Abstract
Epicardial cells are cardiac progenitors that give rise to the majority of cardiac fibroblasts, coronary smooth muscle cells, and pericytes during development. An integral phase of epicardial fate transition is epithelial-to-mesenchymal transition (EMT) that confers motility. We uncover an essential role for the protein arginine methyltransferase 1 (PRMT1) in epicardial invasion and differentiation. Using scRNA-seq, we show that epicardial-specific deletion of Prmt1 reduced matrix and ribosomal gene expression in epicardial-derived cell lineages. PRMT1 regulates splicing of Mdm4, which is a key controller of p53 stability. Loss of PRMT1 leads to accumulation of p53 that enhances Slug degradation and blocks EMT. During heart development, the PRMT1-p53 pathway is required for epicardial invasion and formation of epicardial-derived lineages: cardiac fibroblasts, coronary smooth muscle cells, and pericytes. Consequently, this pathway modulates ventricular morphogenesis and coronary vessel formation. Altogether, our study reveals molecular mechanisms involving the PRMT1-p53 pathway and establish its roles in heart development.
Highlights
Epicardial cells represent an important progenitor population in the heart
To study the role of protein arginine methyltransferase 1 (PRMT1) in epicardial epithelial-tomesenchymal transition (EMT), we used a cell line established from embryonic ventricular epicardial cells, MEC1 (Li et al, 2011)
MEC1 cells produced a dense assemblage of fibronectin fibers in response to TGFb-induced EMT, but Prmt1 depletion prevented fibronectin deposition to the extracellular matrix (ECM) (Figure 1E)
Summary
Epicardial cells represent an important progenitor population in the heart. Epicardial cells undergo epithelial-to-mesenchymal transition (EMT) to invade the developing muscle wall, giving rise to the majority of cardiac fibroblasts, coronary vascular smooth muscle cells (cVSMCs), and pericytes (von Gise and Pu, 2012). The epicardial EMT is a cellular program in which cells lose their epithelial cell morphology and become motile and invasive (Lamouille et al, 2014). EMT is initiated by a network of signaling pathways, including transforming growth factor b (TGF-b), platelet-derived growth factor (PDGF), and Wnt signaling, which converge on key transcription factors such as Snail and Slug to achieve transcriptional reprogramming that leads to morphological changes and acquisition of migratory and invasive propensity (Lamouille et al, 2014). The molecular mechanisms of epicardial cell fate transition are not fully understood
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