Protein arginine methyltransferases 5 and 7 (PRMT5/7) are epigenetic enzymes that catalyze the methylation of arginine residues on histones and non-histone substrates, thereby modulating a wide range of biological processes. Their role in oncology has been well described, with evidence suggesting a functional redundancy between these enzymes. In contrast, their relevance in the heart remains elusive. Surprisingly, we found that PRMT5 and PRMT7 physically interact along with a major dependency on oxygen levels. To address a potential functional relevance in vivo, we generated a mouse model harboring a cardiomyocyte-specific deletion of Prmt5 and Prmt7 (cDKO). Strikingly, Prmt5/7-cDKO mice developed progressive systolic dysfunction characterized by extensive subendocardial fibrosis in response to beta-adrenergic stress, indicating that both enzymes are critically required for cardiac homeostasis, especially in the subendocardium, that is predominantly vulnerable to hypoxic conditions.
Mechanistically, single-nucleus transcriptomics of left ventricular tissue from Prmt5/7-cDKO mice confirmed predominant alterations in non-myocytes, particularly indicating increased mitosis and pro-inflammatory activation of fibroblasts, smooth muscle, and endothelial cells that likely underlie subendocardial remodeling. In order to identify factors that mediate heterocellular cross-talk, ligand-receptor analysis combined with regulatory network prediction was performed. We identified HB-EGF as a highly specific factor regulated by PRMT5/7 in cardiomyocytes, along with differential signaling downstream of its receptor ERBB4 in non-myocytes. Indeed, immunoblot analysis of cardiac tissue validated enhanced expression levels in Prmt5/7-cDKO mice compared to wild-type controls, suggesting biological relevance. Targeted intervention via cell-type-specific CRISPRi in vivo is currently being performed to address HB-EGF's functional contribution to cardiac dysfunction and subendocardial fibrosis. Further studies will moreover focus on the mechanisms underlying PRMT-dependent HB-EGF expression and secretion and their oxygen dependency.
