Loss of Methyltransferase and Hypomethylated m6A Sarcomere Transcripts Leading to Early-Onset Dilated Cardiomyopathy

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RNA metabolism; heart development; dilated cardiomyopathy; m6A methyltransferase; sarcomere Pediatric Dilated Cardiomyopathy (DCM) is genetically heterogeneous with pathologic genetic variation in sarcomeric genes being a significant contributor 1 .Dysregulation of post-transcriptional modification in sarcomere transcripts has been recently linked to DCM phenotype in mice 2 .Among the eukaryotic post-transcriptional modification, N6-methyladenosine (m6A) is the most abundant, significantly affecting mRNA metabolism.The m6A modification is co-installed by the METTL3/METTL14 methyltransferase complex 3 .Deletion of METTL3 in adult mice resulted in heart failure 4 .However, whether posttranscriptional dysregulation of sarcomere transcripts due to aberrant m6A deposition in the developing heart contributes to pediatric/fetal DCM pathogenesis remains unclear.To investigate the role of METTL3/METTL14 methyltransferase complex in cardiac development, we generated mice with cardiomyocyte-specific deletion of Mettl3 (MT3cKO)

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