Loss of YTHDF2 Alters the Expression of m(6)A-Modified Myzap and Causes Adverse Cardiac Remodeling

How post-transcriptional regulation of gene expression, such as through N(6)-methyladenosine (m(6)A) messenger RNA methylation, impacts heart function is not well understood. We found that loss of the m(6)A binding protein YTHDF2 in cardiomyocytes of adult mice drove cardiac dysfunction. By proteomics, we found myocardial zonula adherens protein (MYZAP) within the top up-regulated proteins in knockout cardiomyocytes. We further demonstrated that YTHDF2 binds m(6)A-modified Myzap messenger RNA and controls its stability. Cardiac overexpression of MYZAP has been associated with cardiomyopathy. Thus, our findings provide an important new mechanism for the YTHDF2-dependent regulation of this target and therein its novel role in the maintenance of cardiac homeostasis.