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Molecular Mechanisms Directing PRC2 Recruitment and H3K27 Methylation
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The polycomb repressive complex 2 (PRC2) is a chromatin-associated methyltransferase catalyzing mono-, di-, and trimethylation of lysine 27 on histone H3 (H3K27). This activity is required for normal organismal development and maintenance of gene expression patterns to uphold cell identity. PRC2 function is often deregulated in disease and is a promising candidate for therapeutic targeting in cancer. In this review, we discuss the molecular mechanisms proposed to take part in modulating PRC2 recruitment and shaping H3K27 methylation patterns across the genome. This includes consideration of factors influencing PRC2 residence time on chromatin and PRC2 catalytic activity with a focus on the mechanisms giving rise to regional preferences and differential deposition of H3K27 methylation. We further discuss existing evidence for functional diversity between distinct subsets of PRC2 complexes with the aim of extracting key concepts and highlighting major open questions toward a more complete understanding of PRC2 function.
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“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 Laugesen et al., 2019
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“As nascent transcription can block H3K27me3 deposition (Ho-sogane et al., 2016; Kaneko et al., 2014; Laugesen et al., 2019), transcription might also accelerate removal of the repressive H3K27me3 hotspot, which covers the entire region before differentiation.”
BackgroundPolycomb-dependent histone H2A ubiquitination links developmental disorders with cancer
Tamburri, S., Conway, E., & Pasini, D. (2021) · Trends in Genetics · doi:10.1016/j.tig.2021.07.011 · Cited by 50
Wang, J., Wang, J., Yang, L., Zhao, C., Wu, L.-M. N., Xu, L., Zhang, F., Weng, Q., Wegner, M., & Lu, Q. R. (2020) · Nature Communications · doi:10.1038/s41467-020-17955-2 · Cited by 48
Motif-driven interactions between RNA and PRC2 are rheostats that regulate transcription elongation
Rosenberg, M., Blum, R., Kesner, B., Aeby, E., Garant, J., Szántó, A., & Lee, J. T. (2021) · Nature Structural & Molecular Biology · doi:10.1038/s41594-020-00535-9 · Cited by 48
Histone Modifications in Stem Cell Development and Their Clinical Implications
Völker-Albert, M. C., Bronkhorst, A. J., Holdenrieder, S., & Imhof, A. (2020) · Stem Cell Reports · doi:10.1016/j.stemcr.2020.11.002 · Cited by 52
“It appears that recruitment of PRC2 is, similar to Set1A and MLL-containing complexes, likely not (only) based on the recognition of specific sequences but rather on composition-modulated physical properties of DNA, such as the shape of the DNA, nucleosome density, or overall chromatin conformation (Laugesen et al., 2…”
BackgroundEpigenetic Regulation during Primordial Germ Cell Development and Differentiation
Ramakrishna, N. B., Murison, K., Miska, E. A., & Leitch, H. G. (2021) · Sexual Development · doi:10.1159/000520412 · Cited by 48
“Co-regulation by PRC1 and PRC2 complexes is well described [Laugesen et al., 2019]; however, knockout of PRC1 component Rnf2 in mPGCs does not affect H3K27me3 deposition.”
BackgroundEpigenetics as a versatile regulator of fibrosis
Liu, Y., Wen, D., Ho, C., Li, Y., Zheng, D., O’Reilly, S., Gao, Y., Li, Q., & Zhang, Y. (2023) · Journal of Translational Medicine · doi:10.1186/s12967-023-04018-5 · Cited by 49
Persistent epigenetic reprogramming of sweet taste by diet
Vaziri, A., Khabiri, M., Genaw, B. T., May, C. E., Freddolino, P. L., & Dus, M. (2020) · Science Advances · doi:10.1126/sciadv.abc8492 · Cited by 49
“2, which contain distinct accessory factors that influence the targeting of the core complex to the chromatin (18).”
BackgroundInfluentialZheng, Y., Huang, G., Silva, T. C., Yang, Q., Jiang, Y., Koeffler, H. P., Lin, D., & Berman, B. P. (2021) · Nature Communications · doi:10.1038/s41467-021-22720-0 · Cited by 54
Kuo, F.-C., Neville, M. J., Sabaratnam, R., Wesolowska‐Andersen, A., Phillips, D., Wittemans, L. B. L., van Dam, A. D., Loh, N. Y., Todorčević, M., Denton, N., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111136 · Cited by 50
Murphy, S. E., & Boettiger, A. N. (2024) · Nature Genetics · doi:10.1038/s41588-024-01661-6 · Cited by 53
“In the beginning, we defined a block of ~200 monomers to be blue, mimicking the initialization of Polycomb repression by transiently expressed factors during development 5,40 .”
DeLuca, S. Z., Ghildiyal, M., Niu, W., Pang, L.-Y., & Spradling, A. C. (2020) · eLife · doi:10.7554/elife.56922 · Cited by 46
“Nevertheless, many studies have investigated factors controlling PcG targeting specificity in other cell types in both flies and mammals, which offer clues into how PcG is established in early embryos (recently reviewed in Kassis et al., 2017; Kuroda et al., 2020; Laugesen et al., 2019; Yu et al., 2019).”
BackgroundPolycomb Repressive Complex 2 in Eukaryotes—An Evolutionary Perspective
Vijayanathan, M., Trejo-Arellano, M. G., & Mozgová, I. (2022) · Epigenomes · doi:10.3390/epigenomes6010003 · Cited by 49
“CpG islands, hypomethylated CG-rich chromatin regions of 1–2 kb, are associated with PRC2 recruitment in mammals, where accessory subunits rather than transcription factors mediate the recruitment ([180–182], reviewed in the work of [71]).”
BackgroundThe Role of Polycomb Proteins in Cell Lineage Commitment and Embryonic Development
Loh, C. H., & Veenstra, G. J. C. (2022) · Epigenomes · doi:10.3390/epigenomes6030023 · Cited by 46
“2 complex, is able to bind to H2AK119ub, which is deposited by PRC1.”
BackgroundInfluentialChromatin regulation of transcriptional enhancers and cell fate by the Sotos syndrome gene NSD1
Sun, Z., Lin, Y., Islam, M. T., Koche, R. P., Hedehus, L., Liu, D., Huang, C., Vierbuchen, T., Sawyers, C. L., & Helin, K. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.06.007 · Cited by 45
Shi, Y., Tao, M., Wang, Y., Zang, X., Ma, X., Qiu, A., Zhuang, S., & Liu, N. (2019) · The Journal of Pathology · doi:10.1002/path.5352 · Cited by 45
“Because H3K27me3 tends to form a compact chromatin structure and leads to suppression rather than facilitation of gene expression [49].”
BackgroundChu, L., Qu, Y.-X., An, Y., Hou, L., Li, J., Li, W., Fan, G., Song, B., Li, E., Zhang, L., et al. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-04601-6 · Cited by 47
“The core PRC2 complex is composed of three subunits: catalytic subunit EZH2 or EZH1, scaffolding subunit SUZ12 and EED that allosterically activates EZH2 upon binding to H3K27me3 [3, 4].”
BackgroundFang, P., Chen, H., Ma, Z., Han, C., Yin, W., Wang, S., Zhu, H., Xia, W., Wang, J., Xu, L., et al. (2021) · 癌症：英文版 · doi:10.1002/cac2.12181 · Cited by 44
“EZH2, a PRC2 core component, has been reported to epigenetically regulate target gene expression through H3K27me3 histone modification [24].”
BackgroundThe multiscale effects of polycomb mechanisms on 3D chromatin folding
Cheutin, T., & Cavalli, G. (2019) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2019.1679082 · Cited by 43
“Much work on PcG proteins targeting to chromatin in mammals focused on deposition of PRC2 and H3K27me3, which is a hallmark of canonical PcG silencing (reviewed in Laugesen et al. 2019).”
BackgroundLoss of PRC2 subunits primes lineage choice during exit of pluripotency
Loh, C. H., van Genesen, S. T., Perino, M., Bark, M. R., & Veenstra, G. J. C. (2021) · Nature Communications · doi:10.1038/s41467-021-27314-4 · Cited by 45
Non-canonical functions of EZH2 in cancer
Zimmerman, S. M., Lin, P. N., & Souroullas, G. P. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1233953 · Cited by 43
“Polycomb-mediated gene silencing primarily operates through the regulation of chromatin structure via posttranslational modifications of histone tails (5, 6).”
BackgroundThe functional mechanisms of mutations in myelodysplastic syndrome
Nagata, Y., & Maciejewski, J. P. (2019) · Leukemia · doi:10.1038/s41375-019-0617-3 · Cited by 42
Chomiak, A. A., Tiedemann, R. L., Liu, Y., Kong, X., Cui, Y., Wiseman, A. K., Thurlow, K. E., Cornett, E. M., Topper, M. J., Baylin, S. B., et al. (2024) · Science Advances · doi:10.1126/sciadv.adk4423 · Cited by 44
Williams, K. B., & Largaespada, D. A. (2020) · Genes · doi:10.3390/genes11050477 · Cited by 42
“JARID2 is a critical component of the PCR2 complex required for localization of the PRC2 complex on chromatin, and has been reviewed before [45].”
BackgroundWang, J., Yang, L., Dong, C., Wang, J., Xu, L., Qiu, Y., Weng, Q., Zhao, C., Xin, M., & Lu, Q. R. (2020) · Science Advances · doi:10.1126/sciadv.aaz6477 · Cited by 43
“Since PRC2 activity regulates H3K27me3 levels (6), we examined the H3K27me3 state during OPC maturation.”
BackgroundInfluentialXu, J., Zhao, X., Mao, F., Basrur, V., Ueberheide, B. M., Chait, B. T., Allis, C. D., Taverna, S. D., Gao, S., Wang, W., et al. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkaa1262 · Cited by 45
“While these results implicate long ncRNA and sRNA in Polycomb repression, mechanistic details concerning their role in the recruitment of PcG proteins are still largely missing, and they may differ between species (30– 32).”
Zhang, Q., Agius, S. C., Flanigan, S. F., Uckelmann, M., Levina, V., Owen, B. M., & Davidovich, C. (2021) · Nature Communications · doi:10.1038/s41467-021-24866-3 · Cited by 42
Metadata
- Authors
- Laugesen, A., Højfeldt, J. W., & Helin, K.
- Affiliations
- University of Copenhagen (DK)
- Corresponding author
- Helin, Kristian
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2019-04
- Volume
- 74
- Issue
- 1
- Pages
- 8-18
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC6452890
- OpenAlex
- W2925415367
- Cited by
- 602
- References
- 105
- Citations by year
- 2026: 60 · 2025: 89 · 2024: 85 · 2023: 83 · 2022: 79 · 2021: 87 · 2020: 83 · 2019: 36
- FWCI
- 6.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Danmarks Grundforskningsfond (DNRF 82)
- Novo Nordisk Fonden (NNF16OC0023234)
- National Cancer Institute (P30CA008748)
- 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
- polycomb repressive complex 2, H3K27 methylation, histone methyltransferase, gene silencing, cancer therapy targets
- MeSH terms
- Animals, Histones, Humans, Lysine, Methylation, Protein Binding, DNA Methylation, Chromatin Assembly and Disassembly, Polycomb Repressive Complex 2
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