A Genome-Wide Methylation Approach Identifies a New Hypermethylated Gene Panel in Ulcerative Colitis.

Keunsoo Kang,Eun Kim,Tae-Oh Kim,Jin-Han Bae,Kyudong Han,Joo Yi

doi:10.3390/ijms17081291

Abstract

The cause of inflammatory bowel disease (IBD) is still unknown, but there is growing evidence that environmental factors such as epigenetic changes can contribute to the disease etiology. The aim of this study was to identify newly hypermethylated genes in ulcerative colitis (UC) using a genome-wide DNA methylation approach. Using an Infinium HumanMethylation450 BeadChip array, we screened the DNA methylation changes in three normal colon controls and eight UC patients. Using these methylation profiles, 48 probes associated with CpG promoter methylation showed differential hypermethylation between UC patients and normal controls. Technical validations for methylation analyses in a larger series of UC patients (n = 79) were performed by methylation-specific PCR (MSP) and bisulfite sequencing analysis. We finally found that three genes (FAM217B, KIAA1614 and RIBC2) that were significantly elevating the promoter methylation levels in UC compared to normal controls. Interestingly, we confirmed that three genes were transcriptionally silenced in UC patient samples by qRT-PCR, suggesting that their silencing is correlated with the promoter hypermethylation. Pathway analyses were performed using GO and KEGG databases with differentially hypermethylated genes in UC. Our results highlight that aberrant hypermethylation was identified in UC patients which can be a potential biomarker for detecting UC. Moreover, pathway-enriched hypermethylated genes are possibly implicating important cellular function in the pathogenesis of UC. Overall, this study describes a newly hypermethylated gene panel in UC patients and provides new clinical information that can be used for the diagnosis and therapeutic treatment of IBD.

Highlights

Inflammatory bowel disease (IBD) is a chronic, relapsing, remitting, and/or continuously active disease of the gastrointestinal tract that is occasionally associated with extra-intestinal manifestations [1]
We have previously reported that several genes that are hypermethylated in colon cancer are hypermethylated in ulcerative colitis (UC) patients [12]
This observation suggested that DNA methylation might be useful as a diagnostic or prognostic marker for patients with UC, no inflammatory bowel disease (IBD) direct factors altered by epigenetic regulation have been reported so far

Summary

Introduction

Inflammatory bowel disease (IBD) is a chronic, relapsing, remitting, and/or continuously active disease of the gastrointestinal tract that is occasionally associated with extra-intestinal manifestations [1]. The exact etiology of IBD remains unknown, numerous clinical and experimental reports including genome-wide association studies have suggested that IBD is a consequence of the complex, dysregulated interplay between genetic predispositions, environmental factors, and microbial compositions in the intestine [3,4,5,6]. These genetic studies have suggested that genetic discoveries can help understand the susceptibility to IBD, environmental factors are important in its pathogenesis. Regarding the interaction between the environment and genome, epigenetic mechanisms may contribute to the pathogenesis of IBD

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