Building regulatory landscapes reveals that an enhancer can recruit cohesin to create contact domains, engage CTCF sites and activate distant genes
Open accessAbstract
Developmental gene expression is often controlled by distal regulatory DNA elements called enhancers. Distant enhancer action is restricted to structural chromosomal domains that are flanked by CTCF-associated boundaries and formed through cohesin chromatin loop extrusion. To better understand how enhancers, genes and CTCF boundaries together form structural domains and control expression, we used a bottom-up approach, building series of active regulatory landscapes in inactive chromatin. We demonstrate here that gene transcription levels and activity over time reduce with increased enhancer distance. The enhancer recruits cohesin to stimulate domain formation and engage flanking CTCF sites in loop formation. It requires cohesin exclusively for the activation of distant genes, not of proximal genes, with nearby CTCF boundaries supporting efficient long-range enhancer action. Our work supports a dual activity model for enhancers: its classic role of stimulating transcription initiation and elongation from target gene promoters and a role of recruiting cohesin for the creation of chromosomal domains, the engagement of CTCF sites in chromatin looping and the activation of distal target genes.
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The probability of promoter activation by an enhancer also decreases with increasing genomic distance, although the relationship is not linear.
“Accordingly, the probability of promoter activation by an enhancer also decreases with increasing genomic distance [113,114], although the relationship is not linear [113].”
From Enhancer Function in the 3D Genome (2023) · cites this paper as [114]
The Results section (‘Increased E-P distances lower expression level and stability’; page unavailable) reports that the fraction of cells whose reporter gene was silenced increased as enhancer–promoter distance grew. A separate Results section (‘E-P contacts do not strictly dictate transcription activity’; page unavailable) calls the relationship between contact frequency and transcriptional activity non-linear, but does not establish a non-linear relationship between genomic distance and the probability of promoter activation. (LLM, conf=0.84)
Experimental — accuracy not yet measuredCohesin is required to establish/maintain long-range contacts (100 kb) between enhancer and promoter but does not play a role in maintaining contacts at close distances.
“Consistent with these observations, it was shown in model experiments that cohesin is required to establish/maintain long-range contacts (100 kb) between enhancer and promoter but does not play a role in maintaining contacts at close distances [114].”
From Enhancer Function in the 3D Genome (2023) · cites this paper as [114]
In Results > Enhancer recruits cohesin to form domains and CTCF loops (page unavailable), cohesin depletion caused loss of enhancer-induced contacts in the E100 and E407 distal configurations. Results > Cohesin needed for distal but not proximal enhancer action (page unavailable) shows that proximal gene activation did not require cohesin, but it does not establish that close-range enhancer–promoter contacts were maintained without cohesin. The claim conflates proximal activation with proximal contact maintenance. (LLM, conf=0.86)
Experimental — accuracy not yet measured
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Synergy between regulatory elements can render cohesin dispensable for distal enhancer function
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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
- Nature Structural & Molecular Biology
- Published
- 2022-06
- Volume
- 29
- Issue
- 6
- Pages
- 563-574
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- PMC
- PMC9205769
- OpenAlex
- W4282960707
- Cited by
- 166
- References
- 26
- Citations by year
- 2026: 26 · 2025: 57 · 2024: 42 · 2023: 33 · 2022: 8
- FWCI
- 11.43
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nature Structural & Molecular Biology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (publishedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Funders
- Fondation Leducq (14CVD01)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (724.012.003, OCENW.GROOT.2019.012)
- 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 loop extrusion, chromatin domains, gene activation, chromatin looping, chromatin boundaries, transcriptional regulation, inactive chromatin
- MeSH terms
- CCCTC-Binding Factor, Cohesins, Binding Sites, Chromatin, Chromosomal Proteins, Non-Histone, Enhancer Elements, Genetic, Cell Cycle Proteins
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