Transcriptional regulation and chromatin architecture maintenance are decoupled functions at the Sox2 locus
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Abstract
How distal regulatory elements control gene transcription and chromatin topology is not clearly defined, yet these processes are closely linked in lineage specification during development. Through allele-specific genome editing and chromatin interaction analyses of the Sox2 locus in mouse embryonic stem cells, we found a striking disconnection between transcriptional control and chromatin architecture. We traced nearly all Sox2 transcriptional activation to a small number of key transcription factor binding sites, whose deletions have no effect on promoter–enhancer interaction frequencies or topological domain organization. Local chromatin architecture maintenance, including at the topologically associating domain (TAD) boundary downstream from the Sox2 enhancer, is widely distributed over multiple transcription factor-bound regions and maintained in a CTCF-independent manner. Furthermore, partial disruption of promoter–enhancer interactions by ectopic chromatin loop formation has no effect on Sox2 transcription. These findings indicate that many transcription factors are involved in modulating chromatin architecture independently of CTCF.
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These findings clarify previous reports suggesting that 3D genome folding may be largely decoupled from long-range regulation, which were based on studying Sox2.
“These findings clarify previous reports suggesting that 3D genome folding may be largely decoupled from long-range regulation, which were based on studying Sox2 (39, 41).”
From Synergy between regulatory elements can render cohesin dispensable for distal enhancer function (2026) · cites this paper as [41]
These findings explain how strong CTCF insulators can be bypassed at the Sox2 locus.
“Moreover, they explain how strong CTCF insulators can be bypassed at the Sox2 locus (31, 40, 41).”
From Synergy between regulatory elements can render cohesin dispensable for distal enhancer function (2026) · cites this paper as [41]
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Cited by
Sorted by citations
Synergy between regulatory elements can render cohesin dispensable for distal enhancer function
Hansen, K. L., Adachi, A. S., Braccioli, L., Kadvani, S., Boileau, R. M., Martinovic, M., Pokorny, B., Shah, R., Anderson, E. C., Zhang, K., et al. (2026) · Science · doi:10.1126/science.adt4221 · Cited by 29 · see citing works
- Authors
- Taylor, T., Sikorska, N., Shchuka, V. M., Chahar, S., Ji, C., Macpherson, N. N., Moorthy, S. D., de Kort, M. A. C., Mullany, S., Khader, N., Gillespie, Z. E., Langroudi, L., Tobias, I. C., Lenstra, T. L., Mitchell, J. A., & Sexton, T.
- Affiliations
- University of Toronto (CA)
- Centre National de la Recherche Scientifique (FR)
- The Netherlands Cancer Institute (NL)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2022-06-01
- Volume
- 36
- Issue
- 11-12
- Pages
- 699-717
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC9296009
- OpenAlex
- W4283026547
- Cited by
- 45
- References
- 24
- Citations by year
- 2026: 12 · 2025: 11 · 2024: 8 · 2023: 10 · 2022: 4
- Type
- posted content
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Genes & Development (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Funders
- European Research Council
- European Union's Horizon 2020 research and innovation program (678624)
- ATIP-Avenir (ANR-10-LABX-0030-INRT)
- Agence Nationale de la Recherche
- Investissements d'Avenir (ANR-10-IDEX-0002-02)
- Institut National de la Santé et de la Recherche Médicale
- Canadian Institutes of Health Research (FRN 153186)
- National Institutes of Health (R01-HG010045-01)
- Canada Foundation for Innovation
- Ontario Ministry of Research and Innovation
- Natural Sciences and Engineering Research Council of Canada (Canadian Graduate Scholarship)
- Oncode Institute
- Dutch Cancer Society
- 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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- SOX2, transcriptional regulation, chromatin structure, topologically associating domains, TAD boundaries, enhancer-promoter interactions, chromatin looping, transcription factor binding sites, enhancers, mouse embryonic stem cells, lineage specification
- MeSH terms
- Animals, Chromatin, Enhancer Elements, Genetic, Promoter Regions, Genetic, Transcription Factors, Gene Expression Regulation, Developmental, Mice, SOXB1 Transcription Factors
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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