Abstract
Inflammatory bowel disease is known to be associated with a genetic predisposition involving multiple genes; however, there is growing evidence that abnormal interactions with environmental factors, particularly epigenetic factors, can also significantly contribute to the development of inflammatory bowel disease (IBD). Although many genome-wide association studies have been performed to identify the genetic changes underlying the pathogenesis of Crohn’s disease, the role of epigenetic alterations based on molecular complications arising from Crohn’s disease (CD) is poorly understood. We employed an unbiased approach to define DNA methylation alterations in colonoscopy samples from patients with CD using the HumanMethylation450K BeadChip platform. Technical and functional validation was performed by methylation-specific PCR (MSP) and bisulfite sequencing of a validation set of 207 patients with CD samples. Immunohistochemistry (IHC) analysis was performed in the representative sample sets. DNA methylation profile in CD revealed that 135 probes (24 hypermethylated and 111 hypomethylated probes) were differentially methylated. We validated the methylation levels of 19 genes that showed hypermethylation in patients with CD compared with normal controls. We uniquely identified that the fragile histidine triad (FHIT) gene was hypermethylated in a disease-specific manner and its protein level was downregulated in patients with CD. Pathway analysis of the hypermethylated candidates further suggested putative molecular interactions relevant to IBD pathology. Our data provide information on the biological and clinical implications of DNA hypermethylated genes in CD, identifying FHIT methylation as a promising new biomarker for CD. Further study of the role of FHIT in IBD pathogenesis may lead to the development of new therapeutic targets.
Highlights
Inflammatory bowel diseases (IBDs), containing ulcerative colitis (UC) and Crohn’s disease (CD), are significantly heterogeneous diseases
We examined the CpG islands of the FHIT gene in the UCSC database and found that a typical CpG island was located in the promoter region of the fragile histidine triad (FHIT) gene upstream region (Figure 3a)
These observations suggest that abnormal DNA methylation alterations might be useful as diagnostic or prognostic biomarkers for UC patients, there are few reports of epigenetic factors that have been altered by hypermethylation in IBD
Summary
Inflammatory bowel diseases (IBDs), containing ulcerative colitis (UC) and Crohn’s disease (CD), are significantly heterogeneous diseases. Genetic studies, including linkage mapping analysis and genome-wide association studies (GWAS), have improved our understanding of the importance of genetic susceptibility in IBD, and more than 30 risk-associated loci have been identified by meta-analyses [3,4]. These genetic risk factors can only explain approximately 20% of the disease risk [5], suggesting that epigenetic factors are possibly involved in the pathogenesis of IBD [6]. Abnormally methylated DNA sequences were detected in circulating DNA in the blood of cancer patients by conventional methylation-specific PCR (MSP) and had high sensitivity and specificity compared with tumor tissues [16,17]
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