M6A echoes with DNA methylation: Coordinated DNA methylation and gene expression data analysis identified critical m6A genes associated with asthma

Abstract

Asthma is a chronic inflammatory disease that involves complex gene-environment interactions. Methylation of nucleotides, such as 5-methylcytosine (5mC) in DNA and N6-methyladenosine (m6A) in mRNA, carries important information for gene regulation. Our study screened m6A genes and genes associated with asthma from the Gene Expression Omnibus (GEO) databases GSE63383, GSE119580, GSE38003, GSE34313, GSE13168, and GSE35643. GSE52778, GSE35643, GSE40996, and GSE64744), and DNA methylation data from GSE85568 and GSE146377. We screened out 6 m6A related genes (FTO, IGF2BP2, RBM15, RBMX, WTAP, and YTHDC1) that were significantly dysregulated in asthma or proinflammatory conditions. A correlation study showed a high correlation between m6A genes and gene pairs such as WTAP, IL7R, and TLR2; RBMX, SLC22A4, IL33, TNC, FLG, and IL6R (|r| ≥ 0.8). Following DNA methylation dataset analysis, we proposed several DNA methylation-m6A modification asthma-related gene axes such as cg19032951/cg15153914-IGF2BP2-SMAD3. Interestingly, several target genes, such as SMAD3, possess the ability to participate in DNA methylation processes, which may reciprocally regulate the expression of m6A genes and form a closed-loop regulation axis. Some classic DNA methylation-related genes, such as TET1, UHRF1, and ZBTB4, were also involved. We identified an integrated profile of m6A gene expression in asthma and proposed a novel potential interplay between DNA methylation and m6A modification in asthma pathogenesis. Using the CMAP database, we found that resveratrol may target these dysregulated m6A genes, and therefore may serve as a potential therapeutic agent for asthma.