Cited by 613Epigenetics and DNA MethylationGenomics and Chromatin DynamicsChromatin Remodeling and Cancer

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Molecular Mechanisms Directing PRC2 Recruitment and H3K27 Methylation

Open access

Laugesen, Anne, Højfeldt, Jonas Westergaard, Helin, Kristian·2019·Molecular Cell

DOI 10.1016/j.molcel.2019.03.011PMC PMC6452890

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Abstract

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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Additional file 6 of A DNA adenine demethylase impairs PRC2-mediated repression of genes marked by a specific chromatin signature
Jia, Q., Zhang, X., Liu, Q., Li, J., Wang, W., Ma, X., Zhu, B., Li, S., Gong, S., Tian, J., et al. (2023) · Figshare · doi:10.6084/m9.figshare.24062477
Additional file 3 of A DNA adenine demethylase impairs PRC2-mediated repression of genes marked by a specific chromatin signature
Jia, Q., Zhang, X., Liu, Q., Li, J., Wang, W., Ma, X., Zhu, B., Li, S., Gong, S., Tian, J., et al. (2023) · Figshare · doi:10.6084/m9.figshare.24062468
Additional file 4 of A DNA adenine demethylase impairs PRC2-mediated repression of genes marked by a specific chromatin signature
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Additional file 7 of A DNA adenine demethylase impairs PRC2-mediated repression of genes marked by a specific chromatin signature
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Additional file 5 of A DNA adenine demethylase impairs PRC2-mediated repression of genes marked by a specific chromatin signature
Jia, Q., Zhang, X., Liu, Q., Li, J., Wang, W., Ma, X., Zhu, B., Li, S., Gong, S., Tian, J., et al. (2023) · Figshare · doi:10.6084/m9.figshare.24062474
Additional file 4 of Unveiling the therapeutic potential of IHMT-337 in glioma treatment: targeting the EZH2-SLC12A5 axis
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Additional file 5 of DNA methylation in human gastric epithelial cells defines regional identity without restricting lineage plasticity
Fritsche, K., Boccellato, F., Schlaermann, P., Koeppel, M., Denecke, C., Link, A., Malfertheiner, P., Gut, I., Meyer, T. F., & Berger, H. (2024) · Figshare · doi:10.6084/m9.figshare.26558396
Additional file 2 of Boundaries potentiate polycomb response element-mediated silencing
Erokhin, M., Gorbenko, F. V., Ломаев, Д. В., Mazina, M. Y., Mikhailova, A., Garaev, A. K., Паршиков, А. Ф., Vorobyeva, N. E., Georgiev, P. G., Schedl, P. D., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14721860
Additional file 4 of DNA methylation in human gastric epithelial cells defines regional identity without restricting lineage plasticity
Fritsche, K., Boccellato, F., Schlaermann, P., Koeppel, M., Denecke, C., Link, A., Malfertheiner, P., Gut, I., Meyer, T. F., & Berger, H. (2024) · Figshare · doi:10.6084/m9.figshare.26558393
Additional file 6 of DNA methylation in human gastric epithelial cells defines regional identity without restricting lineage plasticity
Fritsche, K., Boccellato, F., Schlaermann, P., Koeppel, M., Denecke, C., Link, A., Malfertheiner, P., Gut, I., Meyer, T. F., & Berger, H. (2024) · Figshare · doi:10.6084/m9.figshare.26558399
Additional file 8 of A DNA adenine demethylase impairs PRC2-mediated repression of genes marked by a specific chromatin signature
Jia, Q., Zhang, X., Liu, Q., Li, J., Wang, W., Ma, X., Zhu, B., Li, S., Gong, S., Tian, J., et al. (2023) · Figshare · doi:10.6084/m9.figshare.24062483
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Additional file 2 of Autoregulation of JARID2 through PRC2 interaction with its antisense ncRNA
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Additional file 2 of DNA methylation in human gastric epithelial cells defines regional identity without restricting lineage plasticity
Fritsche, K., Boccellato, F., Schlaermann, P., Koeppel, M., Denecke, C., Link, A., Malfertheiner, P., Gut, I., Meyer, T. F., & Berger, H. (2024) · Figshare · doi:10.6084/m9.figshare.26558387
Additional file 1 of DNA methylation in human gastric epithelial cells defines regional identity without restricting lineage plasticity
Fritsche, K., Boccellato, F., Schlaermann, P., Koeppel, M., Denecke, C., Link, A., Malfertheiner, P., Gut, I., Meyer, T. F., & Berger, H. (2024) · Figshare · doi:10.6084/m9.figshare.26558384
Additional file 5 of Unveiling the therapeutic potential of IHMT-337 in glioma treatment: targeting the EZH2-SLC12A5 axis
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Additional file 1 of Liquid–liquid phase separation of H3K27me3 reader BP1 regulates transcriptional repression
Tang, G., Xia, H., Huang, Y., Guo, Y., Chen, Y., Ma, Z., & Liu, W. (2024) · Figshare · doi:10.6084/m9.figshare.25389482
Additional file 2 of Unveiling the therapeutic potential of IHMT-337 in glioma treatment: targeting the EZH2-SLC12A5 axis
Zhang, H., Wang, Z., Qiao, X., Peng, N., Wu, J., Chen, Y., & Cheng, C. (2024) · Figshare · doi:10.6084/m9.figshare.26735265
Additional file 6 of Unveiling the therapeutic potential of IHMT-337 in glioma treatment: targeting the EZH2-SLC12A5 axis
Zhang, H., Wang, Z., Qiao, X., Peng, N., Wu, J., Chen, Y., & Cheng, C. (2024) · Figshare · doi:10.6084/m9.figshare.26735277
Additional file 12 of DNA methylation in human gastric epithelial cells defines regional identity without restricting lineage plasticity
Fritsche, K., Boccellato, F., Schlaermann, P., Koeppel, M., Denecke, C., Link, A., Malfertheiner, P., Gut, I., Meyer, T. F., & Berger, H. (2024) · Figshare · doi:10.6084/m9.figshare.26558417
Additional file 3 of DNA methylation in human gastric epithelial cells defines regional identity without restricting lineage plasticity
Fritsche, K., Boccellato, F., Schlaermann, P., Koeppel, M., Denecke, C., Link, A., Malfertheiner, P., Gut, I., Meyer, T. F., & Berger, H. (2024) · Figshare · doi:10.6084/m9.figshare.26558390
Additional file 9 of DNA methylation in human gastric epithelial cells defines regional identity without restricting lineage plasticity
Fritsche, K., Boccellato, F., Schlaermann, P., Koeppel, M., Denecke, C., Link, A., Malfertheiner, P., Gut, I., Meyer, T. F., & Berger, H. (2024) · Figshare · doi:10.6084/m9.figshare.26558408
Additional file 1 of High methylation of lysine acetyltransferase 6B is associated with the Cobb angle in patients with congenital scoliosis
Wu, Y., Zhang, H., Tang, M., Guo, C., Deng, A., Li, J., Wang, Y., Xiao, L., & Yang, G. (2020) · Figshare · doi:10.6084/m9.figshare.12364145
Additional file 1 of Boundaries potentiate polycomb response element-mediated silencing
Erokhin, M., Gorbenko, F. V., Ломаев, Д. В., Mazina, M. Y., Mikhailova, A., Garaev, A. K., Паршиков, А. Ф., Vorobyeva, N. E., Georgiev, P. G., Schedl, P. D., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14721857
Additional file 3 of Unveiling the therapeutic potential of IHMT-337 in glioma treatment: targeting the EZH2-SLC12A5 axis
Zhang, H., Wang, Z., Qiao, X., Peng, N., Wu, J., Chen, Y., & Cheng, C. (2024) · Figshare · doi:10.6084/m9.figshare.26735268
Additional file 11 of DNA methylation in human gastric epithelial cells defines regional identity without restricting lineage plasticity
Fritsche, K., Boccellato, F., Schlaermann, P., Koeppel, M., Denecke, C., Link, A., Malfertheiner, P., Gut, I., Meyer, T. F., & Berger, H. (2024) · Figshare · doi:10.6084/m9.figshare.26558414
Additional file 8 of DNA methylation in human gastric epithelial cells defines regional identity without restricting lineage plasticity
Fritsche, K., Boccellato, F., Schlaermann, P., Koeppel, M., Denecke, C., Link, A., Malfertheiner, P., Gut, I., Meyer, T. F., & Berger, H. (2024) · Figshare · doi:10.6084/m9.figshare.26558405
Additional file 1 of Autoregulation of JARID2 through PRC2 interaction with its antisense ncRNA
Al‐Raawi, D., & Kanhere, A. (2020) · Figshare · doi:10.6084/m9.figshare.13172574
Additional file 7 of DNA methylation in human gastric epithelial cells defines regional identity without restricting lineage plasticity
Fritsche, K., Boccellato, F., Schlaermann, P., Koeppel, M., Denecke, C., Link, A., Malfertheiner, P., Gut, I., Meyer, T. F., & Berger, H. (2024) · Figshare · doi:10.6084/m9.figshare.26558402
Additional file 4 of Liquid–liquid phase separation of H3K27me3 reader BP1 regulates transcriptional repression
Tang, G., Xia, H., Huang, Y., Guo, Y., Chen, Y., Ma, Z., & Liu, W. (2024) · Figshare · doi:10.6084/m9.figshare.26691619
Additional file 1 of Unveiling the therapeutic potential of IHMT-337 in glioma treatment: targeting the EZH2-SLC12A5 axis
Zhang, H., Wang, Z., Qiao, X., Peng, N., Wu, J., Chen, Y., & Cheng, C. (2024) · Figshare · doi:10.6084/m9.figshare.26735262
Additional file 2 of A DNA adenine demethylase impairs PRC2-mediated repression of genes marked by a specific chromatin signature
Jia, Q., Zhang, X., Liu, Q., Li, J., Wang, W., Ma, X., Zhu, B., Li, S., Gong, S., Tian, J., et al. (2023) · Figshare · doi:10.6084/m9.figshare.24062465
Additional file 1 of Transcriptionally active chromatin loops contain both ‘active’ and ‘inactive’ histone modifications that exhibit exclusivity at the level of nucleosome clusters
Koestler, S. A., Ball, M. L., Mureşan, L., Dinakaran, V., & White, R. A. (2024) · Figshare · doi:10.6084/m9.figshare.25478749
Additional file 10 of DNA methylation in human gastric epithelial cells defines regional identity without restricting lineage plasticity
Fritsche, K., Boccellato, F., Schlaermann, P., Koeppel, M., Denecke, C., Link, A., Malfertheiner, P., Gut, I., Meyer, T. F., & Berger, H. (2024) · Figshare · doi:10.6084/m9.figshare.26558411
Additional file 4 of Boundaries potentiate polycomb response element-mediated silencing
Erokhin, M., Gorbenko, F. V., Ломаев, Д. В., Mazina, M. Y., Mikhailova, A., Garaev, A. K., Паршиков, А. Ф., Vorobyeva, N. E., Georgiev, P. G., Schedl, P. D., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14721869
Additional file 3 of Boundaries potentiate polycomb response element-mediated silencing
Erokhin, M., Gorbenko, F. V., Ломаев, Д. В., Mazina, M. Y., Mikhailova, A., Garaev, A. K., Паршиков, А. Ф., Vorobyeva, N. E., Georgiev, P. G., Schedl, P. D., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14721866
Additional file 2 of Liquid–liquid phase separation of H3K27me3 reader BP1 regulates transcriptional repression
Tang, G., Xia, H., Huang, Y., Guo, Y., Chen, Y., Ma, Z., & Liu, W. (2024) · Figshare · doi:10.6084/m9.figshare.25389913
Additional file 13 of DNA methylation in human gastric epithelial cells defines regional identity without restricting lineage plasticity
Fritsche, K., Boccellato, F., Schlaermann, P., Koeppel, M., Denecke, C., Link, A., Malfertheiner, P., Gut, I., Meyer, T. F., & Berger, H. (2024) · Figshare · doi:10.6084/m9.figshare.26558420
Additional file 9 of A DNA adenine demethylase impairs PRC2-mediated repression of genes marked by a specific chromatin signature
Jia, Q., Zhang, X., Liu, Q., Li, J., Wang, W., Ma, X., Zhu, B., Li, S., Gong, S., Tian, J., et al. (2023) · Figshare · doi:10.6084/m9.figshare.24062486
Additional file 1 of A DNA adenine demethylase impairs PRC2-mediated repression of genes marked by a specific chromatin signature
Jia, Q., Zhang, X., Liu, Q., Li, J., Wang, W., Ma, X., Zhu, B., Li, S., Gong, S., Tian, J., et al. (2023) · Figshare · doi:10.6084/m9.figshare.24062462
Additional file 3 of Liquid–liquid phase separation of H3K27me3 reader BP1 regulates transcriptional repression
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“This concept is similar to other histone methylation recruiters and writers, such as PRC2 for H3K27me3 methylation and SET1 for H3K4me3 methylation, where histone marks persist long after the dissociation of the methyltransferases 32,33 .”
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“In contrast, in mammals, a ‘scanning model’ instead underlies PRC2 genome targeting to unmethylated promoter proximal CpG islands (CGIs) via core and accessory PRC2 components [35, 50].”
The MALAT1-EZH2 axis regulates PRC2 activity and promotes the mesenchymal phenotype in pediatric atypical teratoid/rhabdoid tumors
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“PRC2-mediated tumorigenesis is driven by increased EZH2 activity, yet interactions between PRC2 and lncRNAs remain unclear in AT/RT [21, 22].”
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“Metformin also phosphorylates EZH2 at Thr311 via AMPK, disrupting PRC2 (EED-EZH2) activity and reducing oncogenic gene silencing [36, 37], positioning metformin as a potential epigenetic Fig.”
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Authors: Laugesen, A., Højfeldt, J. W., & Helin, K.
Affiliations: University of Copenhagen (DK)
Corresponding author: Helin, Kristian
ORCID: Laugesen, Anne
Højfeldt, Jonas Westergaard
Helin, Kristian
Venue: Molecular Cell
Publisher: Elsevier BV
Published: 2019-04
Volume: 74
Issue: 1
Pages: 8-18
ISSN: 1097-2765 (ISSN-L)
DOI: 10.1016/j.molcel.2019.03.011
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: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 369 d)
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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Molecular Mechanisms Directing PRC2 Recruitment and H3K27 Methylation

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