Genome-wide DNA Methylation in Treatment-naïve Ulcerative Colitis

Abstract

Background and AimsThe aim of this study was to investigate the genome-wide DNA methylation status in treatment-naïve ulcerative colitis [UC], and to explore the relationship between DNA methylation patterns and gene expression levels in tissue biopsies from a well-stratified treatment-naïve UC patient group.MethodsMucosal biopsies from treatment-naïve patients [n = 10], and a healthy control group [n = 11] underwent genome-wide DNA bisulfite sequencing. Principal component analysis [PCA] and diverse statistical methods were applied to obtain a dataset of differentially methylated genes. DNA methylation annotation was investigated using the UCSC Genome Browser. Gene set enrichments were obtained using the Kyoto Encyclopaedia of Genes and Genomes [KEGG] and PANTHER.ResultsOf all significantly differentially expressed genes [DEGs], 25% correlated with DNA methylation patterns; 30% of these genes were methylated at CpG sites near their transcription start site [TSS]. Hyper-methylation was observed for genes involved in homeostasis and defence, whereas hypo-methylation was observed for genes playing a role in immune response [i.e. chemokines and interleukins]. Of the differentially DNA methylated genes, 25 were identified as inflammatory bowel disease [IBD] susceptibility genes. Four genes [DEFFA6, REG1B, BTNL3, OLFM4] showed DNA methylation in the absence of known CpG islands.ConclusionsGenome-wide DNA methylation analysis revealed distinctive functional patterns for hyper-and hypo-methylation in treatment-naïve UC. These distinct patterns could be of importance in the development and pathogenesis of UC. Further investigation of DNA methylation patterns may be useful in the development of the targeting of epigenetic processes, and may allow new treatment and target strategies for UC patients.

Whole-Genome DNA Methylation Profiling of CD14+ Monocytes Reveals Disease Status and Activity Differences in Crohn’s Disease Patients

“…SLC26A4 encodes pendrin, an anion exchange protein whose clinical relevance is mostly described within the context of hearing impairment [74]. Nonetheless, whole genome bisulfite sequencing and RNA-sequencing analysis of mucosal biopsies of UC patients with non-UC patients indicated promoter hypomethylation and upregulated expression [63], which is in agreement with the observations made in this study. MPEG1 encodes Perforin-2, which is a protein expressed in phagocytes involved in the innate immune response by forming pores in bacteria [75,76].…”

“…We reported previously that SERPINF1 was differentially methylated and expressed when comparing ileal fibroblasts obtained from stenotic tissue with non-inflamed tissue from CD patients [62]. Similarly, PRAP1 was found to be hypermethylated and downregulated in mucosal biopsies obtained from treatment naïve UC patients relative to control patients [63]. At the level of genomics, a meta-analysis suggested that the GSTT1 null mutation was significantly associated with susceptibility to IBD [64].…”

Discovery and validation of mucosal TNF expression combined with histological score - a biomarker for personalized treatment in ulcerative colitis

“…Moreover, this is part of the transomic Advanced Study of In ammatory Bowel disease (ASIB) study where parallel studies of the epigenome, transcriptome, proteome and metabolome are ongoing. 33,[41][42][43][44][45] . This transomic approach at debut of UC will be performed and correlated to long-term clinical outcome.…”

Systems biology in inflammatory bowel diseases: on the way to precision medicine

“…Regarding UC patients, Kang et al also found differentially methylated patterns in UC patients with 3 genes, FAM217B, KIAA1614 and RIBC2, being hypermethylated; thus, this might be a tool for distinguishing UC patients from healthy individuals [72]. In a recent study, mucosal biopsies taken from UC patients showed different methylation patterns from those of healthy individuals; UC patients showed hyper-methylation or hypo-methylation in genes involved in homeostasis and defense, or in immune response pathways, respectively [73]. An epigenome-wide association study revealed that IBD patients bear differentially methylated positions (DMPs) compared with healthy individuals and most of these DMPs found in IBD cases were shared between CD and UC patients.…”