Activation of TWIST Transcription by Chromatin Remodeling Protein BRG1 Contributes to Liver Fibrosis in Mice
Activation of TWIST Transcription by Chromatin Remodeling Protein BRG1 Contributes to Liver Fibrosis in Mice
复制标题
染色质重塑蛋白 BRG1 激活 TWIST 转录导致小鼠肝纤维化
DOI：
10.3389/fcell.2020.00340
复制
发表时间：
2020-05-13
影响因子：
5.5
通讯作者：
Xu, Yong
中科院分区：
文献类型：
--
作者：
Dong, Wenhui;Kong, Ming;Xu, Yong
肝纤维化是一个复杂的病理生理过程，许多不同类型的细胞参与其中。内皮细胞在肝纤维化的调控中发挥着多方面的作用。潜在的表观遗传机制尚未完全理解。在本研究中，我们研究了BRG 1，染色质重塑蛋白，在调节内皮细胞在体外促纤维化刺激和小鼠肝纤维化中的作用。我们报告说，BRG 1的siRNA废除TGF-β或缺氧诱导的内皮标记基因的下调和间充质标记基因的上调培养的内皮细胞中的耗竭。重要的是，内皮特异性BRG 1缺失减弱了CCl 4诱导的小鼠肝纤维化。BRG 1在体外敲除或BRG 1在体内敲除伴随着TWIST的下调，TWIST是内皮表型的关键调节因子。从机制上讲，BRG 1与TWIST启动子相互作用，并被HIF-1 α募集到TWIST启动子中，以激活TWIST转录。BRG 1沉默使TWIST启动子周围的染色质结构更具抑制性，这可能有助于TWIST下调。抑制HIF-1 α活性可抑制小鼠的肝纤维化。类似地，TWIST的药物抑制减轻了小鼠的肝纤维化。总之，我们的数据表明BRG 1对TWIST的表观遗传激活有助于调节内皮表型和肝纤维化。因此，靶向HIF 1 α-BRG 1-TWIST轴可能会产生治疗肝纤维化的新治疗方案。
Liver fibrosis is a complex pathophysiological process to which many different cell types contribute. Endothelial cells play versatile roles in the regulation of liver fibrosis. The underlying epigenetic mechanism is not fully appreciated. In the present study, we investigated the role of BRG1, a chromatin remodeling protein, in the modulation of endothelial cells in response to pro-fibrogenic stimuli in vitro and liver fibrosis in mice. We report that depletion of BRG1 by siRNA abrogated TGF-beta or hypoxia induced down-regulation of endothelial marker genes and up-regulation of mesenchymal marker genes in cultured endothelial cells. Importantly, endothelial-specific BRG1 deletion attenuated CCl4 induced liver fibrosis in mice. BRG1 knockdown in vitro or BRG1 knockout in vivo was accompanied by the down-regulation of TWIST, a key regulator of endothelial phenotype. Mechanistically, BRG1 interacted with and was recruited to the TWIST promoter by HIF-1 alpha to activate TWIST transcription. BRG1 silencing rendered a more repressive chromatin structure surrounding the TWIST promoter likely contributing to TWIST down-regulation. Inhibition of HIF-1 alpha activity dampened liver fibrosis in mice. Similarly, pharmaceutical inhibition of TWIST alleviated liver fibrosis in mice. In conclusion, our data suggest that epigenetic activation of TWIST by BRG1 contributes to the modulation of endothelial phenotype and liver fibrosis. Therefore, targeting the HIF1 alpha-BRG1-TWIST axis may yield novel therapeutic solutions to treat liver fibrosis.