H3K9me2/me3去甲基化酶JMJD1A调控肝星状细胞活化的分子机制初探

项目名称： H3K9me2/me3去甲基化酶JMJD1A调控肝星状细胞活化的分子机制初探

项目编号： No.31301050

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 生物科学

项目作者： 姜燕

作者单位： 复旦大学

项目金额： 23万元

中文摘要： 肝星状细胞（HSC）活化是肝纤维化发生的中心环节，是HSC由具脂肪细胞特性的静息状态转分化为肌成纤维细胞的过程。我们前期实验发现脂肪代谢调控相关H3K9me2/me3去甲基化酶JMJD1A可以调控HSC的活化进程并影响肝纤维化发生，并证明了HSC活化的关键负调控因子PPARG是其靶基因。为进一步深入探索JMJD1A调控HSC活化的表观遗传学机制，本项目将采用ChIP-Seq并结合表达谱芯片技术挖掘HSC活化前后JMJD1A差异结合调控的的候选靶基因，并通过ChIP-qPCR验证JMJD1A与靶基因区的结合及其对靶基因区核小体H3K9的去甲基化作用。同时通过RT-qPCR和Western等验证JMJD1A对靶基因的表达调控作用。以期进一步揭示JMJD1A通过调节靶基因区核小体H3K9甲基化修饰及靶基因的表达进而调控HSC活化的分子机制，丰富对HSC活化和肝纤维化表观遗传学调控规律的认识。

中文关键词： 肝星状细胞活化；肝纤维化；JMJD1A；PPARG；

英文摘要： Hepatic Stellate Cell (HSC) activation is a process in which cells change in morphology from quiescent vitamin A and lipid storing cells to activated myofibroblast-like cells which are pivotal to fibrogenesis.We previous study have found that H3K9 demethylases, jumonji-domain containing protein (Jmjd) Jmjd1a could modulate HSC activation and liver fibrosis, and further investigation showed that PPARγ, a key suppressor of HSC activaiton, was regualted by JMJD1A during HSC activaiton， and the marker by H3K9me2 in its promoter was controled by JMJD1A.It was well known that a certain life process regualted by JMJD1A usually through transcriptional regualtion on hundreds of target genes. so for further investigating the epigenetic mechanism of HSC activaiton modulated by JMJD1A.We will excavate the differential target genes of JMJD1a between quietcent and activated HSC by ChIP-Sequencing and Affymetrix microarray technology, screen the candidate target genes relative to HSC activation, and carry out the functional assay to verify that JMJD1a would regulate target genes expression by controling its marks of methyl-H3K9. Deciphering the epigenetic mechanism of HSC activation will provide a new insight into etiollogy of liver fibrosis and have implication for drug target discovery for this disease.

英文关键词： HSC activation；liver fibrosis；JMJD1A；PPARG；