Spatial enhancer clustering and regulation of enhancer-proximal genes by cohesin
Open accessAbstract
In addition to mediating sister chromatid cohesion during the cell cycle, the cohesin complex associates with CTCF and with active gene regulatory elements to form long-range interactions between its binding sites. Genome-wide chromosome conformation capture had shown that cohesin's main role in interphase genome organization is in mediating interactions within architectural chromosome compartments, rather than specifying compartments per se. However, it remains unclear how cohesin-mediated interactions contribute to the regulation of gene expression. We have found that the binding of CTCF and cohesin is highly enriched at enhancers and in particular at enhancer arrays or “super-enhancers” in mouse thymocytes. Using local and global chromosome conformation capture, we demonstrate that enhancer elements associate not just in linear sequence, but also in 3D, and that spatial enhancer clustering is facilitated by cohesin. The conditional deletion of cohesin from noncycling thymocytes preserved enhancer position, H3K27ac, H4K4me1, and enhancer transcription, but weakened interactions between enhancers. Interestingly, ∼50% of deregulated genes reside in the vicinity of enhancer elements, suggesting that cohesin regulates gene expression through spatial clustering of enhancer elements. We propose a model for cohesin-dependent gene regulation in which spatial clustering of enhancer elements acts as a unified mechanism for both enhancer-promoter “connections” and “insulation.”
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In an enhancer chain, not all enhancers need to contact the gene promoter directly; the signal could be passed along the chain.
“In this mechanism, not all of the enhancers need to contact the gene promoter directly; rather, the signal could be passed along the chain.”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [489]
There is evidence for enhancer-enhancer interactions that create an enhancer chain or network.
“there is also evidence for enhancer–enhancer interactions that create an enhancer “chain” or network [486–489].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [489]
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- Authors
- Ing-Simmons, E., Seitan, V. C., Faure, A. J., Flicek, P., Carroll, T., Dekker, J., Fisher, A. G., Lenhard, B., & Merkenschlager, M.
- Affiliations
- Imperial College London (GB)
- European Bioinformatics Institute (GB)
- University of Massachusetts Chan Medical School (US)
- Corresponding author
- Merkenschlager, Matthias
- ORCID
- Venue
- Genome Research
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2015-02-12
- Volume
- 25
- Issue
- 4
- Pages
- 504-513
- ISSN
- 1088-9051 (ISSN-L)
- 1549-5469
- PMC
- PMC4381522
- OpenAlex
- W2149454526
- Cited by
- 167
- References
- 14
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 9 · 2023: 16 · 2022: 12 · 2021: 21 · 2020: 16 · 2019: 15 · 2018: 25 · 2017: 14 · 2016: 18 · 2015: 10
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genome Research (publishedVersion)
- Research Portal (King's College London) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion, cc-by-nc)
- Spiral (Imperial College London) (submittedVersion)
- Funders
- Wellcome Trust
- Medical Research Council
- 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 › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Keywords
- cohesin, super-enhancers, CTCF, 3D genome organization, long-range enhancer-promoter interactions, thymocytes, H3K27ac, enhancer transcription, gene expression regulation, chromosome conformation capture
- MeSH terms
- CCCTC-Binding Factor, Cohesins, Animals, Binding Sites, Cells, Cultured, Chromosomal Proteins, Non-Histone, Enhancer Elements, Genetic, Gene Expression Regulation, Multigene Family, Histones, Promoter Regions, Genetic, Protein Binding, Repressor Proteins, Cell Cycle Proteins, Mice, Thymocytes
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