miRNAs Influence m6A RNA Methylation through FTO and IGF2BP2 in Pressure Overload-Induced Heart Failure

Abstract

Background: N6-adenosine methylation (m6A) is a prevalent RNA modification associated with heart failure, alongside aberrant miRNA expression. Despite indications of miRNAs regulating m6A modification, their specific influence on m6A in heart failure remains unclear. Methods: The initial analysis utilized transcriptome and methylation sequencing data from GSE131296 in mice to identify key m6A methylation enzymes in heart failure and construct an associated network. Integration of miRNA sequencing data from GSE231700 revealed miRNAs influencing m6A methylation enzymes, contributing to the formation of a comprehensive network. Furthermore, differential miRNA levels in human serum were assessed via qPCR, and the expression of m6A methyltransferases in the heart was confirmed using proteomic databases. Results: In pressure overload-induced heart failure mice, 217 mRNAs showed differential expression, with FTO and IGF2BP2 identified as m6A methylation enzymes. Subsequent methylation sequencing revealed 884 highly-methylated and 178 lowly-methylated peaks, establishing a network linking Fto and Igf2bp2 with these peaks. Additionally, miRNA sequencing identified 156 differentially expressed miRNAs, including let-7b-5p and miR-23b-3p, predicted as m6Aregulating miRNAs, both elevated in heart failure patients. Conclusion: miR-23b-3p and let-7b-5p are identified as potential regulators of RNA methylation in heart failure, acting via FTO and IGF2BP2, offering new insights into the role of miRNA-mediated RNA methylation and its potential therapeutic avenues for heart failure.