Cohesin-Dependent and -Independent Mechanisms Mediate Chromosomal Contacts between Promoters and Enhancers
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Abstract
Abstract It is currently assumed that 3D chromosomal organisation plays a central role in transcriptional control. However, recent evidence shows that steady-state transcription of only a minority of genes is affected by depletion of architectural proteins such as cohesin and CTCF. Here, we have used Capture Hi-C to interrogate the dynamics of chromosomal contacts of all human gene promoters upon rapid architectural protein degradation. We show that promoter contacts lost in these conditions tend to be long-range, with at least one interaction partner localising in the vicinity of topologically associated domain (TAD) boundaries. In contrast, many shorter-range chromosomal contacts, particularly those that connect active promoters with each other and with active enhancers remain unaffected by cohesin and CTCF depletion. We demonstrate that the effects of cohesin depletion on nascent transcription can be explained by changes in the connectivity of their enhancers. Jointly, these results provide a mechanistic explanation to the limited, but consistent effects of cohesin and CTCF on steady-state transcription and point towards the existence of alternative enhancer-promoter pairing mechanisms that are independent of these proteins.
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Deletion or degradation of cohesin or CTCF in differentiated cells has only mild effects on gene expression.
“Surprisingly however, deletion or degradation of cohesin or CTCF in differentiated cells has only mild effects on gene expression [344–349].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [349]
The Introduction says steady-state gene expression is less affected by architectural-protein depletion, and the Results report that most genes were relatively unperturbed after cohesin depletion. But the Introduction also says cohesin depletion impairs activation of inducible genes, so the unqualified claim about gene expression is broader than the paper supports. The paper’s experiments used HeLa Kyoto cells and protein degradation, not deletion. (LLM, conf=0.83)
Experimental — accuracy not yet measuredLoops that require CTCF might be preferentially long-range (>100 kb) and situated in loci where enhancers are generally sparse.
“recent studies suggest that loops that require CTCF might be preferentially long-range (> 100 kb) and situated in loci where enhancers are generally sparse [301, 349].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [349]
The Results section (“Cohesin-Dependent and -Independent Promoter Interactions Have Distinct Properties”; page unavailable) associates longer interaction distances with cohesin-dependent contacts and reports CTCF binding at contacts lost upon cohesin depletion. The Discussion (page unavailable) reports relatively fewer active enhancer-containing interacting regions among those contacts. These findings do not establish a >100 kb threshold, show that the loops require CTCF specifically, or demonstrate that their surrounding loci are generally enhancer-sparse. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPromoter Capture Hi-C-based studies did not observe a significant change in enhancer-promoter contacts upon RNAP inhibition, including in cells rapidly depleted of cohesin or CTCF.
“However, Promoter Capture Hi-C-based studies did not observe a significant change in enhancer–promoter contacts upon RNAP inhibition, including in cells rapidly depleted of cohesin or CTCF [349, 380].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [349]
The Results section on cohesin-dependent and -independent promoter interactions reports that the RNA polymerase II inhibitor triptolide had only a mild effect on promoter interaction profiles. It does not say the effect was statistically insignificant or report that inhibition was tested in cells simultaneously depleted of cohesin or CTCF. A separate Results section reports substantial rewiring of contacts after architectural-protein depletion alone. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe number of enhancers correlates with the expression level of a gene across cell types.
“the number of enhancers correlates with the expression level of a gene across cell types [243, 278, 279, 349].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [349]
The Results section (page unavailable) reports that changes in the number of promoter-connected active enhancers were associated with the direction of transcriptional change after cohesin depletion. It does not establish that the number of enhancers correlates with a gene’s expression level across cell types; the reported association concerns changes within the studied cells. (LLM, conf=0.84)
Experimental — accuracy not yet measuredSignificant numbers of enhancer-promoter contacts remain unaffected upon rapid degradation of cohesin or CTCF, and some contacts even appear de novo.
“Consistent with this, significant numbers of enhancer–promoter contacts remain unaffected upon rapid degradation of these proteins, and some contacts even appear de novo [349, 350].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [349]
Cohesin-dependent enhancers tend to be longer-range than their cohesin-independent counterparts.
“Cohesin-dependent enhancers also tend to be longer-range than their cohesin-independent counterparts [301, 349, 514].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [349]
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- Authors
- Thiecke, M. J., Wutz, G., Muhar, M., Tang, W., Bevan, S., Malysheva, V., Stocsits, R., Neumann, T., Zuber, J., Fraser, P., Schoenfelder, S., Peters, J.-M., & Spivakov, M.
- Affiliations
- Babraham Institute (GB)
- Research Institute of Molecular Pathology (AT)
- Florida State University (US)
- Corresponding author
- Spivakov, Mikhail
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2020-07
- Volume
- 32
- Issue
- 3
- Pages
- 107929
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC7383238
- OpenAlex
- W3044693806
- Cited by
- 177
- References
- 43
- Citations by year
- 2026: 18 · 2025: 27 · 2024: 25 · 2023: 30 · 2022: 28 · 2021: 42 · 2020: 7
- FWCI
- 8.68
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by-nc-nd)
- ETH Zürich Research Collection
- Funders
- 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, CTCF, enhancer-promoter interactions, 3D genome organization, chromatin looping, transcriptional regulation, Capture Hi-C, SLAM-seq
- MeSH terms
- Cohesins, Chromatin, Chromosomal Proteins, Non-Histone, Chromosomes, DNA-Binding Proteins, Enhancer Elements, Genetic, Gene Expression Regulation, HeLa Cells, Humans, Promoter Regions, Genetic, Transcription, Genetic, Cell Cycle Proteins
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