title: Distinct epigenetic signatures elucidate enhancer-gene relationships that delineate CIMP and non-CIMP colorectal cancers.
abstract: Epigenetic changes, like DNA methylation, affect gene expression and in colorectal cancer (CRC), a distinct phenotype called the CpG island methylator phenotype ("CIMP") has significantly higher levels of DNA methylation at so-called "Type C loci" within the genome. We postulate that enhancer-gene pairs are coordinately controlled through DNA methylation in order to regulate the expression of key genes/biomarkers for a particular phenotype.Firstly, we found 24 experimentally-validated enhancers (VISTA enhancer browser) that contained statistically significant (FDR-adjusted q-value of <0.01) differentially methylated regions (DMRs) (1000bp) in a study of CIMP versus non-CIMP CRCs. Of these, the methylation of 2 enhancers, 1702 and 1944, were found to be very well correlated with the methylation of the genes Wnt3A and IGDCC3, respectively, in two separate and independent datasets.We show for the first time that there are indeed distinct and dynamic changes in the methylation pattern of specific enhancer-gene pairs in CRCs. Such a coordinated epigenetic event could be indicative of an interaction between (1) enhancer 1702 and Wnt3A and (2) enhancer 1944 and IGDCC3. Moreover, our study shows that the methylation patterns of these 2 enhancer-gene pairs can potentially be used as biomarkers to delineate CIMP from non-CIMP CRCs.
authors.affiliation: Department of Pathology, National University of Singapore, 119074 Singapore.|Present address: Shanxi Guoxin Caregeno Medical Laboratories, Taiyuan, Shanxi Province, 030006 China.
authors.forename: Allen
authors.initials: A
authors.lastname: Chong
authors.affiliation: Cancer Science Institute, National University of Singapore, 117599 Singapore.
authors.forename: Jing Xian
authors.initials: JX
authors.lastname: Teo
authors.affiliation: Department of Biochemistry, National University of Singapore, 117596 Singapore.|Institute of Molecular and Cell Biology, 138673 Singapore.
authors.forename: Kenneth H K
authors.initials: KH
authors.lastname: Ban
mesh_terms: D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics; D059467:Transcriptome; D060509:Wnt3A Protein / Q000235:genetics
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; C527430:IGDCC3 protein, human; D007136:Immunoglobulins; C555510:WNT3A protein, human; D060509:Wnt3A Protein
keywords: DNA methylation; bioinformatics; colon cancer; enhancers; epigenetics