Building regulatory landscapes: enhancer recruits cohesin to create contact domains, engage CTCF sites and activate distant genes
Open accessAbstract
Developmental gene expression is often controlled by distal tissue-specific enhancers. Enhancer action is restricted to topological chromatin domains, typically formed by cohesin-mediated loop extrusion between CTCF-associated boundaries. To better understand how individual regulatory DNA elements form topological domains and control expression, we used a bottom-up approach, building active regulatory landscapes of different sizes in inactive chromatin. We demonstrate that transcriptional output and protection against gene silencing reduces with increased enhancer distance, but that enhancer contact frequencies alone do not dictate transcription activity. The enhancer recruits cohesin to stimulate the formation of local chromatin contact domains and activate flanking CTCF sites for engagement in chromatin looping. Small contact domains can support strong and stable expression of distant genes. The enhancer requires transcription factors and mediator to activate genes over all distance ranges, but relies on cohesin exclusively for the activation of distant genes. Our work supports a model that assigns two functions to enhancers: its classic role to stimulate transcription initiation and elongation from target gene promoters and a role to recruit cohesin for the creation of contact domains, the engagement of flanking CTCF sites in chromatin looping, and the activation of distal target genes.
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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 [19]
The Introduction and the section on cohesin-dependent gene activation (pages not provided) report mild cohesin reliance at 47 kb, strong reliance at 100 kb or more, and none at 11 kb or less. This supports the possibility of reliance at an intermediate separation, but the paper does not establish that this is much shorter than previously appreciated from synthetic loci or artificial enhancer activation systems. (LLM, conf=0.83)
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Flagged first, then by citations
Research works printed but not linked: 7
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- Authors
- Rinzema, N. J., Sofiadis, K., Tjalsma, S. J. D., Verstegen, M. J. A. M., Oz, Y., Valdes-Quezada, C., Felder, A.-K., Filipovska, T., van der Elst, S., de Andrade dos Ramos, Z., Han, R., Krijger, P. H. L., & de Laat, W.
- Affiliations
- University Medical Center Utrecht (NL)
- ORCID
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2021-10-05
- OpenAlex
- W3202194297
- Cited by
- 8
- References
- 16
- Citations by year
- 2024: 1 · 2023: 4 · 2022: 3
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Funders
- Fondation Leducq (14CVD01)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (724.012.003)
- Oncode Institute
- 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
- enhancers, cohesin, CTCF, chromatin looping, topological domains, loop extrusion, gene activation, gene silencing, Mediator complex, transcription factors, chromatin structure, developmental gene expression
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