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. 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).

心脏成纤维细胞（Cardiac fibroblasts, CFs）是介导细胞外基质重构的核心细胞类型，与心力衰竭（Heart failure, HF）密切相关。既往研究表明，TEAD1缺失会损害心脏发育与稳态维持。然而，TEAD1在心脏重构过程中成纤维细胞中的作用仍未阐明。本研究发现，在主动脉弓缩窄（Transverse aortic constriction, TAC）及血管紧张素II（Angiotensin II, Ang-II）灌注造模4周后的小鼠体内，TEAD1主要在心脏成纤维细胞中表达上调。超声心动图与组织学分析显示，成纤维细胞及肌成纤维细胞特异性敲除TEAD1可缓解TAC诱导的心脏重构；使用TEAD1抑制剂VT103进行干预可重现这一表型效应。机制层面的研究证实，RNA测序（RNA-seq）与染色质免疫沉淀测序（Chromatin immunoprecipitation-sequencing, ChIP-seq）分析显示，TEAD1通过Wnt信号通路（Wnt signalling pathway）促进成纤维细胞向肌成纤维细胞转化。综上，TEAD1是介导病理性心脏重构的促纤维化心脏成纤维细胞表型的关键调控因子，其调控作用依赖于BRD4/Wnt4信号通路（BRD4/Wnt4 signalling pathway）。为全面解析TEAD1介导心脏重构的分子机制，本研究通过全基因组染色质免疫沉淀测序（ChIP-seq），在NMCFs中鉴定TEAD1结合的基因调控元件及对应的转录组变化。实验收集了不同实验组NMCFs的细胞提取物，包括过表达阴性对照组（OE-NC, overexpression negative control）与TEAD1过表达组（OE-TEAD1, TEAD1 overexpression）。