M 6 A reader protein YTHDF3 regulates cardiomyocyte death and atrophy by modulating the alternative splicing program
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Background
The functional impact of m 6 A modifications on RNA is governed by reader proteins that read the m 6 A marks and process the RNA accordingly. Recent studies have highlighted the importance of m 6 A reader proteins in the heart. However, the function of a reader protein Ythdf3 in the heart remains completely unknown.
Objective
We aim to uncover the function of Ythdf3 in the hearts.
Methods& Results
Here, we show that Ythdf3 is indispensable for the heart, and its knockdown leads to cardiac cachexia evident by cardiomyocyte atrophy, death, and less dense myofibrils visualized by electron microscopy. We also found downregulation of Ythdf3 in response to doxorubicin, and its overexpression rescues doxorubicin-induced cardiomyocyte atrophy and death. Contrary to primarily cytoplasmic localization, we found that Ythdf3 localizes in the cardiomyocyte nucleus. Furthermore, using co-immunoprecipitation coupled with LC-MS/MS, we show that Ythdf3 interacts with splicing proteins like DDX5 and HNRNPU and regulates alternative splicing in the heart. Mechanistically, we found that Ythdf3 regulates the splicing of CaMKIIδ, and its knockdown leads to an increase in CaMKIIδA and CaMKIIδC isoforms while a decrease in CaMKIIδ9 isoform.
Conclusion
Collectively, Ythdf3 knockdown in the adult heart leads to cardiac cachexia due to the alteration of the splicing program.
