Clin Res Cardiol (2021). 10.1007/s00392-021-01933-9

Ythdf2-mediated post-transcriptional control of gene expression regulates cardiac remodeling

J. Ölschläger1, V. Kamuf-Schenk1, H. A. Katus2, N. Frey2, M. Völkers2, V. Kmietczyk1

1Klinik für Innere Medizin III: Kardiologie, Angiologie und Pneumologie, Universitätsklinikum Heidelberg, Heidelberg; 2Klinik für Innere Med. III, Kardiologie, Angiologie u. Pneumologie, Universitätsklinikum Heidelberg, Heidelberg;

The reversible mRNA-modification N6-methyladenosine (m6A) influences all aspects of mRNA fate representing a key post-transcriptional mechanism that regulates gene expression. By affecting mRNA’s stability, localization and translation efficiency, it is critical for many biological processes like growth, metabolism, signaling and cellular survival. Within the last three years it was shown that m6A also regulates and affects cardiomyocyte gene expression as well as cardiac function during pathological stress. In heart failure and cardiac remodeling increased levels of m6A were found and decreasing the levels by manipulating writers and erasers protected the heart from heart failure symptoms. The cardiac m6A-mRNA-methylome dynamically changed during pathological remodeling and networks of disease-/condition-specific methylated transcripts were identified. However, how specific mRNAs are regulated by dynamic changes of m6A is largely unknown. m6A is recognized by binding to m6A-readers proteins.  The YTH domain family (Ythdf1-Ythdf3) has been shown to bind m6A mRNAs and individual members of the family affect transcript stability and translation. Here we show that the m6A-reader Ythdf2 is involved in cardiac remodeling. Using primary cardiomyocytes, we show that the loss of Ythdf2 leads to reduced viability and smaller cells with bigger increase of their size when treated in vitro with phenylephrine.  A novel cardiomyocyte specific Ythdf2 knockout mice was generated. Hearts from Ythdf2 knockout mice showed worsened cardiac remodeling after pressure overload in comparison to the control TAC group. This was associated with a higher expression of hypertrophic marker genes. Additionally, more fibrosis was found by Masson Trichrome staining of histological heart sections in Ythdf2 knockout mice compared to control wild type mice along with higher expression of fibrotic genes. Ribo-Seq analysis of Ythdf2 knockout mice identified translational regulated transcripts. However, the Ythdf2 knockout mice did not present a significant decrease of cardiac function compared to wild type mice after TAC surgery. This could be explained by a partial compensation through the other m6A-readers from the YTH domain family. In summary, our study provides evidence that Ythdf2 is involved in cardiac remodeling but its loss is partially compensated. Further studies will be needed to understand the long-term effects of Ythdf2 loss and the molecular mechanisms of coping with it in the remodeling heart.

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