Carm1-mediated transcriptional and posttranscriptional regulation of cardiomyocyte maturation

Cardiomyocytes (CMs), the most prevalent cells in the adult heart, are responsible for driving cardiac contraction. During the neonatal stage, CMs undergo a constellation of molecular, structural, and functional changes known collectively as CM maturation to enhance their ability to generate efficient and forceful contraction throughout postnatal life1. CM maturation has received increased attention recently due to the relative immaturity of pluripotent stem cell-derived CM, which limits its application in regenerative medicine. The importance of understanding postnatal CM maturation is also highly relevant to understanding human heart diseases. Defining key factors and signaling pathways that regulate CM maturation will offer valuable guidance for promoting CM maturation and future diagnosis and treatment of heart disease patients. Protein arginine methyltransferases (PRMTs) are a family of enzymes that catalyze arginine methylation on targeted protein substrates. As one of the most abundant post-translational modifications, protein arginine methylation has been linked to the regulation of a wide range of biological processes. Yet, the roles of PRMTs in CM maturation remain largely unexplored. In this research program, we focus on coactivator-associated arginine methyltransferase 1 (CARM1), the founding member of PRMTs also known as PRMT4. We found that Carm1 mutant CMs exhibit multiple maturation defects, including reduced cell and myofibril size, perturbed mitochondrial fusion, disrupted T-tubule formation, and compromised electrophysiological maturation. Mechanistically, CARM1 regulates genes that underlie CM structural and electrophysiological maturation at both transcriptional and posttranscriptional levels, demonstrating a critical and multifaceted role of CARM1 in controlling CM maturation. We thus hypothesize that CARM1-mediated transcriptional and posttranscriptional regulation controls multiple aspects of CM maturation. Our study will fill critical gaps in our understanding of the transcriptional, epigenetic, and post-transcriptional regulation of CM maturation. This new knowledge, in turn, will undoubtedly pave the way for developing new strategies to augment CM maturation for regenerative medicine.