Global DNA hypomethylation coupled to repressive chromatin domain formation and gene silencing in breast cancer
Open accessAbstract
While genetic mutation is a hallmark of cancer, many cancers also acquire epigenetic alterations during tumorigenesis including aberrant DNA hypermethylation of tumor suppressors, as well as changes in chromatin modifications as caused by genetic mutations of the chromatin-modifying machinery. However, the extent of epigenetic alterations in cancer cells has not been fully characterized. Here, we describe complete methylome maps at single nucleotide resolution of a low-passage breast cancer cell line and primary human mammary epithelial cells. We find widespread DNA hypomethylation in the cancer cell, primarily at partially methylated domains (PMDs) in normal breast cells. Unexpectedly, genes within these regions are largely silenced in cancer cells. The loss of DNA methylation in these regions is accompanied by formation of repressive chromatin, with a significant fraction displaying allelic DNA methylation where one allele is DNA methylated while the other allele is occupied by histone modifications H3K9me3 or H3K27me3. Our results show a mutually exclusive relationship between DNA methylation and H3K9me3 or H3K27me3. These results suggest that global DNA hypomethylation in breast cancer is tightly linked to the formation of repressive chromatin domains and gene silencing, thus identifying a potential epigenetic pathway for gene regulation in cancer cells.
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PMDs in HCC are enriched with repressive histone modifications and associated with transcriptional repression.
“These domains were enriched with repressive histone modifications and associated with transcriptional repression (Supplementary Fig. 2c, d)44–46.”
From Multi-omic analysis of hepatocellular carcinoma reveals aberrant cis-regulatory changes and dysregulated retrotransposons with prognostic potential (2025) · cites this paper as [45]
The sections “Allelic basis of repressive chromatin and DNA methylation” and “Formation of repressive chromatin domains at hypomethylated genomic regions” link PMDs or hypomethylated genes to repressive histone marks and reduced expression. But the study examines HCC1954 breast cancer cells, not hepatocellular carcinoma (HCC), so it does not establish the claim for HCC. (LLM, conf=0.88)
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- Authors
- Hon, G. C., Hawkins, R. D., Caballero, O. L., Lo, C., Lister, R., Pelizzola, M., Valsesia, A., Ye, Z., Kuan, S., Edsall, L. E., Camargo, A. A., Stevenson, B. J., Ecker, J. R., Bafna, V., Strausberg, R. L., Simpson, A. J., & Ren, B.
- Affiliations
- Ludwig Cancer Research (BE)
- University of California San Diego (US)
- Salk Institute for Biological Studies (US)
- SIB Swiss Institute of Bioinformatics (CH)
- Johns Hopkins University (US)
- ORCID
- Venue
- Genome Research
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2011-12-07
- Volume
- 22
- Issue
- 2
- Pages
- 246-258
- ISSN
- 1088-9051 (ISSN-L)
- PMC
- PMC3266032
- OpenAlex
- W2114912562
- Cited by
- 583
- References
- 8
- Citations by year
- 2026: 15 · 2025: 29 · 2024: 22 · 2023: 30 · 2022: 36 · 2021: 54 · 2020: 36 · 2019: 39 · 2018: 39 · 2017: 48 · 2016: 41 · 2015: 58 · 2014: 49 · 2013: 63 · 2012: 23
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genome Research (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion, other-oa)
- BOA (University of Milano-Bicocca) (submittedVersion)
- IRIS (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- National Science Foundation (1115206)
- Howard Hughes Medical Institute
- Gordon and Betty Moore Foundation
- Mary K. Chapman Foundation
- Ludwig Institute for Cancer Research
- National Institutes of Health
- National Human Genome Research Institute (R01HG004962)
- 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
- DNA hypomethylation, breast cancer, epigenetic modifications, gene silencing, repressive chromatin, partially methylated domains, H3K9me3, H3K27me3, histone modifications, methylome, mammary epithelial cells, chromatin modification
- MeSH terms
- Alleles, Breast Neoplasms, Chromatin, Female, Histones, Humans, Models, Genetic, Repetitive Sequences, Nucleic Acid, Transcription, Genetic, Gene Expression Regulation, Neoplastic, Cluster Analysis, DNA Methylation, Gene Silencing, Chromatin Assembly and Disassembly, Epigenesis, Genetic, Cell Line, Tumor
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