PRC1 catalytic activity is central to polycomb system function
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Abstract
The Polycomb repressive system is an essential chromatin-based regulator of gene expression. Despite being extensively studied, how the Polycomb system selects its target genes is poorly understood, and whether its histone-modifying activities are required for transcriptional repression remains controversial. Here, we directly test the requirement for PRC1 catalytic activity in Polycomb system function. To achieve this, we develop a conditional mutation system in embryonic stem cells that completely removes PRC1 catalytic activity. Using this system, we demonstrate that catalysis by PRC1 drives Polycomb chromatin domain formation and long-range chromatin interactions. Furthermore, we show that variant PRC1 complexes with DNA-binding activities occupy target sites independently of PRC1 catalytic activity, providing a putative mechanism for Polycomb target site selection. Finally, we discover that Polycomb-mediated gene repression requires PRC1 catalytic activity. Together these discoveries provide compelling evidence that PRC1 catalysis is central to Polycomb system function and gene regulation.
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EZH2 serves as the catalytic subunit of Polycomb Repressive Complex 2, responsible for depositing the repressive H3K27me3 mark and silencing target genes.
“Within the Polycomb Repressive Complex 2 (PRC2), EZH2 serves as the catalytic subunit responsible for depositing the repressive H3K27me3 mark and silencing target genes (Blackledge et al., 2020; Laugesen et al., 2019).”
From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Blackledge et al., 2020
The Introduction (page unavailable) describes PRC2 as a methyltransferase that deposits H3K27me3 and says Polycomb complexes repress transcription. It does not identify EZH2 as PRC2’s catalytic subunit; the Discussion (page unavailable) also cautions that PRC2 removal caused few gene-expression defects in the embryonic stem cells discussed, so the silencing role should not be read as universal. (LLM, conf=0.86)
Experimental — accuracy not yet measuredChIP-seq bigwigs were generated with scaling factors calculated using the formula (human reads in input) / (mouse reads in input) / (human reads in ChIP) x 15,000,000 to calibrate between mouse ESCs and human HEK spike-in.
“Bigwigs were generated with the bamCoverage function from deepTools (82) with scaling factors calculated using the formula (human reads in input) / (mouse reads in input) / (human reads in ChIP) x 15000000 (83, 84).”
From Synergy between regulatory elements can render cohesin dispensable for distal enhancer function (2026) · cites this paper as [83]
STAR★Methods (Quantification and Statistical Analysis; page unavailable) describes normalizing mouse ChIP-seq reads with human spike-in reads and correcting for the spike-in/mouse ratio in input samples. It does not give the claimed formula or 15,000,000 multiplier; it says cChIP-seq coverage tracks were generated with MACS2 pileup, not bamCoverage. Method Details (page unavailable) confirms that mouse ESCs were mixed with human HEK293T spike-in cells. (LLM, conf=0.85)
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Histone post-translational modifications - cause and consequence of genome function
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Cohesin Disrupts Polycomb-Dependent Chromosome Interactions in Embryonic Stem Cells
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Self-citationSynergy between regulatory elements can render cohesin dispensable for distal enhancer function
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- Authors
- Blackledge, N. P., Fursova, N. A., Kelley, J. R., Huseyin, M. K., Feldmann, A., & Klose, R. J.
- Affiliations
- University of Oxford (GB)
- Corresponding author
- Klose, Robert J.
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2020-02
- Volume
- 77
- Issue
- 4
- Pages
- 857-874.e9
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC7033600
- OpenAlex
- W2997518667
- Cited by
- 243
- References
- 137
- Citations by year
- 2026: 15 · 2025: 32 · 2024: 34 · 2023: 28 · 2022: 42 · 2021: 57 · 2020: 34 · 2019: 1
- FWCI
- 11.09
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust (209400/Z/17/Z)
- European Research Council (681440)
- Lister Institute of Preventive Medicine
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- 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
- Keywords
- PRC1, polycomb repressive complex, transcriptional repression, histone modifications, long-range chromatin interactions, conditional mutations, embryonic stem cells
- MeSH terms
- Animals, Cell Line, Chromatin, Gene Expression Regulation, Histones, Humans, Male, Point Mutation, Ubiquitin-Protein Ligases, Mice, Embryonic Stem Cells, Biocatalysis, HEK293 Cells, Polycomb Repressive Complex 1, Polycomb Repressive Complex 2
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