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Cited by 162Genomics and Chromatin DynamicsChromatin Remodeling and CancerEpigenetics and DNA Methylation

WAPL maintains a cohesin loading cycle to preserve cell-type-specific distal gene regulation

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Liu, Ning Qing, Maresca, Michela, van den Brand, Teun, Braccioli, Luca, Schijns, Marijne M. G. A., Teunissen, Hans, Bruneau, Benoit G., Nora, Elphѐge P. +1 more·2021·Nature Genetics
DOI 10.1038/s41588-020-00744-4PMC PMC7610352

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Abstract

The cohesin complex has an essential role in maintaining genome organization. However, its role in gene regulation remains largely unresolved. Here we report that the cohesin release factor WAPL creates a pool of free cohesin, in a process known as cohesin turnover, which reloads it to cell-type-specific binding sites. Paradoxically, stabilization of cohesin binding, following WAPL ablation, results in depletion of cohesin from these cell-type-specific regions, loss of gene expression and differentiation. Chromosome conformation capture experiments show that cohesin turnover is important for maintaining promoter-enhancer loops. Binding of cohesin to cell-type-specific sites is dependent on the pioneer transcription factors OCT4 (POU5F1) and SOX2, but not NANOG. We show the importance of cohesin turnover in controlling transcription and propose that a cycle of cohesin loading and off-loading, instead of static cohesin binding, mediates promoter and enhancer interactions critical for gene regulation.

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  • GSEA underscored disruption of developmentally relevant pathways without highlighting cell cycle terms in NIPBL-depleted ESCs, in contrast to cohesin-depleted ESCs.

    “Gene set enrichment analysis (GSEA) underscored the disruption of developmentally relevant pathways without highlighting cell cycle terms, in contrast to cohesin-depleted ESCs (fig. S5) (7).”

    From Synergy between regulatory elements can render cohesin dispensable for distal enhancer function (2026) · cites this paper as [7]

    The Results section, “WAPL is required for maintaining the pluripotent transcriptional state” (page unavailable), reports GSEA enrichment for developmental processes and no strong enrichment for cell-cycle categories, but these findings concern WAPL-depleted, not NIPBL-depleted, mouse ESCs. The Results section, “Cohesin is required for maintaining pluripotency-specific gene expression” (page unavailable), reports RAD21 depletion and similar expression changes to WAPL depletion; it does not establish the claimed GSEA contrast with NIPBL-depleted ESCs. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Depleting RAD21 or CTCF also down-regulated Car2.

    “Depleting RAD21 or CCCTC-binding factor (CTCF) also down-regulated Car2 (fig. S12C) (7, 30)”

    From Synergy between regulatory elements can render cohesin dispensable for distal enhancer function (2026) · cites this paper as [7]

    The Results section on cohesin and pluripotency-specific gene expression reports that RAD21 depletion decreased expression of Sik1, Hsf2bp and Rrp1b, but does not mention Car2. A search for Car2 found no passage in our copy, and the passages on CTCF do not report Car2 expression after CTCF depletion. Page numbers are unavailable in our copy. (LLM, conf=0.76)

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Cited by

Sorted by citations

Authors
Liu, N. Q., Maresca, M., van den Brand, T., Braccioli, L., Schijns, M. M. G. A., Teunissen, H., Bruneau, B. G., Nora, E. P., & de Wit, E.
Affiliations
  • The Netherlands Cancer Institute (NL)
  • Gladstone Institutes (US)
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2020-12-14
Volume
53
Issue
1
Pages
100-109
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/s41588-020-00744-4
PMC
PMC7610352
OpenAlex
W3112289427
Cited by
162
References
24
Citations by year
2026: 27 · 2025: 27 · 2024: 16 · 2023: 29 · 2022: 38 · 2021: 23 · 2020: 2
FWCI
7.37
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Genetics (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
Nederlandse Organisatie voor Wetenschappelijk Onderzoek (016.161.316)
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 › Epigenetics and DNA Methylation
Keywords
WAPL, cohesin loading, cell type-specific gene regulation, chromatin looping, Oct4, SOX2, Nanog, pioneer transcription factors, cell differentiation, gene expression, chromosome conformation capture
MeSH terms
Mouse Embryonic Stem Cells, Cohesins, Animals, Binding Sites, Cell Differentiation, Cell Line, Chromatin, Chromosomal Proteins, Non-Histone, DNA-Binding Proteins, Enhancer Elements, Genetic, Gene Expression Regulation, Models, Biological, Proteins, Transcription Factors, Transcription, Genetic, Cell Cycle Proteins, Pluripotent Stem Cells, Mice

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