The m(6)A-binding protein YTHDF3 modulates the cardiac response to stress.

Transcriptional regulation of gene expression has long been studied; however, only recently has the impact of chemical mRNA modification on protein synthesis emerged. Among posttranscriptional modifications, methylation of the N(6)-adenosine site of mRNA (m(6)A) is very prevalent in eukaryotes and plays a critical role in the heart. To date, the mechanism through which m(6)A controls cardiac function remains elusive. The fate of m(6)A-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 m(6)A impacts cardiac function.