Loss of YTHDF2 Alters the Expression of m6A-Modified Myzap and Causes Adverse Cardiac Remodeling
Volha A. Golubeva, Lisa E. Dorn, Christopher J. Gilbert, Charles P. Rabolli, Anindhya Sundar Das, Vishmi Samudika Wanasinghe, Roland Veress, Dmitry Terentyev, Federica Accornero
Abstract
How post-transcriptional regulation of gene expression, such as through N6-methyladenosine (m6A) messenger RNA methylation, impacts heart function is not well understood. We found that loss of the m6A 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 m6A-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.