Remodeling of the m 6 A 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 (m ⁶ A) has recently emerged as a critical post-transcriptional mechanism underlying heart disease. Thousands of mammalian mRNAs are known to be m ⁶ A-modified, suggesting that remodeling of the m ⁶ A landscape may play an important role in cardiac pathophysiology. Here we found an increase in m ⁶ A content in human heart failure samples. We then adopted genome-wide analysis to define all m ⁶ A-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 m ⁶ A sites regulated in human hearts with the ones occurring in isolated rat hypertrophic cardiomyocytes to define cardiomyocyte-specific m ⁶ A events conserved across species. Our results identified 38 shared transcripts targeted by m ⁶ A 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 m ⁶ A on post-transcriptional regulation of gene expression in the heart.
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