Remodeling of the mA landscape in the heart reveals few conserved post-transcriptional events underlying cardiomyocyte hypertrophy.

Regulation of gene expression plays a fundamental role in cardiac stress-responses. Modification of coding transcripts by adenosine methylation (mA) has recently emerged as a critical post-transcriptional mechanism underlying heart disease. Thousands of mammalian mRNAs are known to be mA-modified, suggesting that remodeling of the mA landscape may play an important role in cardiac pathophysiology. Here we found an increase in mA content in human heart failure samples. We then adopted genome-wide analysis to define all mA-regulated sites in human failing compared to non-failing hearts and identified targeted transcripts involved in histone modification as enriched in heart failure. Further, we compared all mA sites regulated in human hearts with the ones occurring in isolated rat hypertrophic cardiomyocytes to define cardiomyocyte-specific mA events conserved across species. Our results identified 38 shared transcripts targeted by mA during stress conditions, and 11 events that are unique to unstressed cardiomyocytes. Of these, further evaluation of select mRNA and protein abundances demonstrates the potential impact of mA on post-transcriptional regulation of gene expression in the heart.