The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores

Abstract

Alterations in DNA methylation (DNAm) in cancer have been known for 25 years, including hypomethylation of oncogenes and hypermethylation of tumor suppressor genes1. 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 islands2,3. 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 surprising overlap (45-65%) of the location 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 non-colon normal tissues. Thus, methylation changes in cancer are at sites that vary normally in tissue differentiation, and they are consistent with the epigenetic progenitor model of cancer4, that epigenetic alterations affecting tissue-specific differentiation are the predominant mechanism by which epigenetic changes cause cancer.

Genome-scale profiling reveals a subset of genes regulated by DNA methylation that program somatic T-cell phenotypes in humans

“…In total there were 87 probes with membership in the R-DMR category, and these localized to 44 unique genes, including genes responsive to transforming growth factor B signaling (SMAD3, SMAD7), fibroblast growth factor signaling (FGF20), as well as various receptor molecules utilized in the brain, heart or olfactory system (Table 2). Consistent with previous studies, these differentially methylated regions were mostly localized to the shores of CpG islands, 21 and increased in methylation from birth to 12 months, concurrent with the reduced gene expression relative to neonatal levels ( Figure 4). Taken together, the data support a model whereby epigenetic changes in R-DMRs support Table 5).…”

Epigenetic regulation of the human p53 gene promoter by the CTCF transcription factor in transformed cell lines

“…We do not believe that CTCF is always located at the boundaries of promoter regions (Barski et al, 2007;Irizarry et al, 2009;Su et al, 2009), and that its intergenic and/or intragenic distribution may also direct an optimal topology of each chromatin domain inside the cell nucleus. Therefore, it is attractive to consider CTCF as having a key role in tumor suppressor gene regulation, through mechanisms of action that probably occur at multiple levels.…”

Reduced DNA methylation patterning and transcriptional connectivity define human skin aging

“…We also used minfi to analyze methylation patterns at the level of epigenomic substructures, such as CpG islands, shores, shelves, and open sea regions (Irizarry et al ., 2009; Sandoval et al ., 2011). The results again indicated only minor differences between the young and old samples for most substructures, but revealed a robust and highly significant ( P  = 2.0e‐171) hypermethylation of CpG islands in the old samples (Fig.…”