Abstract
Aberrant methylation of CpG islands (CGI) occurs in many genes expressed in colonic epithelial cells, and may contribute to the dysregulation of signalling pathways associated with carcinogenesis. This cross-sectional study assessed the relative importance of age, nutritional exposures and other environmental factors in the development of CGI methylation. Rectal biopsies were obtained from 185 individuals (84 male, 101 female) shown to be free of colorectal disease, and for whom measurements of age, body size, nutritional status and blood cell counts were available. We used quantitative DNA methylation analysis combined with multivariate modelling to investigate the relationships between nutritional, anthropometric and metabolic factors and the CGI methylation of 11 genes, together with LINE-1 as an index of global DNA methylation. Age was a consistent predictor of CGI methylation for 9/11 genes but significant positive associations with folate status and negative associations with vitamin D and selenium status were also identified for several genes. There was evidence for positive associations with blood monocyte levels and anthropometric factors for some genes. In general, CGI methylation was higher in males than in females and differential effects of age and other factors on methylation in males and females were identified. In conclusion, levels of age-related CGI methylation in the healthy human rectal mucosa are influenced by gender, the availability of folate, vitamin D and selenium, and perhaps by factors related to systemic inflammation.
Highlights
Cytosine exhibits a nonuniform pattern of methylation in the human genome
Global hypomethylation contributes to genome instability, whereas CpG islands (CGI) hypo- and hypermethylation lead, respectively, to increased and decreased transcription of genes important for regulating processes disrupted during carcinogenesis (Jones & Baylin, 2002)
Aberrant DNA methylation is observed in the early stages of neoplasia in the human colon (Chan et al, 2002) and occurs in many apparently healthy tissues (Christensen et al, 2009), including the epithelial cells of the morphologically normal colonic crypt (Belshaw et al, 2010)
Summary
Cytosine exhibits a nonuniform pattern of methylation in the human genome. Typically, Cytosine-Guanine dinucleotides (CpGs) distributed within both coding and noncoding regions are methylated, whereas those located within CpG islands (CGI), sequences with significantAccepted for publication 04 November 2012 overrepresentation of CpGs and located within the promoter regions of more than 50% of mammalian genes, are usually unmethylated. There is compelling evidence for an association between colorectal carcinogenesis and aberrant DNA methylation (Lao & Grady, 2011), which includes both genome-wide loss of DNA methylation (global hypomethylation) and differential methylation of CGI of specific genes (CGI hypo- or hypermethylation). We have shown that methylation levels measured within mucosal biopsies reflect highly variable levels of methylation in individual crypts (Belshaw et al, 2010). This mosaic pattern of CGI methylation in the mucosal field is probably a consequence of the unique methylation signatures of the corresponding stem cells
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