The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores
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For the past 25 years, it has been known that alterations in DNA methylation (DNAm) occur in cancer, including hypomethylation of oncogenes and hypermethylation of tumor suppressor genes. However, most studies of cancer methylation have assumed that functionally important DNAm will occur in promoters, and that most DNAm changes in cancer occur in CpG islands. Here we show that most methylation alterations in colon cancer occur not in promoters, and also not in CpG islands, but in sequences up to 2 kb distant, which we term 'CpG island shores'. CpG island shore methylation was strongly related to gene expression, and it was highly conserved in mouse, discriminating tissue types regardless of species of origin. There was a notable overlap (45-65%) of the locations of colon cancer-related methylation changes with those that distinguished normal tissues, with hypermethylation enriched closer to the associated CpG islands, and hypomethylation enriched further from the associated CpG island and resembling that of noncolon normal tissues. Thus, methylation changes in cancer are at sites that vary normally in tissue differentiation, consistent with the epigenetic progenitor model of cancer, which proposes that epigenetic alterations affecting tissue-specific differentiation are the predominant mechanism by which epigenetic changes cause cancer.
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A substantial portion of DNA methylation sites is positively correlated with gene expression.
“recent large-scale analyses of gene expression profiles and DNA methylomes showed that a substantial portion of DNA methylation sites is positively correlated with gene expression31”
From Transcription factors as readers and effectors of DNA methylation (2016) · cites this paper as [31]
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- Authors
- Irizarry, R. A., Ladd-Acosta, C., Wen, B., Wu, Z., Montano, C., Onyango, P., Cui, H., Gabo, K., Rongione, M., Webster, M., Ji, H., Potash, J. B., Sabunciyan, S., & Feinberg, A. P.
- Affiliations
- Johns Hopkins University (US)
- Brown University (US)
- Uniformed Services University of the Health Sciences (US)
- Corresponding author
- Irizarry, Rafael A
- Feinberg, Andrew P
- ORCID
- Venue
- Nature Genetics
- Published
- 2009-01-18
- Volume
- 41
- Issue
- 2
- Pages
- 178-186
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC2729128
- OpenAlex
- W2148521032
- Cited by
- 2,177
- References
- 39
- Citations by year
- 2026: 31 · 2025: 46 · 2024: 93 · 2023: 75 · 2022: 95 · 2021: 92 · 2020: 99 · 2019: 101 · 2018: 115 · 2017: 133 · 2016: 153 · 2015: 185 · 2014: 203 · 2013: 193 · 2012: 245
- FWCI
- 75.48
- 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)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Stanley Medical Research Institute
- National Institutes of Health
- National Human Genome Research Institute (P50HG003233)
- National Cancer Institute (R37CA054358, R37CA54358, R01CA054358)
- National Institute of General Medical Sciences (R01GM083084)
- National Center for Research Resources (R01RR021967)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- colon cancer, DNA methylation, CpG island shores, promoter methylation, tissue-specific methylation, gene expression, histogenesis, cancer epigenetics
- MeSH terms
- Carcinoma, Chromosome Mapping, Colonic Neoplasms, Humans, Organ Specificity, DNA Modification Methylases, Genome, Human, Gene Expression Regulation, Neoplastic, Conserved Sequence, CpG Islands, DNA Methylation, Oligonucleotide Array Sequence Analysis, Gene Silencing, Gene Expression Profiling, HCT116 Cells
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