m⁶A-mRNA methylation regulates cardiac gene expression and cellular growth

Conceptually similar to modifications of DNA, mRNAs undergo chemical modifications, which can affect their activity, localization, and stability. The most prevalent internal modification in mRNA is the methylation of adenosine at the N⁶-position (m⁶A). This returns mRNA to a role as a central hub of information within the cell, serving as an information carrier, modifier, and attenuator for many biological processes. Still, the precise role of internal mRNA modifications such as m⁶A in human and murine-dilated cardiac tissue remains unknown. Transcriptome-wide mapping of m⁶A in mRNA allowed us to catalog m⁶A targets in human and murine hearts. Increased m⁶A methylation was found in human cardiomyopathy. Knockdown and overexpression of the m⁶A writer enzyme Mettl3 affected cell size and cellular remodeling both in vitro and in vivo. Our data suggest that mRNA methylation is highly dynamic in cardiomyocytes undergoing stress and that changes in the mRNA methylome regulate translational efficiency by affecting transcript stability. Once elucidated, manipulations of methylation of specific m⁶A sites could be a powerful approach to prevent worsening of cardiac function.