Dual roles of chromatin remodeling protein BRG1 in angiotensin II-induced endothelial-mesenchymal transition
Dual roles of chromatin remodeling protein BRG1 in angiotensin II-induced endothelial-mesenchymal transition
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染色质重塑蛋白 BRG1 在血管紧张素 II 诱导的内皮间质转化中的双重作用
DOI：
10.1038/s41419-020-02744-y
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发表时间：
2020-07-18
影响因子：
9
通讯作者：
Xu, Yong
中科院分区：
文献类型：
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作者：
Li, Zilong;Kong, Xiaochen;Xu, Yong
内皮-间质转化（EndMT）被认为是通过促进肌成纤维细胞池而导致组织纤维化的过程之一。在本研究中，我们研究了血管紧张素II（Ang II）调节EndMT促进心脏纤维化的表观遗传机制，重点关注染色质重塑蛋白BRG1的作用。在培养的血管内皮细胞中，BRG1 敲低或抑制可减弱 Ang II 诱导的 EndMT，这一点可通过内皮标记物 CDH5 的下调和间充质标记物 COL1A2 的上调来证明。一方面，BRG1 与 Sp1 相互作用并被 Sp1 招募到 SNAI2（编码 SLUG）启动子，以响应 Ang II 刺激而激活 SNAI2 转录。一旦激活，SLUG 就会与 CDH5 启动子结合，抑制 CDH5 转录。另一方面，BRG1与COL1A2启动子相互作用并被SRF招募至COL1A2启动子以激活COL1A2转录。从机制上讲，BRG1 从靶启动子中驱逐组蛋白，以促进 Sp1 和 SRF 的结合。最后，与野生型（WT）同窝小鼠相比，内皮条件性 BRG1 敲除小鼠（CKO）对慢性 Ang II 输注的反应显示出心脏纤维化的减少。总之，我们的数据表明，BRG1 是一个关键的转录协调子，编程 Ang II 诱导的 EndMT 从而促进心脏纤维化。
Endothelial-mesenchymal transition (EndMT) is considered one of the processes underlying tissue fibrosis by contributing to the pool of myofibroblasts. In the present study, we investigated the epigenetic mechanism whereby angiotensin II (Ang II) regulates EndMT to promote cardiac fibrosis focusing on the role of chromatin remodeling protein BRG1. BRG1 knockdown or inhibition attenuated Ang II-induced EndMT, as evidenced by down-regulation ofCDH5, an endothelial marker, and up-regulation ofCOL1A2, a mesenchymal marker, in cultured vascular endothelial cells. On the one hand, BRG1 interacted with and was recruited by Sp1 to theSNAI2(encoding SLUG) promoter to activateSNAI2transcription in response to Ang II stimulation. Once activated, SLUG bound to theCDH5promoter to repressCDH5transcription. On the other hand, BRG1 interacted with and was recruited by SRF to theCOL1A2promoter to activateCOL1A2transcription. Mechanistically, BRG1 evicted histones from the target promoters to facilitate the bindings of Sp1 and SRF. Finally, endothelial conditional BRG1 knockout mice (CKO) exhibited a reduction in cardiac fibrosis, compared to the wild type (WT) littermates, in response to chronic Ang II infusion. In conclusion, our data demonstrate that BRG1 is a key transcriptional coordinator programming Ang II-induced EndMT to contribute to cardiac fibrosis.