YTHDC1 regulates the postnatal development of heart

Abstract

Abstract This study aimed to investigate the role of the N6-methyladenosine (m6A) reader protein YTHDC1 in heart development and its potential molecular mechanisms. Animal experiments were conducted using cardiac-specific Ythdc1 knockout (Ythdc1-CKO) mice, and human heart samples were collected from aborted fetuses. Echocardiography, immunoblotting, RNA-Seq, and ATAC-Seq were performed to assess cardiac function, gene expression, and chromatin accessibility. The results revealed that YTHDC1 expression was highest during embryonic and early postnatal stages and gradually decreased with age. Cardiac-specific deletion of Ythdc1 resulted in abnormal heart development, early dilated cardiomyopathy, and severe heart failure. RNA-Seq analysis revealed significant changes in gene expression profiles, particularly genes related to cardiac contraction and transmembrane transport. ATAC-Seq analysis demonstrated significant changes in chromatin accessibility, and the binding motifs of the transcription factors Mef2a, Mef2b, Mef2c, and Mef2d, which are essential for cardiac development, were switched off in Ythdc1-CKO mouse hearts. In conclusion, this study demonstrates that YTHDC1 plays a critical role in heart development and its deficiency leads to abnormal cardiac development and function. The findings provide insights into the molecular mechanisms underlying heart development and suggest potential therapeutic targets for heart diseases.