Activation of imprinted gene Pw1 promotes cardiac fibrosis after ischemic injury [control_and_Pw1 CKO]

The activation of fibroblasts and production of extracellular matrix (ECM) after cardiac injury has been the focus of research on cardiac fibrosis. Whether imprinted genes play a role in the fibrogenesis or extracellular matrix production after heart damage has not been studied. Here, we show that the imprinted gene Pw1 directed ECM production by regulating de novo purine synthesis (DNPB) after myocardial infarction (MI). After MI, the DNA methylation of the imprinting control region (ICR) of Pw1 gene in the injured area was reduced and both alleles of Pw1 in fibroblasts are activated. Further, loss of Pw1 in fibroblasts can enhance cardiac function, reduce cardiac fibrosis and extracellular matrix secretion after cardiac injury. To screen the targets of PW1, we contrasted chromatin immunoprecipitation (ChIP)-seq and RNA-seq using the injured left ventricles at 7 days post-MI, we next found PW1 binds directly upstream of the Pfas gene that encodes one of the DNPB enzymes phosphoribosylformylglycinamidine synthase (PFAS) in heart after injury. Similarly, specific knockout of pfas in fibroblasts also improves cardiac function and reduces ECM production. Moreover, de novo purine biosynthesis is necessary for ECM production in activated fibroblasts. These observations implicate understanding the mechanism of Pw1 in the repair of cardiac injury will provide new ideas for the treatment of cardiovascular diseases.