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

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Molecular Mechanisms Directing PRC2 Recruitment and H3K27 Methylation

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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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Background
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Background
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Method
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“6 component, is enriched at silenced proviruses was unexpected given that HUSH predominantly mediates transcriptional silencing via an H3K9me3-driven repression pathway [3], while components of polycomb complexes generally catalyze mono-, di-, and tri-methylation of H3K27 [45–47].”
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Juárez-González, V. T., de Felipe, C. C., & Martínez, G. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-19051-3.00012-7 · Cited by 1
EZH2 ‐mediated downregulation of miR ‐155‐5p contributes to prostate cancer cell malignancy through SMAD2 and TAB2
Bai, Z., Liu, J., Xing, W., & Wang, H. (2025) · The Kaohsiung Journal of Medical Sciences · doi:10.1002/kjm2.12936 · Cited by 1
RACK7 Interacts with PRC2 Complex to Regulate Astrocyte Development
Jiao, F., Tang, T., Wang, B., He, S., Zhang, Y., Dong, L., Xu, B., Liu, Y., Zhu, P., & Guo, R. (2025) · Advanced Science · doi:10.1002/advs.202416350 · Cited by 1
Periodontal Ligament Stem Cell Aging in Age‐Related Orthodontic Changes: Mechanisms and Rescue Strategies
Tang, J., & Yang, K. (2025) · The FASEB Journal · doi:10.1096/fj.202501731r · Cited by 2
“Notably, enhancer of zeste homolog 2 (EZH2), a key methyltransferase responsible for modulating H3K27me3, induces chromatin compaction and gene repression [136].”
SUZ12 promotes pancreatic ductal adenocarcinoma <?A3B2 pi6?>progression and chemoresistance by epigenetically silencing NCOA4-induced ferroptosis
Yin, L., Li, B., Wei, Y., Li, Z., Yang, Y., Zhang, J., Fan, G., Jing, D., Shi, Y., Yuan, H., et al. (2025) · Acta Biochimica et Biophysica Sinica · doi:10.3724/abbs.2025215 · Cited by 1
EZH2 Inhibitors Sensitize Breast Cancer to HER2 Kinase Inhibitors through Cooperative Effects on YAP and Proapoptotic Regulators
Perurena, N., Watanabe, M., Schade, A. E., Brown, W. R., Luo, E. Y., Gardner, A., Indeglia, A., Yoshinaga, A., Sahu, R., Yang, Y., et al. (2026) · Cancer Research · doi:10.1158/0008-5472.can-24-3113 · Cited by 1
Targeting epigenetic regulators to boost T cell immunotherapy against cancer
Xiao, T., & Zhang, Y. E. (2026) · Cell & Bioscience · doi:10.1186/s13578-026-01533-y · Cited by 2
“PRC2 components, including EZH2, SUZ12, EED, and RBBP4, work together to deposit and maintain this modification [58].”
Epigenetic landscape of the H3K27me3 mark in macrophages transformed by Theileria annulata
Sakura, T., Tajeri, S., Rchiad, Z., Ansari, H. R., Kaushik, A., Mourier, T., Pain, A., Wassef, M. A., & Langsley, G. (2026) · Communications Biology · doi:10.1038/s42003-026-09735-3 · Cited by 1
“45,46.”
Discovery of Small-Molecule Antagonists of PHF1 and 19 Demonstrates the Ligandability of PRC2 Accessory Proteins
Amick, I., Johnson, R. L., Liu, J., Bussey-Sutton, C. R., Mancera-Ortiz, I. Y., Norris-Drouin, J. L., Boyd, S. R., Cholensky, S. H., Spangler, C. J., McGinty, R. K., et al. (2026) · ACS Bio & Med Chem Au · doi:10.1021/acsbiomedchemau.5c00150 · Cited by 1
Biological Evaluation of a Novel Compound with Predicted EZH2 and EED Binding Against Human Malignant Melanoma Cells
Gorbunov, S., Kyriakou, S., Anestopoulos, I., Khoso, S., Manfredi, M., Franco, R., Pappa, A., & Panayiotidis, M. I. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27062647 · Cited by 1
“However, to be fully functional, EZH2 requires interaction with the EED and SUZ12 components [11,12].”
Targeting the Polycomb repressive complexes in hepatocellular carcinoma: A comprehensive and updated analysis of mechanistic insights and clinical application
Liu, Z., Wu, D., Zhao, X., Deng, H., & Guan, X. (2026) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2026.189589 · Cited by 1
Targeting EZH2 in Cancer: From Molecular Mechanisms to Clinical Translation
Zhong, X., Li, J., Pan, M., Ke, X., & Cui, H. (2026) · MedComm – Oncology · doi:10.1002/mog2.70070 · Cited by 1
Polycomb-mediated 3D-genome organization controls replication timing
Chetlangia, N., Thakur, B. L., Redon, C. E., Zinder, O. J., Mishra, M., Liu, D., Pongor, L. S., Song, Y. J., Asoudegi, D., Fields, C. J., et al. (2026) · Science Advances · doi:10.1126/sciadv.adx7445 · Cited by 1
Opposing function of AEBP2 isoforms fine-tune PRC2 catalytic activity
Li, Y., Kwon, C., Kim, H., & Lee, C. (2026) · Nucleic Acids Research · doi:10.1093/nar/gkag694 · Cited by 1
“Most accessory proteins serve to stimulate PRC2 activity, including PHF1, MTF2, PHF19, JARID2, EPOP, and the short isoform of AEBP2 [ 2 , 29 , 30 ].”
A maternal Polycomb imprint is maintained in early Drosophila development through lower-order methylation states
Degen, E. A., Gonzaga-Saavedra, N., & Blythe, S. A. (2026) · Cell Reports · doi:10.1016/j.celrep.2026.117679 · Cited by 7
“2,3,5,19,20,22,31,32 , 19 Here, we investigate the kinetics of maternal H3K27 methylation states in Drosophila embryos through computational modeling and in vivo experiments.”
The Epigenetic Architecture of Classical Hodgkin Lymphoma: Lineage Erasure, Immune Escape, and Therapeutic Reprogramming
Seleusan, M., Cenariu, D., Țigu, A. B., Gulei, D., Nistor, M., Mureșan, X. M., & Zdrenghea, M. (2026) · Medicina · doi:10.3390/medicina62091740 · Cited by 1
“This sequence is partly illustrated by the regulation of NFATC1 : the withdrawal of receptor-dependent signaling first leads to the loss of activating histone acetylation marks and H3K4me3, after which DNA methylation may stabilize the resulting repressed state [30,31,33,37,38,40,41,71,72].”
Bioinformatics analysis reveals that CBX2 promotes enzalutamide resistance in prostate cancer
Wen, Z., Li, Q., & Hu, G. (2024) · European journal of medical research · doi:10.1186/s40001-024-02021-0 · Cited by 1
“PRC2 triggers transcriptional silencing by methylating H3K27 to H3K27me3 through EZH2 [17].”
Background
EZH2 variants derived from cryptic splice sites govern distinct epigenetic patterns during embryonic development
Guo, N., Guo, Q., Zhan, H., Lv, J., Yu, F., Li, J., Wang, J., Li, D., Ma, X., Yan, Q., et al. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkaf869 · Cited by 2
“…catalyzes H3K27me3 deposition [ 21–24 ]; embryonic ectoderm development (EED), which contains the H3K27me3-binding pocket that allows for epigenetic inheritance of the mark [ 25 ]; suppressor of zeste 12 (SUZ12), which functions as a scaffold [ 26–28 ]; and the histone chaperone RbAp46 / 48 [ 29 ].”
Untangling the Epigenetic Imbalance in B cell Lymphoma
Wu, R. (2020) · Current Pharmacology Reports · doi:10.1007/s40495-020-00214-9 · Cited by 1
BENDing with Polycomb in pluripotency and cancer
Khan, A. A., & Prasanth, S. G. (2023) · BioEssays · doi:10.1002/bies.202300046 · Cited by 1
EZH2 inhibition results in genome-wide PRC2 redistributionPreprint
Yuan, C.-C., Jeon, A., Tucker‐Kellogg, G., Bryant, B. M., & Trojer, P. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/713842 · Cited by 1
“It has been hypothesized that Polycomb-mediated repressive domains in the genome are formed by the spreading of PRC2 from nucleation sites at CpG islands where there is no DNA methylation and no transcription (Cooper et al., 2014; van Heeringen et al., 2014; Ku et al., 2008; Laugesen et al., 2019; Oksuz et al., 2018)…”
Background
Influence of paternal consumption of a high-fat/high-sugar diet and/or orange juice during preconception on C57BL/6 female mice offspring breast cancer risk
Silva, L. B. A. R. (2019) · doi:10.11606/t.9.2019.tde-18122019-112452 · Cited by 1
Polycomb suppresses a female gene regulatory network to ensure testicular differentiationPreprint
Maezawa, S., Yukawa, M., Hasegawa, K., Sugiyama, R., Hu, M., Vidal, M., Koseki, H., Barski, A., DeFalco, T., & Namekawa, S. H. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.01.19.427322 · Cited by 1
“While a portion of PRC2-mediated H3K27me3 is regulated by variant PRC1 (37, 38), 289 another portion of H3K27me3, mediated by canonical PRC1 and PRC2 complexes, is not 290 downstream of PRC1 (47).”
Background
KDM6A knockout in human iPSCs alters the genome-wide histone methylation profile at active and poised enhancers, activating expression of ectoderm gene expression pathwaysPreprint
Maurya, S. S., Yang, W., Zhang, Q., Erdmann-Gilmore, P., Bystry, A., Townsend, R., & Druley, T. E. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.03.09.434633 · Cited by 1
RBBP4 modulates gene activity through acetylation and methylation of histone H3 lysine 27Preprint
Mu, W., Murcia, N. S., Smith, K. N., Menon, D. U., Yee, D., & Magnuson, T. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.09.09.459568 · Cited by 1
H3.3K27M Mutation Promotes The Migration and Invasion of Glioma Cells By Activating β-Catenin/USP1 SignalingPreprint
Sun, Z., Zhu, Y., Feng, X., Liu, X., Zhou, K., & Shi, H. (2022) · Research Square · doi:10.21203/rs.3.rs-1215261/v1 · Cited by 1
“PRC2 is a chromatin-associated methyltransferase catalyzing the mono-, di-, and trimethylation of lysine 27 on histone H3 (H3K27)[13].”
Background
Snip1 and PRC2 coordinate intrinsic apoptosis, cell division, and neurogenesis in the developing brainPreprint
Matsui, Y., Djekidel, M. N., Lindsay, K., Samir, P., Connolly, N., Chen, H., Fan, Y., Xu, B., & Peng, J. C. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.04.27.489801 · Cited by 1
Nucleation and Spreading Rejuvenate Polycomb Domains Every Cell CyclePreprint
Veronezi, G. M. B., & Ramachandran, S. (2022) · SSRN Electronic Journal · doi:10.2139/ssrn.4193114 · Cited by 1
Differential chromatin enrichment of histone H3K27me3 underlies variable cell responses to estrogen and endocrine treatment
Chapus, F., Day, C. R., Kammel, L. G., Yaşar, P., Bennett, B. D., Scappini, E., Tucker, C. J., Sifre, M. I., Bregio, C., & Rodriguez, J. (2026) · Journal of Biological Chemistry · doi:10.1101/2025.09.18.677184 · Cited by 1
“Given that H3K27me3 is a stable repressive mark associated with prolonged transcriptional repression 29,30 , and its presence across the TFF1 locus in TFF1 low cells, we sought to determine the temporal stability of TFF1 expression states.”
Nucleation-dependent propagation of Polycomb modifications emerges during the Drosophila maternal to zygotic transitionPreprint
Gonzaga-Saavedra, N., Degen, E. A., Soluri, I. V., Croslyn, C., & Blythe, S. A. (2025) · eLife · doi:10.7554/elife.108371.1 · Cited by 1
Sex-Specific Induction of H3K27me1 in the Prefrontal Cortex Mediates the Enduring Effects of Early Life StressPreprint
Nguyen, J., Byragoni, N., Arinzeh, N., Bortolami, A., Sidoli, S., Russo, S. J., Nestler, E. J., & Torres‐Berrío, A. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.11.25.690167 · Cited by 1
Mitotic bookmarking by Prox1 preserves mammalian neuronal lineage identity memory via promoting timely H3K27me3 restorationPreprint
Wong, C., Liu, J., Yang, H., Li, H., Luo, X., Li, T., Chen, Z., Chu, J., Shen, Y., Long, S., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.02.25.707603 · Cited by 1
Functional involvement of two histone-methyltransferases in response to stress and in regulation of flowering time in Arabidopsis thaliana
Zhang, X. (2019) · theses.fr (ABES) · doi:10.70675/299aa774z2e73z48acz89fcz20db55683507 · Cited by 1
Genome-wide occupancy of Polycomb group proteins and chromatin remodeler SPLAYED and their interplay in Arabidopsis
Shu, J. (2019) · Scholarship@Western (Western University)
Genome-wide epigenetic profiling of B cell leukemia and lymphoma
Morsy, M. H. A. (2019) · Gothenburg University Publications Electronic Archive (Gothenburg University)
Transcriptional elongation machinery controls vulnerability of breast cancer cells to PRC2 inhibitorsPreprint
Chan, N. T., Liu, P., Huang, J., Wang, Y., Ong, I. M., Li, L., & Xu, W. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.01.08.898577
“This is also consistent with the role of the active histone marks in inhibiting PRC2 activity in transcribed regions (Laugesen et al., 2019) and that both H3K4me3 and H3K36me2/3 are inhibitory to PRC2 activity (Ballare et al., 2012; Schmitges et al., 2011).”
Background
Control and Function of Histone H3 Lysine 27 Methylation in Neurospora crassa
McNaught, K. J. (2020) · Scholars' Bank (University of Oregon)
Differential metabolic profiles mediated SLC1A2 confer resistance in glioblastoma therapies : stratification goals and implementation
Koh, L. (2019) · doi:10.32657/10356/138683
STX18-AS1 is a Long Noncoding RNA predisposing to Atrial Septal Defect via downregulation of NKX2-5 in differentiating cardiomyocytesPreprint
Liu, Y., Choy, M., Abraham, S., Tenin, G., Black, G. C. M., & Keavney, B. D. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.05.27.118349
Autoregulation of JARID2 through PRC2 interaction with its antisense ncRNA
Al‐Raawi, D., & Kanhere, A. (2020) · BMC Research Notes · doi:10.1186/s13104-020-05348-z
“PRC2 catalyses mono-, di- and trimethylation of histone H3 at lysine 27 (H3K27me3) [3, 4].”
Background
Histone Demethylase UTX Compromises Articular Chondrocyte Anabolism and Aggravates Osteoarthritic DegenerationPreprint
Lian, W., Wu, R., Ko, J., Chen, Y., Wang, S.-Y., Yu, C.-P., Jahr, H., & Wang, F. (2021) · Research Square · doi:10.21203/rs.3.rs-467396/v1
MDM2 as a chromatin modifier
Gerber, S. (2020) · eDiss (Georg-August-Universität Göttingen) · doi:10.53846/goediss-8184
Targeting Cooperation of Chronic Inflammation with Epigenetic Reprogramming Triggers a Synthetic Lethality in Glioblastoma MultiformePreprint
Lin, K., Gao, W., Chen, N., Wang, H., Wang, R., Yang, S., Xie, F., Meng, J., Lam, E. W. ‐., Ma, C., et al. (2022) · Research Square · doi:10.21203/rs.3.rs-1394307/v1
Canonical PRC1 Recruitment Is Promoted by EZH1-PRC2 Independent of H3K27me3 in Quiescent CellsPreprint
Healy, E., McCole, R., Monger, C., Brien, G. L., Wang, C., Neikes, H. K., Potjewyd, F., Vermeulen, M., James, L. I., & Bracken, A. P. (2022) · SSRN Electronic Journal · doi:10.2139/ssrn.4089979
PHF1 compartmentalizes PRC2 at target loci via phase separationPreprint
Lu, G., & Li, P. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.10.20.513034
CRISPR, epigenetics, and cancer
Martella, A. (2023) · Elsevier eBooks · doi:10.1016/b978-0-323-91367-6.00007-6
Applications of bioinformatics and machine learning in the analysis of proteomics data
Li, B. (2023) · Utrecht University Repository (Utrecht University) · doi:10.33540/1818

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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