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Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer
Abstract
Many genes associated with CpG islands undergo de novo methylation in cancer. Studies have suggested that the pattern of this modification may be partially determined by an instructive mechanism that recognizes specifically marked regions of the genome. Using chromatin immunoprecipitation analysis, here we show that genes methylated in cancer cells are specifically packaged with nucleosomes containing histone H3 trimethylated on Lys27. This chromatin mark is established on these unmethylated CpG island genes early in development and then maintained in differentiated cell types by the presence of an EZH2-containing Polycomb complex. In cancer cells, as opposed to normal cells, the presence of this complex brings about the recruitment of DNA methyl transferases, leading to de novo methylation. These results suggest that tumor-specific targeting of de novo methylation is pre-programmed by an established epigenetic system that normally has a role in marking embryonic genes for repression.
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“hypermethylated regions (HyperDMRs) in HCC were enriched in the promoters of developmental genes and in genic features such as untranslated regions (UTRs) and exons (Fig. 1b and Supplementary Fig. 2f)47,48.”
From Multi-omic analysis of hepatocellular carcinoma reveals aberrant cis-regulatory changes and dysregulated retrotransposons with prognostic potential (2025) · cites this paper as [48]
In the citing paper
“EZH2 inhibition has been shown to augment interferoninduced gene expression in tumour cells 227-229 .”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [227]
In the citing paper
“Despite global DNA hypomethylation, a limited number of genomic loci gain DNA methylation during aging and in cancer.”
From Dynamic DNA methylation: In the right place at the right time (2018) · cites this paper as [47]
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Rodríguez, C., Borgel, J., Court, F., Cathala, G., Forné, T., & Piette, J. (2010) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2009.12.159 · Cited by 65
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“In fact, the suppression of gene expression seemed to result from chromatin remodeling associated with repressive chromatin marks, including trimethyl-H3K27, as we and others have reported that trimethyl-H3K27 can be linked to DNA methylation [50,51].”
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“The Polycomb group target genes (PCGT) status for a given CpG loci was based on whether the gene associated with that CpG was described as a PcG target in previously published works [52–55].”
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Chen, Y., Breeze, C. E., Zhen, S., Beck, S., & Teschendorff, A. E. (2016) · Epigenetics & Chromatin · doi:10.1186/s13072-016-0058-4 · Cited by 67
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BackgroundThe Epigenome in Multiple Myeloma: Impact on Tumor Cell Plasticity and Drug Response
Smedt, E. D., Lui, H., Maes, K., Veirman, K. D., Menu, E., Vanderkerken, K., & Bruyne, E. D. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00566 · Cited by 62
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Takeshima, H., Niwa, T., Takahashi, T., Wakabayashi, M., Yamashita, S., Ando, T., 稲川, 悠., Taniguchi, H., Katai, H., Sugiyama, T., et al. (2014) · Cancer Letters · doi:10.1016/j.canlet.2014.11.038 · Cited by 61
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Κhan, P., Siddiqui, J. A., Maurya, S. K., Lakshmanan, I., Jain, M., Ganti, A. K., Salgia, R., Batra, S. K., & Nasser, M. W. (2020) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2020.11.006 · Cited by 64
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“The absence or increase of certain PcG proteins has been linked to tumorigenesis in various contexts and model organisms (Varambally et al. 2002; Bracken et al. 2003; Kleer et al. 2003; Schlesinger et al. 2007; Kondo et al. 2008; Classen et al. 2009; Martinez et al. 2009).”
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BackgroundRUNX3 Methylation Reveals that Bladder Tumors Are Older in Patients with a History of Smoking
Wolff, E. M., Liang, G., Cortez, C. C., Tsai, Y., Castelao, J. E., Cortessis, V. K., Tsao-Wei, D. D., Groshen, S. G., & Jones, P. A. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-6616 · Cited by 61
“TNM stage Ta 154 (45) CIS 9 (3) T1 93 (27) T2 54 (16) T3 18 (5) T4 13 (4) Grade 1 109 (32) 2 134 (39) 3 87 (25) 4 11 (3) Sex Male 259 (76) Female 83 (24) Age at diagnosis (y) V40 22 (6) 41–50 60 (18) 51–60 175 (51) 61–65 84 (25) Median (range) 58 (25–65) Smoking history Never/irregular 45 (13) Former 137 (40) Current…”
Oldridge, E. E., Walker, H. F., Stower, M. J., Simms, M. S., Mann, V. M., Collins, A. T., Pellacani, D., & Maitland, N. J. (2013) · Oncogenesis · doi:10.1038/oncsis.2013.6 · Cited by 60
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“the polycomb group protein H3K27me3 in normal prostate epithelial cells, which is then replaced by DNA methylation in LNCaP cells, consistent with the finding that genes that are commonly methylated in cancer are often marked by H3K27me3 in the embryonic stem cells (42, 50, 51).”
BackgroundDNA Methylation Changes in Prostate Cancer
Goering, W., Kloth, M. T., & Schulz, W. A. (2012) · Methods in molecular biology · doi:10.1007/978-1-61779-612-8_4 · Cited by 60
Role of DNA methylation in human age prediction
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“There were 8 classes significantly associated with age: (12) CGI|MIR; (16) PcG|TFBS; (20) PcG; (23) TFBS; (24) PcG|MIR|TFBS; (27) MIR|TFBS; (29) CGI|PcG|LINE2; (31) LINE2|TFBS.”
Monk, M., Hitchins, M. P., & Hawes, S. M. (2008) · Molecular Human Reproduction · doi:10.1093/molehr/gan025 · Cited by 58
“Recently, several papers have reported that stem cells and cancer cells share a common subpopulation of genes, which repress differentiation, marked (and silenced) by heterochromatic modifications and methylation, respectively (Ohm et al., 2007; Schlesinger et al., 2007; Widschwendter et al., 2007).”
BackgroundInfluentialDNA methylation and chromatin modifiers in colorectal cancer
Vymetalkova, V. P., Vodička, P., Vodenková, S., Alonso, S., & Schneider‐Stock, R. (2019) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2019.04.002 · Cited by 58
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Breast Tumor Kinase (Brk/PTK6) Is a Mediator of Hypoxia-Associated Breast Cancer Progression
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“hemoglobin B (HBB) gene (33) served as a negative control (Fig.”
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“polycomb-regulated genes and a very high percentage of the methylated genes was pre-marked with trimethylated H3K27 in addition to other polycomb components (10), further study is needed to clarify which gene is involved and whether or not methylation of H3K27 also plays a role in the interaction with this hypermethyl…”
BackgroundHOXC8 regulates self-renewal, differentiation and transformation of breast cancer stem cells
Shah, M., Cardenas, R. P., Wang, B. L., Persson, J. L., Mongan, N. P., Grabowska, A. M., & Allegrucci, C. (2017) · Molecular Cancer · doi:10.1186/s12943-017-0605-z · Cited by 58
“These findings suggest a model whereby stem cells could be the cell of origin of breast tumours, as developmental genes that are normally reversibly silenced by polycomb complexes in these cells [43] become permanently silenced via DNA methylation during carcinogenesis [40, 44, 45].”
BackgroundMethylation-Based Therapies for Colorectal Cancer
Cervena, K., Siskova, A., Buchler, T., Vodicka, P., & Vymetalkova, V. (2020) · Cells · doi:10.3390/cells9061540 · Cited by 57
Yu, H., Simons, D. L., Segall, I., Cárcamo‐Cavazos, V., Schwartz, E., Yan, N., Zuckerman, N. S., Dirbas, F. M., Johnson, D. L., Holmes, S., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0051239 · Cited by 59
“Molecular mechanisms involving PRC2 proteins have attracted significant attention in cancer research due to their critical role in controlling differentiation and tumorigenesis [7,18,19].”
BackgroundHistone Methyltransferase Inhibitors: Novel Epigenetic Agents for Cancer Treatment
Zagni, C., Chiacchio, U., & Rescifina, A. (2012) · Current Medicinal Chemistry · doi:10.2174/092986713804806667 · Cited by 59
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Mechanisms of chromatin-based epigenetic inheritance
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“Methylation of histone H3 lysine 9 and lysine 27 was suggested to be a prerequisite for de novo DNA methylation in cancer (33, 38).”
BackgroundSarah Derks, A., Bosch, L. J. W., Niessen, H. E. C., Moerkerk, P. T. M., van den Bosch, S. M., Carvalho, B. G., Mongera, S., Voncken, J. W., Meijer, G. A., A, A. P. D. B., et al. (2009) · Carcinogenesis · doi:10.1093/carcin/bgp073 · Cited by 56
“genes which become de novo methylated in cancer are often bivalently marked by both active (H3K4me3) and repressive (H3K27me3) histone marks in human embryonal stem cells [14,41].”
BackgroundTsang, D. P., Wu, W. K. K., Kang, W., Lee, Y., Wu, F., Yu, Z., Xiong, L., Chan, A. W. H., TONG, J. H. M., Yang, W., et al. (2016) · The Journal of Pathology · doi:10.1002/path.4688 · Cited by 56
“PRC2 targets are also more likely to have cancer-specific DNA hypermethylation than non-targets [26].”
BackgroundWijetunga, N. A., Pascual, M., Tozour, J. N., Delahaye, F., Alani, M. T., Adeyeye, M., Wolkoff, A. W., Verma, A. K., & Greally, J. M. (2016) · Oncogene · doi:10.1038/onc.2016.340 · Cited by 57
“They also correspond to bivalent chromatin domains in pluripotent cells 49 , loci that are targets of the polycomb repressive complex in early development that are believed to be unusually prone to the acquisition of DNA methylation later in life as part of oncogenesis 50–52 .”
CRISPR/Cas mediated epigenome editing for cancer therapy
Ansari, I., Chaturvedi, A., Chitkara, D., & Singh, S. P. (2021) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2020.12.018 · Cited by 58
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“This fraction of Polycombtargeted events seems substantially smaller than those found in colorectal cancers or lung cancers [17, 43].”
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The Cancer Epigenome: Its Origins, Contributions to Tumorigenesis, and Translational Implications
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A Role for EZH2 in Silencing of IFN-γ Inducible MHC2TA Transcription in Uveal Melanoma
Holling, T. M., Bergevoet, M. W. T., Wilson, L., van Eggermond, M. C. J. A., Schooten, E., Steenbergen, R. D. M., Snijders, P. J. F., Jager, M. J., & van den Elsen, P. J. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.8.5317 · Cited by 55
“This notion is in line with the recent observation that the 3Me-K27-H3 modification premarks genes for de novo methylation in cancer (42).”
ResultMismatch Repair Proteins Initiate Epigenetic Alterations during Inflammation-Driven Tumorigenesis
Maiuri, A. R., Peng, M., Podicheti, R., Sriramkumar, S., Kamplain, C. M., Rusch, D. B., Shields, C. E. D., Sears, C. L., & O’Hagan, H. M. (2017) · Cancer Research · doi:10.1158/0008-5472.can-17-0056 · Cited by 57
“are bivalent (containing both H3K4me3 and H3K27me3) in mouse embryonic stem cells (Figure S1B) (20-24).”
BackgroundChromatin activation as a unifying principle underlying pathogenic mechanisms in multiple myelomaPreprint
Ciriza, R. O., Kulis, M., Russiñol, N., Chapaprieta, V., Carrasco‐Leon, A., García-Torre, B., Charalampopoulou, S., Clot, G., Beekman, R., Meydan, C., et al. (2020) · Genome Research · doi:10.1101/gr.265520.120 · Cited by 54
Mechanisms of DNA Methylation Regulatory Function and Crosstalk with Histone Lysine Methylation
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Molecular Rules Governing De Novo Methylation in Cancer
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Self-citationChromatin maps, histone modifications and leukemia
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The Dynamics of DNA Methylation Covariation Patterns in Carcinogenesis
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“compared to normal tissue [1–7].”
The good, the bad and the ugly: Epigenetic mechanisms in glioblastoma
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“…a significant fraction of genes that display DNA hypermethylation at promoters in GBM, are sites of repression by PRC2 in ES cells, an observation that has now been described for several solid tumours (Martin-Subero et al., 2009; Martinez et al., 2009; Ohm et al., 2007; Schlesinger et al., 2007).”
BackgroundProfiling Epigenetic Alterations in Disease
Martín-Subero, J. I., & Esteller, M. (2011) · Advances in experimental medicine and biology · doi:10.1007/978-1-4419-8216-2_12 · Cited by 53
Histone modifications as a pathogenic mechanism of colorectal tumorigenesis
Gargalionis, A. N., Piperi, C., Adamopoulos, C., & Papavassiliou, A. G. (2012) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2012.05.002 · Cited by 53
Stem Cell Origin of Death-from-Cancer Phenotypes of Human Prostate and Breast Cancers
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“, embryonic stem cells), indicated that the Polycomb-associated chromatin modification, H3K27me3, predisposes sequences towards DNA hypermethylation in cancer (15-17, 20).”
Epigenetics, stem cells and epithelial cell fate
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“…di- and trimethylation of H3 lysine 9 (H3K9) and trimethylation of H3K27 elicit the compaction of chromatin and thus gene silencing through the recruitment of heterochromatin protein 1 (HP1) and polycomb group (PcG) proteins, respectively (Bannister et al., 2001; Schlesinger et al., 2007).”
BackgroundLauss, M., Aine, M., Sjödahl, G., Veerla, S., Patschan, O., Guðjónsson, S., Chebil, G., Lövgren, K., Fernö, M., Månsson, W., et al. (2012) · Epigenetics · doi:10.4161/epi.20837 · Cited by 53
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“For colorectal cancers (CRCs), of the genes that show cancer-associated hypermethylation in their promoter CpG island loci, approximately 10% are active genes that are expressed in normal colonic epithelial cells.(1,2) Inactivation of actively expressed tumor suppressor genes or tumor-related genes by promoter CpG isl…”
BackgroundHistone methylase MLL1 coordinates with HIF and regulate lncRNA HOTAIR expression under hypoxia
Bhan, A., Deb, P., Shihabeddin, N., Ansari, K. I., Brotto, M., & Mandal, S. S. (2017) · Gene · doi:10.1016/j.gene.2017.07.069 · Cited by 54
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“Of note, genes that gain DNA methylation in CIMP were in majority repressed and marked by H3K27me3 in normal kidneys consistent with previous findings(22).”
Acute lymphoblastic leukemia displays a distinct highly methylated genome
Hetzel, S., Mattei, A. L., Kretzmer, H., Qu, C., Chen, X. '., Fan, Y., Wu, G., Roberts, K. G., Luger, S. M., Litzow, M. R., et al. (2022) · Nature Cancer · doi:10.1038/s43018-022-00370-5 · Cited by 52
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“Furthermore, H3K27me3 has been proposed to ‘pre-mark’ genes for de novo methylation in cancer by favoring the aberrant recruitment of DNA methyltransferases [53], which suggests that KDM6A mutations may play an important role for the establishment of CIMP.”
BackgroundGolbabapour, S., Majid, N. B. A., Hassandarvish, P., Hajrezaie, M., Abdulla, M. A., & Hadi, A. H. A. (2013) · OMICS A Journal of Integrative Biology · doi:10.1089/omi.2012.0105 · Cited by 55
“…prostate cancer (Ren et al., 2012), PcG proteins repress tumor suppressor genes (Dietrich et al., 2007; Gil and Peters, 2006) through the accumulation of DNA methylation in the promoter regions of their targets, thus altering their methylation profiles (Ohm et al., 2007; Schlesinger et al., 2007).”
BackgroundMomparler, R. L., Idaghdour, Y., Márquez, V. E., & Momparler, L. F. (2012) · Leukemia Research · doi:10.1016/j.leukres.2012.03.001 · Cited by 54
“This is due to the recruitment by EZH2 of DNA methyltransferases (DNMTs) to the promoter region of PcG target genes [19,20].”
Javierre, B. M., Rodríguez‐Ubreva, J., Al‐Shahrour, F., Corominas, M., Graña‐Castro, O., Ciudad, L., Agirre, X., Pisano, D. G., Valencia, A., Román‐Gómez, J., et al. (2011) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-10-0515 · Cited by 52
“For instance, polycomb-induced H3K27 trimethylation, which is involved in gene silencing during development, associates with DNA hypermethylation in cancer (5, 6).”
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MUC1-C activates EZH2 expression and function in human cancer cells
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“Accordingly, we generated GST-EZH2(501–614) and GST-EZH2(615–751).”
Influential3D chromatin architecture and epigenetic regulation in cancer stem cells
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“3 and the core histones display highly dynamic kinetics in their association with chromatin in ESCs, further opening the chromatin structure (Azuara et al., 2006; Meshorer et al., 2006; Schlesinger et al., 2017).”
BackgroundRole of primary aging hallmarks in Alzheimer´s disease
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“Figure 4 highlights the molecules which mediate the Theranostics 2023, Vol. 13, Issue 1 https://www.thno.org 218 coupling of REST and CTCF.”
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“Connections between DNA methylation and histone, polycomb and transcription factor (TF) proteins are increasingly apparent (1,3).”
BackgroundGenome-Wide Epigenetic Modifications in Cancer
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Epigenetic Therapeutics in Autoimmune Disease
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Giacopelli, B., Wang, M., Sher, A. C., Wu, Y.-Z., Schultz, A. R., Schmutz, M., Blachly, J. S., Eisfeld, A., Mundy-Bosse, B. L., Vosberg, S., et al. (2021) · Genome Research · doi:10.1101/gr.269233.120 · Cited by 58
“…shown that CIMP fre- quently targets promoters that aremarked by the polycomb repressive mark H3K27me3 in developmental precursors, which commonly mark poised promoters of developmentally regulated genes (Bernstein et al. 2006; Ohm et al. 2007; Schlesinger et al. 2007; Widschwendter et al. 2007).”
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Unmasking the Lung Cancer Epigenome
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Metadata
- Authors
- Schlesinger, Y., Straussman, R., Keshet, I., Farkash, S., Hecht, M., Zimmerman, J., Eden, E., Yakhini, Z., Ben-Shushan, E., Reubinoff, B. E., Bergman, Y., Simon, I., & Cedar, H.
- Affiliations
- Hebrew University of Jerusalem (IL)
- Technion – Israel Institute of Technology (IL)
- Corresponding author
- Cedar, Howard
- Venue
- Nature Genetics
- Published
- 2006-12-31
- Volume
- 39
- Issue
- 2
- Pages
- 232-236
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W1969670934
- Cited by
- 1,226
- References
- 31
- Citations by year
- 2026: 17 · 2025: 41 · 2024: 40 · 2023: 34 · 2022: 33 · 2021: 77 · 2020: 51 · 2019: 47 · 2018: 37 · 2017: 53 · 2016: 68 · 2015: 65 · 2014: 67 · 2013: 80 · 2012: 98
- FWCI
- 27.70
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Prostate Cancer Foundation
- Philip Morris International
- 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 › Cancer-related gene regulation
- Keywords
- Polycomb group proteins, H3K27me3, de novo methylation, CpG islands, EZH2, DNA methyltransferases, epigenetic inheritance, cancer epigenetics
- MeSH terms
- Carrier Proteins, Cells, Cultured, Colonic Neoplasms, Histones, Humans, Lysine, Methylation, Methyltransferases, Neoplasms, Viral Envelope Proteins, CpG Islands, Caco-2 Cells, DNA Methylation, Epigenesis, Genetic
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