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Previous studies indicated that m<jats:sup>6<\/jats:sup>A methyltransferase METTL3 (\u2018writer\u2019) and demethylase FTO (\u2018eraser\u2019) play critical roles in heart\u2010related disease. However, in the heart, the function of m<jats:sup>6<\/jats:sup>A \u2018reader\u2019, such as YTH (YT521\u2010B homology) domain\u2010containing proteins remains unclear. Here, we report that the defect in YTHDC1 but not other YTH family members contributes to dilated cardiomyopathy (DCM) in mice. Cardiac\u2010specific conditional <jats:italic>Ythdc1<\/jats:italic>\u00a0knockout led to obvious left ventricular chamber enlargement and severe systolic dysfunction. YTHDC1 deficiency also resulted in the decrease of cardiomyocyte contractility and disordered sarcomere arrangement. By means of integrating multiple high\u2010throughput sequence technologies, including m<jats:sup>6<\/jats:sup>A\u2010MeRIP, RIP\u2010seq and mRNA\u2010seq, we identified 42 transcripts as potential downstream targets of YTHDC1. Amongst them, we found that <jats:italic>Titin<\/jats:italic> mRNA was decorated with m<jats:sup>6<\/jats:sup>A modification and depletion of YTHDC1 resulted in aberrant splicing of <jats:italic>Titin<\/jats:italic>. Our study suggests that <jats:italic>Ythdc1<\/jats:italic> plays crucial role in regulating the normal contractile function and the development of DCM. These findings clarify the essential role of m<jats:sup>6<\/jats:sup>A reader in cardiac biofunction and provide a novel potential target for the treatment of DCM.<\/jats:p>","DOI":"10.1111\/jcmm.16955","type":"journal-article","created":{"date-parts":[[2021,10,30]],"date-time":"2021-10-30T07:42:02Z","timestamp":1635579722000},"page":"10879-10891","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Depletion of m<sup>6<\/sup>A reader protein YTHDC1 induces dilated cardiomyopathy by abnormal splicing of <i>Titin<\/i>"],"prefix":"10.1111","volume":"25","author":[{"given":"Siyun","family":"Gao","sequence":"first","affiliation":[{"name":"Department of Cardiology Shanghai East Hospital Tongji University School of Medicine Shanghai China"},{"name":"Key Laboratory of Arrhythmias of the Ministry of Education of China Shanghai East Hospital Tongji University School of Medicine Shanghai 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