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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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“Furthermore, polycomb mediated pre-marks, indicated by histone H3K27 methylation, have been shown to recruit DNMTs, and could, therefore, have a role in the misdirection of methyltransferases in cancer”
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Esteller, M. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddm018 · Cited by 725
“The use of epigenomic technologies for different acetylation and methylation modifications of histones (71,72) and methylated DNA (51,52) in embryonic stem cells provides a chromatin signature of pluripotent cell lines.”
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“In vitro we see an increase in DNA methylation that correlates with the low basal expression level of these genes, which harbor PcG complexes in embryonic stem and progenitor cells (Ohm et al., 2007; Schlesinger et al., 2007; Widschwendter et al., 2007).”
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BackgroundUnderstanding the relationship between DNA methylation and histone lysine methylation
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“Our findings support previous observations showing significant differences between the characteristics of genes that gain DNA methylation during tumorigenesis, vs. those that lose DNA methylation (Ohm et al. 2007; Schlesinger et al. 2007).”
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“Whereas H3K27me3 has been shown to 'prime' gene promoters for later DNA methylation (Schlesinger et al. 2007; Mohn et al. 2008; Widschwendter et al. 2007; Ohm et al. 2007; Gal-Yam et al. 2008), several reports have shown antagonism or mutual exclusiveness between H3K27me3 and DNA methylation (Wu et al.”
BackgroundInfluentialA DNA methylation fingerprint of 1628 human samplesPreprint
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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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