Comprehensive Analysis of Transcriptome-wide M6A Methylation for Hepatic Ischemia Reperfusion Injury in Mice

Background: Hepatic ischemia reperfusion injury (IRI) is a complex clinical complication during surgery and often leads to cell damage and dysfunction. N6-Methyladenosine (m6A) is an emerging epigenetic modification that plays key roles in the regulation of biological functions and cellular mechanisms in IR injury in different organs. However, the understanding of m6A-modified mRNAs in hepatic IRI is limited. Methods: Methylated RNA immunoprecipitation with high-throughput sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) were used to profile the transcriptome-wide distribution of m6A methylation for hepatic IRI in mice. Results: In this study, there were 2061 nonoverlapping m6A peaks within 22471 coding gene transcripts (mRNAs) in the sham group and 2669 nonoverlapping m6A peaks within 22766 coding gene transcripts in the hepatic IR group. The distribution of m6A peaks was especially enriched in the coding sequence (CDS) and 3'UTR. Moreover, functional enrichment analysis demonstrated that the significantly enriched terms of genes with upmethylated m6A sites were the mRNA surveillance pathway, purine metabolism and metabolic pathways, and the significantly enriched terms of genes with downmethylated m6A sites were the Rap1 signaling pathway, sphingolipid signaling pathway, platelet activation, Wnt signaling pathway, chemokine signaling pathway and focal adhesion. Furthermore, we identified a relationship between differentially methylated genes and differentially expressed genes to obtain the three overlapping predicted target genes (Fnip2, Phldb2, and Pcf11). Conclusions: Our study first identified a transcriptome-wide map of m6A mRNAs in hepatic IRI. An in-depth analysis according to methylation modifications will provide effective treatment strategies and a theoretical basis for future research in terms of molecular mechanisms. Overall design: The mRNA profiles of m6A methylation for hepatic IR group and the sham group in mice