Genome-wide methylation analysis of human colon cancer reveals similar hypo- and hypermethylation at conserved tissue-specific CpG island shores
By Rafael A. Irizarry, Christine Ladd-Acosta, Bo Wen, Zhijin Wu, C. Montano, P. Onyango, H. Cui, Kevin Gabo, Michael A Rongione, M. Webster and 4 more. Nature Genetics, 2009
1,750 citations recorded by the source corpus.
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.
Subfields: Molecular Biology
View Paper: https://www.semanticscholar.org/paper/f9e02232a145ba69c37eeaa331a58510c05a1563
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Citations in the corpus
- Dynamic DNA methylation across diverse human cell lines and tissues (2013, background): “Hypomethylation across the genome has been reported in cancer (Irizarry et al. 2009; Hansen et al. 2011; Berman et al. 2012; Hon et al. 2012).”
- Regions of focal DNA hypermethylation and long-range hypomethylation in colorectal cancer coincide with nuclear lamina–associated domains (2011, background): “Genome-scale studies have yielded important insights into these change”
- Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts (2009, positive): “Recently, we described differential methylation patterns that distinguish among normal tissue types (T-DMRs) and patterns that can segregate colorectal cancer tissue from matched normal tissues (C-DMRs”
- A decade of exploring the cancer epigenome — biological and translational implications (2011, background): “DNA methylation patterns for conserved gene sequences several kilobases upstream or downstream of promoter CpG islands, and termed shores, are tightly linked with the tissue of origi”
- Neuronal activity modifies DNA methylation landscape in the adult brain (2011, background): “or mainly focused on CpGs within promoter regions in heterogeneous tissue”
- CpG islands – ‘A rough guide’ (2009, background): “Characterisation of these differences identifies the existence of tissue specific CGI methylation fingerprints which may demarcate cellular functions [69,71].”
- The Behaviour of 5-Hydroxymethylcytosine in Bisulfite Sequencing (2010, background): “(ii) Methylation-sensitive enzymes such as HpaII or McrBC do not reliably distinguish 5mC and 5-hmC [37,38].”
- Dynamic changes in the human methylome during differentiation. (2010, background): “Cell-type-specific differentially methylated regions (DMRs) are associated with differences in gene expression (Dindot et al. 2009; Irizarry et al. 2009).”
- High-resolution genome-wide DNA methylation maps of mouse primary female dermal fibroblasts and keratinocytes (2014, positive): “These studies revealed several interesting observations: hypermethylation of CGI shores toward the gene body was shown to be positively correlated with gene expression [18,22]; expressed protein-coding genes appear to have high CG methylation over their gene body [15,18,23,24]; CG methylation underg”
- Aberrant epigenetic landscape in cancer: how cellular identity goes awry. (2010, background): “Some of this could be achieved by analyzing patterns on a genome-wide scale, an approach that has at last become possible thanks to recent technological advances (Bernstein et al., 2007; Barski et al., 2007; Irizarry et al., 2009).”