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Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes
Published on: June 3, 2018
Activation of Imprinted Gene PW1 Promotes Cardiac Fibrosis After Ischemic Injury
Shan Kou1,2, Zhengkai Lu2, Defang Deng1
1School of Life Science and Technology (S.K., D.D., M.Y., Y.S., T.F., Z.J., J.M., C.L., X.L., H.Z.), ShanghaiTech University, Shanghai, China.
Background:
Cardiac fibrosis, characterized by excessive extracellular matrix (ECM) deposition in the myocardium, is an important target for heart disease treatments. Pw1 (paternally expressed gene 3) is an imprinted gene expressed from the paternal allele, and de novo purine biosynthesis (DNPB) is a crucial pathway for nucleotide synthesis. However, the roles of PW1 and DNPB in ECM production by cardiac fibroblasts during myocardial ischemia are not yet understood.
Methods:
To induce myocardial damage, we performed left anterior descending coronary artery ligation. We generated Pw1 and Pw1 knock-in mouse lines to evaluate the expression of the 2 Pw1 alleles in normal and injured hearts. Bisulfite sequencing was used to analyze the DNA methylation of the Pw1 imprinting control region. We identified the phosphoribosylformylglycinamidine synthase (Pfas) gene, encoding the DNPB enzyme PFAS, as a direct target of PW1 using chromatin immunoprecipitation sequencing and real-time quantitative polymerase chain reaction. The role of DNPB in ECM production and cardiac fibrosis after injury was examined in vitro using cultured cardiac fibroblasts and in vivo with Pfas-deficient mice.
Results:
Our study demonstrates that myocardial infarction reduces DNA methylation at the imprinting control region of the maternally imprinted gene Pw1, triggering a switch from monoallelic imprinting to biallelic expression of Pw1 in cardiac fibroblasts. In activated cardiac fibroblasts, increased Pw1 expression promotes purine biosynthesis and induces ECM production by transcriptionally activating the DNPB factor Pfas. We identified that DNPB is essential for ECM production in activated fibroblasts and that loss of Pfas in fibroblasts limits cardiac fibrosis and improves heart function after injury.
Conclusions:
This study demonstrates that Pw1 imprinting is disrupted after injury and reveals a novel role for the downstream target PFAS in ECM production and cardiac fibrogenesis. Targeting the PW1/PFAS signaling pathway presents a promising therapeutic strategy for improving cardiac repair after injury.
