Cited by 1,226Epigenetics and DNA MethylationGenomics and Chromatin DynamicsCancer-related gene regulation

The DOI matches its Crossref record; 31 of the 31 references it cites were found in a registry or an index.

Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer

Schlesinger, Yeshayahu, Straussman, Ravid, Keshet, Ilana, Farkash, Shlomit, Hecht, Merav, Zimmerman, Joseph, Eden, Eran, Yakhini, Zohar, Ben-Shushan, Etti, Reubinoff, Benjamin E, Bergman, Yehudit, Simon, Itamar, Cedar, Howard·2007·Nature Genetics

DOI 10.1038/ng1950

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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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Background
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Method
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Background
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Background
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ResultInfluential
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Background
Methylation across the central dogma in health and diseases: new therapeutic strategies
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Self-citation
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BackgroundInfluential
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“This is similar to what has been found in other tumor types, for example lung (14, 18), breast (32, 33), and colorectal cancer (15, 34), lymphomas (35), as well as being similar to a recent report on glioblastoma multiforme (41%, 807 genes were analyzed; ref.”
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Background
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Background
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Background
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Background
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Background
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Lechner, M., Fenton, T. R., West, J., Wilson, G. A., Feber, A., Henderson, S. R., Thirlwell, C., Dibra, H. K., Jay, A., Butcher, L. M., et al. (2013) · Genome Medicine · doi:10.1186/gm419 · Cited by 128
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“…but by polycomb chromatin, which in the ESCsmostly occurs in the setting of bivalent chromatin involving both H3K4me3 and H3K27me3 marks at the promoters (Berman et al., 2011; Easwaran et al., 2012; Gal-Yam et al., 2008; Ohm et al., 2007; Schlesinger et al., 2007; Widschwendter et al., 2007).”
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Background
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Background
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“PcG Polycomb targets compiled from four sources [48-51] 3614 3523 41,942”
Background
Sustained JNK1 activation is associated with altered histone H3 methylations in human liver cancer
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“Emerging evidence suggests that EZH2 along with other assembled PRC2 subunits represses expression of the genes required for cell differentiation, lineage development, and tumor suppression through methylations on H3K9, H3K27, and DNA [47–49].”
Background
Bivalent domains enforce transcriptional memory of DNA methylated genes in cancer cells
Rodríguez, J., Muñoz, M., Vives, L., Frangou, C. G., Groudine, M. T., & Peinado, M. A. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0810133105 · Cited by 123
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Background
Coordinate Regulation of DNA Methylation and H3K27me3 in Mouse Embryonic Stem Cells
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“Antibodies specific to H3K9me2, H3K9me3, H3K27me2, and H3K27me3 show enrichment for H3K9me3 and H3K27me3 at the DMD. Positive control PCRs for H3K9me2 and H3K27me2 (Charlie [1]), H3K9me3 (Actin), and H3K27me3 (Hoxa9 [2]) are included as well as a test for the Rasgrf1 DMD. NTC, no template control; WCE, whole cell extr…”
Background
An Integrated Prognostic Classifier for Stage I Lung Adenocarcinoma Based on mRNA, microRNA, and DNA Methylation Biomarkers
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“In cancer cells, marking by polycomb proteins and H3K27me3 mediates de novo DNA methylation.(41) Methylation of ESC polycomb targets(42) and a stem cell-like gene expression signature(26) provide a mechanism for the acquisition of stem cell-like features that are observed in many tumors.”
Background
Pluripotent stem cells escape from senescence-associated DNA methylation changesPreprint
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BackgroundInfluential
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DNA methylation dynamics and dysregulation delineated by high-throughput profiling in the mouse
Zhou, W., Hinoue, T., Barnes, B., Mitchell, O. D., Iqbal, W., Lee, S. M., Foy, K. K., Lee, K., Moyer, E. J., VanderArk, A., et al. (2022) · Cell Genomics · doi:10.1016/j.xgen.2022.100144 · Cited by 116
“It has long been known that cancer-associated CpG-island hypermethylation in human tumors is enriched for regions occupied by polycomb repressors in stem cells (Ohm et al., 2007; Schlesinger et al., 2007; Widschwendter et al., 2007).”
Background
Prognostic significance of global histone modifications in resected squamous cell carcinoma of the esophagus
Tzao, C., Tung, H., Jin, J., Sun, G.-H., Hsu, H., Chen, B.-H., Yu, C., & Lee, S.-C. (2008) · Modern Pathology · doi:10.1038/modpathol.2008.172 · Cited by 121
Promoter DNA Hypermethylation and Gene Repression in Undifferentiated Arabidopsis Cells
Berdasco, M., Alcázar, R., García‐Ortiz, M. V., Ballestar, E., Fernández, A. F., Roldán‐Arjona, T., Tiburcio, A. F., Altabella, T., Buisine, N., Quesneville, H., et al. (2008) · PLoS ONE · doi:10.1371/journal.pone.0003306 · Cited by 124
“This is exemplified by the observations that human embryonic stem cells have specific epigenetic signatures [12–14], many tissue-specific genes present promoter DNA methylation-dependent regulation (reviewed in [15,16]), and finally, aberrant hypermethylation-mediated repression of genes involved in cell differentiati…”
Background
Differential variability improves the identification of cancer risk markers in DNA methylation studies profiling precursor cancer lesions
Teschendorff, A. E., & Widschwendter, M. (2012) · Bioinformatics · doi:10.1093/bioinformatics/bts170 · Cited by 115
“Thus, parametric testing using t-tests or regularized versions thereof has been the standard approach for identifying and ranking features of interest (Smyth, 2004; Tibshirani et al., 2002; Tusher et al., 2001; Wettenhall and Smyth, 2004).”
Method
Nucleosomes containing methylated DNA stabilize DNA methyltransferases 3A/3B and ensure faithful epigenetic inheritance
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“We and others have previously shown that DNMT3A/3B, but not DNMT1, are strongly anchored to nucleosomes containing methylated DNA in somatic cells [22,26].”
Background
Epigenetics Lessons from Twins: Prospects for Autoimmune Disease
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“DNA methylation and histone modifications are coupled by multiple mechanisms (Fig. 2). For instance, methylated DNA sequences are generally packaged with nucleosomes containing histone H3 trimethylated on K27, and this mark has been shown to be established and maintained by EZH2containing Polycomb (PcG) complexes [ 32…”
Background
Epigenetic Drift, Epigenetic Clocks and Cancer Risk
Zheng, S., Widschwendter, M., & Teschendorff, A. E. (2016) · Epigenomics · doi:10.2217/epi-2015-0017 · Cited by 118
Chronic IL-1β-induced inflammation regulates epithelial-to-mesenchymal transition memory phenotypes via epigenetic modifications in non-small cell lung cancer
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DNA methylation patterns in lung carcinomas
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“The finding of widespread methylation of homeobox genes in lung cancers lends support to the hypothesis that a substantial fraction of genes methylated in cancer are targets of the Polycomb complex [78,39-42,34].”
A central role for G9a and EZH2 in the epigenetic silencing of cyclooxygenase‐2 in idiopathic pulmonary fibrosis
Coward, W. R., Feghali‐Bostwick, C. A., Jenkins, G. R., Knox, A. J., & Pang, L. (2014) · The FASEB Journal · doi:10.1096/fj.13-241760 · Cited by 118
“There are reports indicating that EZH2 directly interacts with Dnmts and is necessary for de novo DNA methylation for PRC2 target gene promoters (6, 7).”
Background
Epigenetics and cancer
Kanwal, R., & Gupta, S. (2010) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00066.2010 · Cited by 124
Aberrant DNA methylation in contrast with mutations
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Action at a distance: epigenetic silencing of large chromosomal regions in carcinogenesis
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The role of 5-hydroxymethylcytosine in human cancer
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Polycomb-mediated silencing in neuroendocrine prostate cancer
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“In line with those results, increasing evidence supports the idea that PcG activity dictates DNMT recruitment to chromatin at target loci, implying a central role for PcG complexes in DNA methylation and its resulting epigenetic effects [42,43].”
Result
DNMT1 and DNMT3B Modulate Distinct Polycomb-Mediated Histone Modifications in Colon Cancer
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“Schlesinger and colleagues showed that genes subject to tumorspecific hypermethylation in colon cancer were significantly more likely to be marked by H3K27 methylation in normal tissues than genes lacking H3K27 methylation (17).”
Influential
DNA Methylation and Complete Transcriptional Silencing of Cancer Genes Persist after Depletion of EZH2
McGarvey, K. M., Greene, E., Fahrner, J. A., Jenuwein, T., & Baylin, S. B. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-2029 · Cited by 116
3‐Deazaneplanocin A is a promising therapeutic agent for the eradication of tumor‐initiating hepatocellular carcinoma cells
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“PcG-mediated trimethylation on H3K27 reportedly pre-marks genes for de novo methylation in colon cancer cells.(33) Although DZNep or EZH2 knockdown is not effective in reactivating genes silenced by DNA methylation, it reactivates developmental genes not silenced by DNA methylation in cancer cells.”
Background
BIM promoter directly targeted by EBNA3C in polycomb-mediated repression by EBV
Paschos, K., Parker, G. A., Watanatanasup, E., White, R. E., & Allday, M. J. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks391 · Cited by 117
“A chromatin immunoprecipitation (ChIP) assay kit from Millipore (17-295) was used, according to the manufacturer’s protocol.”
DNA methylation and repressive histones in the promoters of PD-1, CTLA-4, TIM-3, LAG-3, TIGIT, PD-L1, and galectin-9 genes in human colorectal cancer
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“It has been reported that promoter demethylation and distribution of repressive histones work together for the upregulation of many genes in cancers [13].”
Background
Polycomb Group (PcG) Proteins and Human Cancers: Multifaceted Functions and Therapeutic Implications
Wang, W. T., Qin, J., Voruganti, S., Nag, S. A., Zhou, J., & Zhang, R. (2015) · Medicinal Research Reviews · doi:10.1002/med.21358 · Cited by 118
EPISCORE: cell type deconvolution of bulk tissue DNA methylomes from single-cell RNA-Seq data
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Ectopic expression of the histone methyltransferase Ezh2 in haematopoietic stem cells causes myeloproliferative disease
Herrera-Merchan, A., Arranz, L., Ligos, J. M., de Molina-Iracheta, A., Domı́nguez, O., & González, S. (2012) · Nature Communications · doi:10.1038/ncomms1623 · Cited by 121
Retracted
RIP140 directs histone and DNA methylation to silence Ucp1 expression in white adipocytes
Kiskinis, E., Hallberg, M., Christian, M., Olofsson, M., Dilworth, S. M., White, R., & Parker, M. G. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601908 · Cited by 111
The H3K27me3 Demethylase dUTX Is a Suppressor of Notch- and Rb-Dependent Tumors in Drosophila
Herz, H., Madden, L. D., Chen, Z., Bolduc, C., Buff, E. M., Gupta, R., Davuluri, R. V., Shilatifard, A., Hariharan, I. K., & Bergmann, A. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.01633-09 · Cited by 116
“a leading cause of certain human cancers (7, 37, 39, 64, 78).”
Background
Epigenetic Priming in Cancer Initiation
Vicente‐Dueñas, C., Hauer, J., Cobaleda, C., Borkhardt, A., & Sánchez-Garcı́a, I. (2018) · Trends in cancer · doi:10.1016/j.trecan.2018.04.007 · Cited by 107
The role of DNA methylation in directing the functional organization of the cancer epigenomePreprint
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“2010), since the presence of the Polycombmark in normal precursor cells is a strong predictor of methylation gain in cancer (Ohm et al. 2007; Schlesinger et al. 2007; Widschwendter et al. 2007) and is postulated to be part of a global “epigenetic switch” from Polycomb repression to DNA methylation (Gal-Yam”
Background
Concepts of epigenetics in prostate cancer development
Cooper, C. S., & Foster, C. S. (2008) · British Journal of Cancer · doi:10.1038/sj.bjc.6604771 · Cited by 108
A DNMT3A PWWP mutation leads to methylation of bivalent chromatin and growth retardation in mice
Sendžikaitė, G., Hanna, C. W., Stewart-Morgan, K. R., Ivanova, E., & Kelsey, G. (2019) · Nature Communications · doi:10.1038/s41467-019-09713-w · Cited by 112
Retraction Note: Ectopic expression of the histone methyltransferase Ezh2 in haematopoietic stem cells causes myeloproliferative disease
Herrera-Merchan, A., Arranz, L., Ligos, J. M., de Molina-Iracheta, A., Domı́nguez, O., & González, S. (2017) · Nature Communications · doi:10.1038/ncomms14005 · Cited by 108
Retracted
Epigenetic regulation of hepatocellular carcinoma in non-alcoholic fatty liver disease
Tian, Y., Wong, V. W., Chan, H. L., & Cheng, A. S. L. (2013) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2013.08.010 · Cited by 108
Genome-wide Analysis of CpG Island Methylation in Bladder Cancer Identified TBX2, TBX3, GATA2, and ZIC4 as pTa-Specific Prognostic Markers
Kandimalla, R., van Tilborg, A. A. G., Kompier, L. C., Stumpel, D. J. P. M., Stam, R. W., Bangma, C. H., & Zwarthoff, E. C. (2012) · European Urology · doi:10.1016/j.eururo.2012.01.011 · Cited by 106
“In line with previous reports in solid tumours [18,19,41], a high proportion of the genes we find de novo methylated in BCa are repressed by polycomb complexes in embryonic stem cells.”
BackgroundResult
Estradiol-Induced Epigenetically Mediated Mechanisms and Regulation of Gene Expression
Kovács, T., Szabó‐Meleg, E., & Ábrahám, I. M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21093177 · Cited by 112
EZH2: Not EZHY (Easy) to Deal
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“Subsequent findings provided more inputs to the EZH2–DNA methylation link by comparing gene profiles of EZH2 target genes in normal versus cancer cells, and revealed that EZH2 targets that display H3K27Me3 in normal cells are correlated to the aberrantly hypermethylated corresponding genes in cancer cells (46, 47).”
Background
The context and potential of epigenetics in oncology
Lopez, J. S., Percharde, M., Coley, H. M., Webb, A., & Crook, T. (2009) · British Journal of Cancer · doi:10.1038/sj.bjc.6604930 · Cited by 106
HOXA11 DNA methylation—A novel prognostic biomarker in ovarian cancer
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Overexpression of enhancer of zeste homolog 2 with trimethylation of lysine 27 on histone H3 in adult T-cell leukemia/lymphoma as a target for epigenetic therapy
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“EZH2 is a critical component of PRC2, which mediates epigenetic gene silencing through trimethylation of H3K27.”
Background
Epigenetic regulation of myogenesis
Perdiguero, E., Sousa‐Victor, P., Ballestar, E., & Muñoz‐Cánoves, P. (2009) · Epigenetics · doi:10.4161/epi.4.8.10258 · Cited by 103
Overexpression of the EZH2, RING1 and BMI1 genes is common in myelodysplastic syndromes: relation to adverse epigenetic alteration and poor prognostic scoring
Xu, F., Li, X., Wu, L., Zhang, Q., Yang, R., Yang, Y., Zhang, Z., He, Q., & Chang, C. (2010) · Annals of Hematology · doi:10.1007/s00277-010-1128-5 · Cited by 103
“He: C. Chang Department of Hematology, The Sixth people Hospital, Shanghai JiaoTong University, ShangHai Jiaotong University School of Medicine, Building NO 600, Yishan Road, Shanghai 200233, People’s Republic of China e-mail: lixiao3326@yahoo.com.cn Ann Hematol (2011) 90:643–653 DOI 10.1007/s00277-010-1128-5 promoter…”
BackgroundInfluential
Stem Cell Chromatin Patterns: An Instructive Mechanism for DNA Hypermethylation?
Ohm, J. E., & Baylin, S. B. (2007) · Cell Cycle · doi:10.4161/cc.6.9.4210 · Cited by 102
Chronic Inflammation Induces a Novel Epigenetic Program That Is Conserved in Intestinal Adenomas and in Colorectal Cancer
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“Together, these data suggest that inflammation-related methylation changes are targeted to a specific subset of DMVs that are associated with active genes and thus define an epigenetic program that is clearly distinct from the previously described H3K27me3associated de novo methylation of CpG island-associated cancer…”
BackgroundSelf-citation
Targeting DNA repair in cancer: current state and novel approaches
Klinakis, A., Karagiannis, D., & Rampias, T. N. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03299-8 · Cited by 108
“Several studies have demonstrated that H3K27me3-marked genes are targets for aberrant DNA methylation in cancer cells [217, 218].”
Background
TET-Mediated Hypermethylation Primes SDH-Deficient Cells for HIF2α-Driven Mesenchymal Transition
Morin, A., Goncalves, J., Moog, S., Castro‐Vega, L. J., Job, S., Buffet, A., Fontenille, M., Woszczyk, J., Gimenez‐Roqueplo, A., Letouzé, É., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.03.022 · Cited by 110

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
ORCID: Straussman, Ravid
Hecht, Merav
Reubinoff, Benjamin E
Bergman, Yehudit
Simon, Itamar
Cedar, Howard
Venue: Nature Genetics
Publisher: Springer Science and Business Media LLC
Published: 2006-12-31
Volume: 39
Issue: 2
Pages: 232-236
ISSN: 1061-4036 (ISSN-L)
1546-1718
DOI: 10.1038/ng1950
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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Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer

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