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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HyperDMRs in HCC are enriched in promoters of developmental genes and in genic features such as UTRs and exons.
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From Multi-omic analysis of hepatocellular carcinoma reveals aberrant cis-regulatory changes and dysregulated retrotransposons with prognostic potential (2025) · cites this paper as [48]
EZH2 inhibition has been shown to augment interferon-induced gene expression in tumour cells.
“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]
Despite global DNA hypomethylation, a limited number of genomic loci gain DNA methylation during aging and in cancer.
“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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- 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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