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Implication of m6A mRNA Methylation in Susceptibility to Inflammatory Bowel Disease.

ABSTRACT: Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract that develops due to the interaction between genetic and environmental factors. More than 160 loci have been associated with IBD, but the functional implication of many of the associated genes remains unclear. N6-Methyladenosine (m6A) is the most abundant internal modification in mRNA. m6A methylation regulates many aspects of mRNA metabolism, playing important roles in the development of several pathologies. Interestingly, SNPs located near or within m6A motifs have been proposed as possible contributors to disease pathogenesis. We hypothesized that certain IBD-associated SNPs could regulate the function of genes involved in IBD development via m6A-dependent mechanisms. We used online available GWAS, m6A and transcriptome data to find differentially expressed genes that harbored m6A-SNPs associated with IBD. Our analysis resulted in five candidate genes corresponding to two of the major IBD subtypes: UBE2L3 and SLC22A4 for Crohn's Disease and TCF19, C6orf47 and SNAPC4 for Ulcerative Colitis. Further analysis using in silico predictions and co-expression analyses in combination with in vitro functional studies showed that our candidate genes seem to be regulated by m6A-dependent mechanisms. These findings provide the first indication of the implication of RNA methylation events in IBD pathogenesis.

SUBMITTER: Sebastian-delaCruz M

PROVIDER: S-EPMC8594712 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundN6-methyladenosine (m6A) methylation has been reported to participate in inflammatory bowel disease (including Crohn disease [CD]). However, the prognostic and therapeutic implication of m6A methylation modification in CD is still unclear.MethodsGenomic information of CD patients was integrated to assess disease-related m6A regulators, and difference and correlation analyses of m6A regulators were explored by using the R packages. Next, CD patients were classified by the expression of differential and intersecting genes in m6A regulators, and difference and correlation analyses were conducted among immune infiltration and therapeutic responses. Finally, colon tissue resected from patients with CD were assessed to verify expression of Wilms tumor 1-associated protein (WTAP) and METTL14 from these m6A regulators.ResultsWe identified 23 m6A regulators in CD patients. Difference analysis of these regulators showed that expression of METTL14, WTAP, RBM15 and YTHDF2/3 was upregulated in the treatment group compared with the control group, with expression of METTL3, YTHDF1, leucine-rich pentatricopeptide repeat motif-containing protein, HNRNPA2B1, IGF2BP1 and fat mass and obesity-associated protein downregulated. Moreover, RBM15, WTAP, leucine-rich pentatricopeptide repeat motif-containing protein, YTHDF1 and YTHDF3 were considered the characteristic genes of CD in m6A regulators. In addition, we identified 4 intersection genes of 3 m6A cluster patterns. Based on the expression of these intersection genes, difference analysis among m6A regulators indicated that the expression of 8 m6A regulators had statistical differences among the 3 geneCluster patterns. Assays of colon tissues from CD patients showed that expression of WTAP and METTL14 were higher in areas of stenosis than non-stenosis.Conclusionm6A methylation modification might affect disease risk, immune infiltration and therapeutic responses in CD. Evaluating the expression of m6A regulators might provide insight into the prediction of disease prognosis and therapeutic responses.

Project description:BackgroundInflammatory bowel disease (IBD) has an unknown etiology; however, accumulating evidence suggests that IBD is a multifactorial disease influenced by a combination of genetic and environmental factors. The influence of genetic variants on DNA methylation in cis and cis effects on expression have been demonstrated. We hypothesized that IBD susceptibility single-nucleotide polymorphisms (SNPs) regulate susceptibility gene expressions in cis by regulating DNA methylation around SNPs. For this, we determined cis-regulated allele-specific DNA methylation (ASM) around IBD susceptibility genes in CD4+ effector/memory T cells (Tem) in lamina propria mononuclear cells (LPMCs) in patients with IBD and examined the association between the ASM SNP genotype and neighboring susceptibility gene expressions.MethodsCD4+ effector/memory T cells (Tem) were isolated from LPMCs in 15 Japanese IBD patients (ten Crohn's disease [CD] and five ulcerative colitis [UC] patients). ASM analysis was performed by methylation-sensitive SNP array analysis. We defined ASM as a changing average relative allele score ([Formula: see text]) >0.1 after digestion by methylation-sensitive restriction enzymes. Among SNPs showing [Formula: see text] >0.1, we extracted the probes located on tag-SNPs of 200 IBD susceptibility loci and around IBD susceptibility genes as candidate ASM SNPs. To validate ASM, bisulfite-pyrosequencing was performed. Transcriptome analysis was examined in 11 IBD patients (seven CD and four UC patients). The relation between rs36221701 genotype and neighboring gene expressions were analyzed.ResultsWe extracted six candidate ASM SNPs around IBD susceptibility genes. The top of [Formula: see text] (0.23) was rs1130368 located on HLA-DQB1. ASM around rs36221701 ([Formula: see text] = 0.14) located near SMAD3 was validated using bisulfite pyrosequencing. The SMAD3 expression was significantly associated with the rs36221701 genotype (p = 0.016).ConclusionsWe confirmed the existence of cis-regulated ASM around IBD susceptibility genes and the association between ASM SNP (rs36221701) genotype and SMAD3 expression, a susceptibility gene for IBD. These results give us supporting evidence that DNA methylation mediates genetic effects on disease susceptibility.

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Implication of m6A mRNA Methylation in Susceptibility to Inflammatory Bowel Disease.

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