SETD1A调控巨噬细胞表型参与非酒精性脂肪肝炎的机制研究

Studies predict that non-alcoholic steatohepatitis (NASH) and its related diseases will be the main cause of liver-related morbidity and mortality in the following 20 years. Therefore, it is necessary to explore new strategies to prevent and control NASH. In recent years, more and more studies have suggested that methylation of histones is associated with the pathological course of NASH. SETD1A is the core component of the mammalian H3K4 methyltransferase complex (COMPASS).Our current research demonstrated SETD1A was increased in the diet-induced NASH model.Meanwhile,macrophage-specific knockout of SETD1A had an antagonistic effect on high fat diet-induced NASH mice. Therefore, we propose a hypothesis: under the stimulation of nutrient surplus, SETD1A participates in the development of NASH via regulating relative transcription factors，synergistically regulating macrophage phenotypic switching, promoting inflammatory response and oxidative stress.In the project,We intend to elucidate the epigenetic mechanism of SETD1A accounting for NASH pathogenesis , verify the therapeutic effect of intervention of SETD1A expression on NASH and provide new ideas and methods for the treatment of NASH.

研究预测，在未来20年内，非酒精性脂肪肝炎（NASH）及其相关疾病将会成为肝脏相关发病率和死亡率的主要原因，因此，探索防治NASH的新策略十分必要。近年来，越来越多的研究提示，组蛋白的甲基化修饰与NASH的病理病程相关。SETD1A作为组蛋白H3K4Me3修饰酶COMPASS的催化核心，课题组前期研究初步证实：饮食诱导的NASH模型中，小鼠肝巨噬细胞SETD1A表达上调。同时，巨噬细胞特异性敲除SETD1A对高脂饮食诱导的NASH有拮抗作用。因此我们提出假说：营养应激状态下，SETD1A通过调节相关转录因子活性，并与其协同调控肝脏巨噬细胞的表型转化，促进炎症反应和氧化应激，进而推进NASH的病理进程。该项目中，我们拟深入探索SETD1A调控NASH发生发展过程的表观遗传学机制，验证干预SETD1A表达对NASH的治疗效果，为NASH的治疗提供新思路和方法。

非酒精性脂肪肝炎（NASH）及其相关疾病已经成为慢性肝病致死的主要原因。因此，探索防治NASH的新策略十分必要。近年来越来越多的研究提示，组蛋白的甲基化修饰与NASH发生发展相关。在本项目中，我们探索了以组蛋白H3K4甲基转移酶SET1A为核心的转录复合物调控NASH的表观遗传学机制。项目实施三年来的主要成果有：（1）SET1A通过改变巨噬细胞表型促进NASH；在巨噬细胞中特异敲除SET1A显著削弱NASH发生发展。（2）锌指结构转录因子EGR1和辅因子Nab1互作通过招募组蛋白修饰酶抑制肝细胞中脂肪酸氧化相关基因转录从而促进NASH发生发展。(3) Notch信号通路下游转录因子Hes5通过招募组蛋白去乙酰酶SIRT1抑制促凋亡分子LIGHT转录，从而保护NASH过程中肝细胞凋亡。（4）染色质重构蛋白BRG1通过激活DDIT4转录，促进MAPK-p38信号转导复合物的组装，从而激活活性氧释放和NASH病变。以上成果已经在国际期刊发表研究论文2篇，另有数篇论文正在整理投稿过程中。