome organization, enhancer-promoter interactions, CTCF, chromatin condensation, mouse embryonic stem cells, enhancer activation
- MeSH terms
- CCCTC-Binding Factor, Cohesins, Animals, Chromatin, Chromosomal Proteins, Non-Histone, Enhancer Elements, Genetic, Mammals, Transcription Factors, Cell Cycle Proteins, Mice, Hedgehog Proteins
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