组蛋白甲基化酶EZH2特异性调控狼疮相关I IFN通路的分子机制研究

Anti-type I interferon pathway (I IFN) has been emerging as a new therapy in the treatment of systemic lupus erythematosus(SLE), but the specific regulational mechanism of the interferon inducible genes (ISGs) is unclear. We previously found that histone methyltransferase ,EZH2, may be involved in the selective regulation of I IFN, and EZH2 targeted genes were associated with the pathogenesis of systemic lupus erythematosus. It was found that the expression of EZH2 in monocytes from patients was significantly higher than that from normal controls and correlated with expression of I IFN. Meanwhile，we first found that GSK126 can decrease expression of ISGs in vivo expreriments. On the basis of the above, this project will use epigenome technology combining with high-throughput genomic sequencing and bioinformatics analysis to study the epigenomics information of ISGs in monocytes and the fine selective regulational molecular mechanism of ISGs. Besides we also try to explore the change of lupus phenotype by intervention of EZH2 in vivo experiments, such as IFN accelerated lupus mice. This study will provide a theoretical basis for new therapeutic target finding.

I型干扰素（IFN-I）通路是狼疮发病的关键致病通路，针对IFN-I通路的治疗是新兴的狼疮靶向治疗方法之一，然而特异性调控致病性干扰素诱导基因（ISGs）表达的机制尚不清楚。我们发现组蛋白甲基化酶EZH2可能参与IFN-I通路的选择性调控，同时EZH2可以调控与狼疮发病相关的基因表达。狼疮患者单核细胞中EZH2相较正常对照显著升高且与患者体内升高的IFN-I相关。同时，我们证明EZH2抑制剂GSK126在小鼠体内可以下调部分ISGs。在此基础上，本项目将利用表观组学、高通量测序及生物信息学分析生理和病理条件下EZH2及对应的组蛋白修饰（H3K27me3）在单核细胞基因组中的分布模式，并深入研究其选择性调控ISGs表达的机制，并利用IFN-I加速的狼疮鼠模型，研究体内干预EZH2对SLE表型的影响，为进一步发现新的靶向治疗分子提供理论基础。

系统性红斑狼疮（SLE）是一种高度异质性的疾病，甚至同一患者中存在多种疾病驱动途径。不同致病途径的共同调节剂可以是多价治疗靶标。本项目评估EZH2在I型干扰素（IFN-I）信号传导途径中的调节功能。我们发现SLE患者外周血单个核细胞和肾组织中EZH2的表达上调，与干扰素刺激基因（ISGs）的过表达呈正相关。抑制EZH2减少了STAT1的磷酸化和IFN-I刺激的ISG的诱导。 EZH2抑制剂可减弱NZB / NZW F1小鼠体内IFN-I的激活并减轻狼疮性肾炎。因此EZH2参与了SLE中IFN-I信号通路的过度激活。 EZH2抑制剂具有治疗狼疮肾炎的潜力。 EZH2是SLE的有效多价治疗靶标。