The DNA Methylome of Inflammatory Bowel Disease (IBD) reflects intrinsic and extrinsic factors in intestinal epithelial cells

Abstract

Abnormal DNA methylation has been described in human inflammatory conditions of the gastrointestinal tract, such as inflammatory bowel disease (IBD). As other complex diseases, IBD results from the balance between genetic predisposition and environmental exposures. As such, DNA methylation may be placed as an effector of both, genetic susceptibility variants and/or environmental signals such as cytokine exposure. We attempted to discern between these two non-excluding possibilities by performing a meta-analysis of DNA methylation data in intestinal epithelial cells of IBD and control samples. We identified abnormal DNA methylation at different levels: deviation from mean methylation signals at site and region levels, and differential variability. A fraction of such changes are associated with genetic polymorphisms linked to IBD susceptibility. In addition, by comparing with another intestinal inflammatory condition (i.e. celiac disease) we propose that aberrant DNA methylation can also be the result of unspecific processes such as chronic inflammation. Our characterization suggests that IBD methylomes combine intrinsic and extrinsic responses in intestinal epithelial cells, and could point to knowledge-based biomarkers of IBD detection and progression. Graphical AbstractConceptual representation of the study. Using a meta-analysis strategy we identified differentially methylated positions or regions (DMP/DMR) in IBD. Our assumption is that gene expression changes (IBD phenotype) take place downstream of DNA methylation. In turn, abnormal DNA methylation can be explained by a direct effect of inflammatory cytokines ("signaling") and/or the result of a genetic polymorphism (SNP). SNP-DMP associations are called methylation quantitative trait loci (mQTL). O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/565200v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@b9fc96org.highwire.dtl.DTLVardef@7619c5org.highwire.dtl.DTLVardef@1961352org.highwire.dtl.DTLVardef@1ce9d84_HPS_FORMAT_FIGEXP M_FIG C_FIG