The function of TEAD1 in cardiac fibroblast activation [ChIP-Seq]
Cardiac fibroblasts (CFs) are the primary cells tasked with extracellar matrix reorganization and significantly associated with heart failure (HF). Previous studies have shown that TEAD1 deficiency deteriorated heart development and homeostasis. However, the role of TEAD1 in fibroblasts during cardiac remodeling was still undiscovered. Our study demonstrated that TEAD1 was upregulated predominently in cardiac fibroblasts in mice 4 weeks after transverse aortic constriction (TAC) and Ang-II infusion. Echocardiographic and histological analyses demonstrated that CFs- and myofibroblasts-specific TEAD1 deficiency ameliorated TAC-induced cardiac remodeling and treatment with TEAD1 inhibitor, VT103, mimiced this phenotypic effect. Mechanistically, RNA-seq analysis , ChIP-Seq analysis identified TEAD1 promotes the fibroblast-to-myofibroblast transition through the Wnt signalling pathway. In conclusion, TEAD1 is an essential regulator of the pro-fibrotic CFs phenotype associated with pathological cardiac remodeling via the BRD4/Wnt4 signalling pathway. Overall design: To fully understand the molecular mechanisms underlying TEAD1-mediated cardiac remodeling, we whole-genome chromatin immunoprecipitation-sequencing (ChIP-seq) to identify the transcriptomic changes the gene regulatory elements bound by TEAD1 in NMCFs. Cell extracts were collected from NMCFs in different experimental groups, including OE-NC (overexpression negative control), and OE-TEAD1 (TEAD1 overexpression).