Analysis of sub-kilobase chromatin topology reveals nano-scale regulatory interactions with variable dependence on cohesin and CTCF
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Abstract
Enhancers and promoters predominantly interact within large-scale topologically associating domains (TADs), which are formed by loop extrusion mediated by cohesin and CTCF. However, it is unclear whether complex chromatin structures exist at sub-kilobase-scale and to what extent fine-scale regulatory interactions depend on loop extrusion. To address these questions, we present an MNase-based chromosome conformation capture (3C) approach, which has enabled us to generate the most detailed local interaction data to date (20 bp resolution) and precisely investigate the effects of cohesin and CTCF depletion on chromatin architecture. Our data reveal that cis -regulatory elements have distinct internal nano-scale structures, within which local insulation is dependent on CTCF, but which are independent of cohesin. In contrast, we find that depletion of cohesin causes a subtle reduction in longer-range enhancer-promoter interactions and that CTCF depletion can cause rewiring of regulatory contacts. Together, our data show that loop extrusion is not essential for enhancer-promoter interactions, but contributes to their robustness and specificity and to precise regulation of gene expression.
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Cohesin depletion significantly suppresses the activation of inducible genes, especially when the enhancer is located at a significant distance from the promoter.
“At the same time, cohesin depletion significantly suppresses the activation of inducible genes, especially when the enhancer is located at a significant distance from the promoter [120,121,122].”
From Enhancer Function in the 3D Genome (2023) · cites this paper as [121]
The Results report reduced expression of several genes in mouse embryonic stem cells after cohesin depletion, and the Discussion reports little change in enhancer–promoter interactions below 5 kb but reductions in interactions and expression at loci spanning about 20 and 50 kb. The paper did not test activation of inducible genes in those experiments; it describes the importance of cohesin for gene expression upon stimuli as consistent with other reports. Thus, the specific claim about significantly suppressed activation of inducible genes goes beyond its findings. (LLM, conf=0.85)
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Osato, N., & Hamada, M. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.01.20.573595 · Cited by 1 · see citing works
Wagner, T., Priyanka, P., Micheletti, R., Friedman, M. J., Nair, S. J., Gamliel, A., Taylor, H., Song, X., Cho, M., Oh, S., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.05.17.594600 · Cited by 1 · see citing works
Karpińska, M. A., Zhu, Y., Ghazvini, Z. F., Ramasamy, S., Barbieri, M., Cao, T. B. N., Varahram, N., Aljahani, A., Lidschreiber, M., Papantonis, A., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.11.20.624447 · Cited by 1 · see citing works
Self-citation
- Authors
- Aljahani, A., Hua, P., Karpinska, M. A., Quililan, K., Davies, J. O. J., & Oudelaar, A. M.
- Affiliations
- Max Planck Institute for Multidisciplinary Sciences (DE)
- University of Oxford (GB)
- Corresponding author
- Davies, James O. J.
- Oudelaar, A. Marieke
- ORCID
- Venue
- Nature Communications
- Published
- 2022-04-19
- Volume
- 13
- Issue
- 1
- Pages
- 2139-2139
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC9019034
- OpenAlex
- W4226081743
- Cited by
- 121
- References
- 73
- Citations by year
- 2026: 15 · 2025: 24 · 2024: 35 · 2023: 34 · 2022: 13
- FWCI
- 8.65
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
- Funders
- Max-Planck-Gesellschaft
- Medical Research Council (MR/R008108/1, MC_UU_00029/4, MR/R008108, MC_UU_00021/2)
- 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 › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Keywords
- chromatin topology, loop extrusion, cohesin, CTCF, topologically associating domains, enhancer-promoter interactions, cis-regulatory elements, chromatin insulation, 3C, gene expression regulation
- MeSH terms
- CCCTC-Binding Factor, Cohesins, Chromatin, Chromosomal Proteins, Non-Histone, Chromosomes, Cell Cycle Proteins
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