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PRMT1-Mdm4-p53 pathway controls epicardial invasion and cell fate transition

ABSTRACT: Epicardial cells are progenitors giving rise to the majority of cardiac fibroblasts, coronary smooth muscle cells, and pericytes during cardiac development, and critically modulating heart morphogenesis and coronary development. An integral phase of epicardial cell fate transition is epithelial-to-mesenchymal transition (EMT), which confers motility and facilitates cell fate transition. We identify a pathway involving protein arginine methyltransferase 1 (PRMT1) and its downstream p53 signaling that drives epicardial EMT and invasion. We show that PRMT1 determines the half-life of p53 through regulating alternative splicing of Mdm4, which is a key controller of p53 degradation. Loss of PRMT1 promotes the expression of Mdm4 short form, which inhibits p53 degradation. Accumulation of p53 subsequently enhances Slug degradation and blocks epicardial EMT. We further demonstrated that the PRMT1-Mdm4-p53 pathway drives epicardial cell fate transition into cardiac fibroblasts, coronary smooth muscle cells and pericytes in vivo, and modulates ventricular morphogenesis and coronary vessel formation. Together, our results establish critical functions of the PRMT1-Mdm4-p53 pathway in epicardial EMT, invasion and cell fate transition.

ORGANISM(S): Mus musculus

PROVIDER: GSE122200 | GEO | 2020/08/18

REPOSITORIES: GEO

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PRMT1-Mdm4-p53 pathway controls epicardial invasion and cell fate transition

Project description:PRMT1-Mdm4-p53 pathway controls epicardial invasion and cell fate transition

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2011-02-28 | E-GEOD-27181 | biostudies-arrayexpress

Comparison of gene expression data between control and tissue specific epicardial PDGF receptor (a and b) knockout embryonic hearts

2011-02-28 | GSE27181 | GEO

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Project description:Nonmuscle myosin IIB (NMIIB; heavy chain encoded by MYH10) is essential for cardiac myocyte cytokinesis. The role of NMIIB in other cardiac cells is not known. Here, we show that NMIIB is required in epicardial formation and functions to support myocardial proliferation and coronary vessel development. Ablation of NMIIB in epicardial cells results in disruption of epicardial integrity with a loss of E-cadherin at cell-cell junctions and a focal detachment of epicardial cells from the myocardium. NMIIB-knockout and blebbistatin-treated epicardial explants demonstrate impaired mesenchymal cell maturation during epicardial epithelial-mesenchymal transition. This is manifested by an impaired invasion of collagen gels by the epicardium-derived mesenchymal cells and the reorganization of the cytoskeletal structure. Although there is a marked decrease in the expression of mesenchymal genes, there is no change in Snail (also known as Snai1) or E-cadherin expression. Studies from epicardium-specific NMIIB-knockout mice confirm the importance of NMIIB for epicardial integrity and epicardial functions in promoting cardiac myocyte proliferation and coronary vessel formation during heart development. Our findings provide a novel mechanism linking epicardial formation and epicardial function to the activity of the cytoplasmic motor protein NMIIB.

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Project description:Cardiac fibrosis is a detrimental pathophysiological state involved in a number of cardiovascular diseases. Myofibroblasts mediate fibrosis by excessive remodeling of the extracellular matrix, which ultimately leads to tissue stiffness and impaired heart performance. Recently, it was shown that a substantial fraction of cardiac myofibroblasts may originate from the epicardium through Epithelial-to-Mesenchymal Transition (EMT). We have developed a cellular model of EMT in which adult murine epicardium-derived cells are differentiated into myofibroblast-like cells in the presence of Interleukin-1beta, Tumor Necrosis Factor-alpha, or Transforming Growth Factor-beta. Using this model of EMT, the microRNAome was assessed by microRNA (miRNA) arrays. Subsequently, expression levels of differentially expressed miRNAs were validated by qPCR. These miRNAs were targeted by transfecting epicardium-derived cells with anti- or pre-miRs prior to EMT initiation. The ability of the anti- or pre-miRs to inhibit EMT was assessed on a number of phenotypic markers. In this study we have identified a number of miRNAs that potentially play an intrinsic role in cardiac EMT. We speculate that by targeting those miRNA, the onset and long-term progression of cardiac fibrosis can be substantially reduced. Epicardial mesothelial cells were isolated and expanded from the epicardium of adult rats (8-10 weeks). Epithelial-to-mesenchymal Transition was induced by 10 ng/mL Interleukin-1beta, Tumor Necrosis Factor-alpha, or Transforming Growth Factor-beta1 for 48h. The assocciated differential microRNA expressions relative to a control treatment was computed by microRNA arrays. The experiment was conducted on biological quadruplicates for the control treatment and biological triplicates for cytokine treatments.

2012-04-26 | E-GEOD-37627 | biostudies-arrayexpress

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2015-12-15 | E-GEOD-75583 | biostudies-arrayexpress

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