The m6A binding protein YTHDF3 modulates the cardiac response to stress

Abstract

Transcriptional regulation of gene expression has long been studied, however only recently the impact of chemical mRNA modification on protein synthesis has emerged. Among post-transcriptional modifications, methylation of the N6-Adenosine site of mRNA (m6A) is very prevalent in eukaryotes and plays a critical role in the heart. To date, the mechanism through which m6A controls cardiac function remains elusive. The fate of m6A-modified mRNAs is regulated by members of the YTH Domain Family (YTHDF), such as YTHDF3. Here we report that mice with a cardiomyocyte-specific deletion of YTHDF3 have attenuated pathological remodeling following pressure overload injury. Mechanistically, we found that YTHDF3 regulates global stress-induced protein synthesis, and that this protein controls cardiomyocyte size. Altogether, this study uncovered a potential cardioprotective role for YTHDF3 inhibition and improves our understanding on the mechanism through which m6A impacts cardiac function.