A stem cell–like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing
Open accessAbstract
Adult cancers may derive from stem or early progenitor cells. Epigenetic modulation of gene expression is essential for normal function of these early cells but is highly abnormal in cancers, which often show aberrant promoter CpG island hypermethylation and transcriptional silencing of tumor suppressor genes and pro-differentiation factors. We find that for such genes, both normal and malignant embryonic cells generally lack the hypermethylation of DNA found in adult cancers. In embryonic stem cells, these genes are held in a 'transcription-ready' state mediated by a 'bivalent' promoter chromatin pattern consisting of the repressive mark, histone H3 methylated at Lys27 (H3K27) by Polycomb group proteins, plus the active mark, methylated H3K4. However, embryonic carcinoma cells add two key repressive marks, dimethylated H3K9 and trimethylated H3K9, both associated with DNA hypermethylation in adult cancers. We hypothesize that cell chromatin patterns and transient silencing of these important regulatory genes in stem or progenitor cells may leave these genes vulnerable to aberrant DNA hypermethylation and heritable gene silencing during tumor initiation and progression.
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HyperDMRs in HCC are enriched in promoters of developmental genes and in genic features such as UTRs and exons.
“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 [47]
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From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [226]
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- Authors
- Ohm, J. E., McGarvey, K. M., Yu, X., Cheng, L., Schuebel, K. E., Cope, L., Mohammad, H. P., Chen, W., Daniel, V. C., Yu, W., Berman, D. M., Jenuwein, T., Pruitt, K., Sharkis, S. J., Watkins, D. N., Herman, J. G., & Baylin, S. B.
- Affiliations
- Johns Hopkins University (US)
- Research Institute of Molecular Pathology (AT)
- Corresponding author
- Baylin, Stephen B
- ORCID
- Venue
- Nature Genetics
- Published
- 2007-01-09
- Volume
- 39
- Issue
- 2
- Pages
- 237-242
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC2744394
- OpenAlex
- W2170210082
- Cited by
- 1,130
- References
- 30
- Citations by year
- 2026: 9 · 2025: 26 · 2024: 33 · 2023: 53 · 2022: 33 · 2021: 56 · 2020: 38 · 2019: 36 · 2018: 27 · 2017: 50 · 2016: 57 · 2015: 54 · 2014: 70 · 2013: 82 · 2012: 105
- FWCI
- 40.71
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r01hl073781-10)
- Sidney Kimmel Comprehensive Cancer Center
- Sidney Kimmel Center for Prostate and Urologic Cancers
- National Heart, Lung, and Blood Institute (HL073781)
- National Cancer Institute (R01CA116160, CA116160, R01CA043318, CA 043318)
- 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 › Genetics › Genetic Syndromes and Imprinting
- Keywords
- tumor suppressor, DNA hypermethylation, chromatin, embryonic stem cells, embryonal carcinoma cells, H3K27 methylation, Polycomb group proteins, H3K4 methylation, H3K9 dimethylation, H3K9 trimethylation, CpG island hypermethylation, transcriptional silencing, stem cells, tumor initiation and progression
- MeSH terms
- Adult, Chromatin, Histones, Humans, Promoter Regions, Genetic, Repressor Proteins, Stem Cells, Tumor Cells, Cultured, Genes, Tumor Suppressor, DNA Methylation, Gene Silencing, Cell Proliferation, Embryonic Stem Cells, Polycomb-Group Proteins
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