HIF-1/COMPASS调控缺氧诱导Brg1和Brm表达上调的机制研究

项目名称： HIF-1/COMPASS调控缺氧诱导Brg1和Brm表达上调的机制研究

项目编号： No.81501626

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 陈德伟

作者单位： 中国人民解放军第三军医大学

项目金额： 18万元

中文摘要： 我们最近研究发现，Brg1和Brm介导的表观遗传调控在缺氧性肺动脉高压(HPH)的发生发展中具有重要作用。缺氧可诱导大鼠肺血管及内皮细胞Brg1和Brm表达增多，介导粘附分子(CAMs)和ET-1转录激活，参与肺血管炎症反应及肺血管重构，最终导致HPH。但是，缺氧时Brg1和Brm表达上调的转录调控机制目前尚不清楚。我们经生物信息学分析发现Brg1和Brm启动子区域含有缺氧反应元件(HRE)；预实验发现，干扰组蛋白甲基转移酶复合物(COMPASS)Wdr5、Ash2和Set1亚基可显著抑制Brg1表达，提示HIF-1和COMPASS可能分别或相互作用，共同调控缺氧诱导Brg1和Brm表达上调。因此，本研究拟从HPH动物和细胞水平，研究缺氧时HIF-1/COMPASS介导Brg1和Brm表达上调的转录调控机制，深入阐明HPH发生的分子机制，为临床HPH防治提供理论和实验依据。

中文关键词： 缺氧性肺动脉高压；组蛋白甲基转移酶；染色质重构；表观遗传；缺氧

英文摘要： Pulmonary vasoconstriction mediated by endothelin, and inflammation associated with the up-regulation of cell adhesion molecules (CAMs) play an important role in the development of hypoxia pulmonary hypertension. Our previous studies found that Brg1 and Brm were upregulated by hypoxia in rat pulmonary vascular and endothelial cells. Brg1 and Brm were able to enhance the activation of CAMs and ET-1 by hypoxia, and play an important role in HPH. But the mechanism of Brg1/Brm transactivation in response to hypoxia in endothelial cells leading up to HPH is not fully appreciated. Bioinformatics analysis found that the Brg1 and Brm promoter regions contain HRE. Our preliminary experiment found that when knocked down the expression of endogenous Wdr5、Ash2、Set1 using siRNA, the induction of endogenous Brg1 and Brm messages was limited in endothelial cell. So we speculated that the nuclear transcription factor HIF-1, histone H3K4 methylation mediated by histone methylation transferase COMPASS complex, as well as their crosstalk influence hypoxia-induced Brg1/Brm transactivation. This study intends to adopt the pulmonary artery endothelial cells and rat HPH model as the research object, using plasmid overexpressing, RNAi interference technology, combining with methods such as reporter assays, CHIP, Re-CHIP to clarify the mechanism of Brg1/Brm transactivation. This study will further clarify the molecular mechanism of HPH. And provide theoretical and experimental evidence for HPH prevention and cure.

英文关键词： Hypoxia pulmonary hypertension;Histone methylation transferase ;Chromatin remodeling;Epigenetic;Hypoxia