Chromatin interaction analyses elucidate the roles of PRC2-bound silencers in mouse development
Open accessAbstract
Lineage-specific gene expression is modulated by a balance between transcriptional activation and repression during animal development. Knowledge about enhancer-centered transcriptional activation has advanced considerably, but silencers and their roles in normal development remain poorly understood. Here, we performed chromatin interaction analyses of Polycomb repressive complex 2 (PRC2), a key inducer of transcriptional gene silencing, to uncover silencers, their molecular identity and associated chromatin connectivity. Systematic analysis of cis-regulatory silencer elements reveals their chromatin features and gene-targeting specificity. Deletion of certain PRC2-bound silencers in mice results in transcriptional derepression of their interacting genes and pleiotropic developmental phenotypes, including embryonic lethality. While some PRC2-bound elements function as silencers in pluripotent cells, they can transition into active tissue-specific enhancers during development, highlighting their regulatory versatility. Our study characterizes the molecular profile of silencers and their associated chromatin architectures, and suggests the possibility of targeted reactivation of epigenetically silenced genes.
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Some enhancers are marked with H3K27me3 alone and are considered to be Polycomb-repressed.
“Finally, some enhancers are marked with H3K27me3 alone and are considered to be “Polycomb-repressed” [139–141].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [139]
The Results section ('PRC2-associated silencers transition into active enhancers during differentiation'; page unavailable) describes PRC2-bound silencers that can become active enhancers, supporting the Polycomb-repression aspect. It reports H3K27me3 co-enriched with H3K4me1, however, not enhancers marked by H3K27me3 alone. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn mammals, PcG-associated promoters and enhancers engage in multitudes of looping contacts, particularly in early development.
“In mammals, PcG-associated promoters and enhancers also engage in multitudes of looping contacts, particularly in early development [139, 141, 276, 357].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [139]
The Results section on PRC2-mediated chromatin interactions reports numerous loops involving promoters and distal regions at developmentally regulated genes in mouse embryonic stem cells (page unavailable). The section on PRC2-associated silencers identifies some distal anchors as having poised-enhancer signatures, but says their enhancer activity can emerge during differentiation. It does not establish that active PcG-associated enhancers generally engage in many loops throughout early mammalian development. (LLM, conf=0.84)
Experimental — accuracy not yet measuredMany developmental enhancers are found in the poised or Polycomb-repressed state in early development.
“Many developmental enhancers are found in the poised or Polycomb-repressed state in early development [139, 142, 143], and the functional role of these states remains an area of active research.”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [139]
EZH2 binding sites mostly overlapped with H3K27me3 peaks in P-S loop anchors.
“Next, we performed CUT&Tag for EZH2, a subunit of Polycomb repressive complex II, in THP-1 cells and observed that EZH2 binding sites mostly overlapped with H3K27me3 peaks in the P-S loop anchors (Extended Data Fig. 6d), consistent with the previously reported promoter-silencer loops30,31.”
From Subtype-specific 3D genome alteration in acute myeloid leukaemia (2022) · cites this paper as [30]
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- Authors
- Ngan, C. Y., Wong, C. H., Tjong, H., Wang, W., Goldfeder, R. L., Choi, C., He, H., Gong, L., Lin, J., Urban, B., Chow, J., Li, M., Lim, J., Philip, V., Murray, S. A., Wang, H., & Wei, C.-L.
- Affiliations
- The Jackson Laboratory for Genomic Medicine (US)
- Shanghai Jiao Tong University (CN)
- Joint Genome Institute (US)
- Jackson Laboratory (US)
- Chinese Academy of Sciences (CN)
- Corresponding author
- Wei, Chia-Lin
- ORCID
- Venue
- Nature Genetics
- Published
- 2020-02-24
- Volume
- 52
- Issue
- 3
- Pages
- 264-272
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC7869692
- OpenAlex
- W3007150393
- Cited by
- 140
- References
- 72
- Citations by year
- 2026: 7 · 2025: 16 · 2024: 28 · 2023: 28 · 2022: 23 · 2021: 25 · 2020: 11 · 2019: 1
- FWCI
- 7.13
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Funders
- National Human Genome Research Institute (UM1HG009409)
- National Cancer Institute (P30CA034196)
- National Institute of General Medical Sciences (R01GM127531)
- National Institute of Diabetes and Digestive and Kidney Diseases (U54DK107967)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- polycomb repressive complex 2, silencers, cis-regulatory elements, chromatin interactions, transcriptional repression, enhancers, embryonic lethality, developmental phenotypes, pluripotent cells, epigenetic silencing, gene reactivation, mouse development
- MeSH terms
- Mouse Embryonic Stem Cells, Animals, Cell Line, Chromatin, Enhancer Elements, Genetic, Female, Male, Organ Specificity, Phenotype, Repressor Proteins, Transcriptional Activation, Mice, Knockout, Gene Silencing, Silencer Elements, Transcriptional, Mice, Polycomb Repressive Complex 2
About these checks
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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