Genome-wide map of N-methyladenosine circular RNAs identified in mice model of severe acute pancreatitis.

Background: Severe acute pancreatitis (SAP) is a deadly inflammatory disease with complex pathogenesis and lack of effective therapeutic options. N-methyladenosine (mA) modification of circRNAs plays important roles in physiological and pathological processes. However, the roles of mA circRNA in the pathological process of SAP remains unknown.

Aim: To identify transcriptome-wide map of mA circRNAs and to determine their biological significance and potential mechanisms in SAP.

Methods: The SAP in C57BL/6 mice was induced using 4% sodium taurocholate salt. The transcriptome-wide map of mA circRNAs was identified by mA-modified RNA immunoprecipitation sequencing. The biological significance of circRNAs with differentially expressed mA peaks was evaluated through gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis. The underlying mechanism of mA circRNAs in SAP was analyzed by constructing of mA circRNA-microRNA networks. The expression of demethylases was determined by quantitative polymerase chain reaction and western blot to deduce the possible mechanism of reversible mA process in SAP.

Results: Fifty-seven circRNAs with differentially expressed mA peaks were identified by mA-modified RNA immunoprecipitation sequencing, of which 32 were upregulated and 25 downregulated. Functional analysis of these mA circRNAs in SAP found some important pathways involved in the pathogenesis of SAP, such as regulation of autophagy and protein digestion. In mA circRNA-miRNA networks, several important miRNAs participated in the occurrence and progression of SAP were found to bind to these mA circRNAs, such as miR-24-3p, miR-26a, miR-92b, miR-216b, miR-324-5p and miR-762. Notably, the total mA level of circRNAs was reduced, while the demethylase alkylation repair homolog 5 was upregulated in SAP.

Conclusion: mA modification of circRNAs may be involved in the pathogenesis of SAP. Our findings may provide novel insights to explore the possible pathogenetic mechanism of SAP and seek new potential therapeutic targets for SAP.