Epigenetic Repression of Chloride Channel Accessory 2 Transcription in Cardiac Fibroblast: Implication in Cardiac Fibrosis.
Epigenetic Repression of Chloride Channel Accessory 2 Transcription in Cardiac Fibroblast: Implication in Cardiac Fibrosis.
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心脏成纤维细胞中氯离子通道辅助 2 转录的表观遗传抑制：对心脏纤维化的影响
DOI：
10.3389/fcell.2021.771466
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发表时间：
2021
影响因子：
5.5
通讯作者：
Fang M
中科院分区：
文献类型：
--
作者：
Shao T;Xue Y;Fang M
心脏纤维化是导致心力衰竭的关键病理生理过程。暴露于各种刺激的心脏驻留成纤维细胞能够转分化成肌成纤维细胞并介导心脏中的促纤维化反应。本研究旨在探讨心脏成纤维细胞中氯通道附件2（Clca 2）转录的调控机制及其在成纤维细胞-肌成纤维细胞转化（FMyT）中的潜在意义。我们报告说，Clca 2表达下调，在激活的心脏成纤维细胞（肌成纤维细胞）相比，静止的心脏成纤维细胞在两种不同的动物模型的心脏纤维化。Clca 2表达也被FMyT的有效诱导剂TGF-β下调。TGF-β可能通过Clca 2启动子-516和-224之间的E-box元件在转录水平上抑制Clca 2表达。进一步的分析显示，Twist 1直接与E-box元件结合，而Twist 1缺失消除了TGF-β诱导的Clca 2反式阻遏。Twist 1介导的Clca 2抑制伴随着组蛋白H3/H4乙酰化从Clca 2启动子的擦除。Twist 1与HDAC 1相互作用，并将HDAC 1募集到Clca 2启动子上，从而抑制Clca 2的转录。最后，观察到Clca 2过表达减弱，而Clca 2敲低增强FMyT。总之，我们的数据表明，Twist 1-HDAC 1复合物抑制Clca 2在心脏成纤维细胞中的转录，这可能有助于FMyT和心脏纤维化。
Cardiac fibrosis is a key pathophysiological process that contributes to heart failure. Cardiac resident fibroblasts, exposed to various stimuli, are able to trans-differentiate into myofibroblasts and mediate the pro-fibrogenic response in the heart. The present study aims to investigate the mechanism whereby transcription of chloride channel accessory 2 (Clca2) is regulated in cardiac fibroblast and its potential implication in fibroblast-myofibroblast transition (FMyT). We report that Clca2 expression was down-regulated in activated cardiac fibroblasts (myofibroblasts) compared to quiescent cardiac fibroblasts in two different animal models of cardiac fibrosis. Clca2 expression was also down-regulated by TGF-β, a potent inducer of FMyT. TGF-β repressed Clca2 expression at the transcriptional level likely via the E-box element between −516 and −224 of the Clca2 promoter. Further analysis revealed that Twist1 bound directly to the E-box element whereas Twist1 depletion abrogated TGF-β induced Clca2 trans-repression. Twist1-mediated Clca2 repression was accompanied by erasure of histone H3/H4 acetylation from the Clca2 promoter. Mechanistically Twist1 interacted with HDAC1 and recruited HDAC1 to the Clca2 promoter to repress Clca2 transcription. Finally, it was observed that Clca2 over-expression attenuated whereas Clca2 knockdown enhanced FMyT. In conclusion, our data demonstrate that a Twist1-HDAC1 complex represses Clca2 transcription in cardiac fibroblasts, which may contribute to FMyT and cardiac fibrosis.
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