组蛋白甲基转移酶SETD3调控CD4+T细胞分化及其在系统性红斑狼疮发病中的作用研究

Dysregulated differentiation of naive CD4+ T cells into distinct functional subsets has been associated with the pathogenesis of systemic lupus erythematosus. However, their mechanisms remain unclear. Epigenetic regulation of cytokine and transcription factor loci has proven to be of eminent importance in the process of directing lineage differentiation. Our previous study showed that histone methyltransferanse SETD3 was overexpressed in CD4+ T cells from SLE. Surprisingly, our studies aslo demonstrated that Icaritin could change H3K4 trimethyaltion status of Foxp3 promoter, as well as its expression by up-regulating SETD3 expression, which leaded to the enhanced Treg cells suppressive activities ultimately. So, we propose that this newly identified histone methyltransferanse Setd3 may play an important role in the phenotype and function of CD4+ T cell subsets and therefore implicated in the immuno-pathology processes of SLE. Thus a better understanding of the epigenetic mechanisms that control CD4+Tcell differentiation may provide novel therapeutic targets to treat a wide range of autoimmune disease such as SLE.

CD4+T细胞分化异常及亚群失衡在系统性红斑狼疮（SLE）病理机制中起重要作用，然而调控CD4+T细胞分化的具体机制尚不清楚。组蛋白甲基化修饰是一种重要的基因表达调控机制。我们的前期研究发现SLE CD4+T细胞组蛋白甲基转移酶SETD3表达下降，而在筛选生物单体治疗狼疮鼠实验中进一步发现，分子单体淫羊藿素能够通过上调SETD3增加调节性T细胞（Treg细胞）Foxp3基因启动子区H3K4me3水平、增强Foxp3表达，从而增强Treg细胞抑制功能。但是组蛋白甲基转移酶SETD3是否调控其它CD4+T细胞亚群分化尚不清楚。本项目拟在前期研究基础上，探讨SETD3通过动态改变组蛋白甲基标志如H3K4,H3K36me3从而调控CD4+T细胞亚群分化，并揭示其在SLE发病中所起的作用。本研究将有助于进一步阐明SLE CD4+T细胞亚群失衡的表观遗传学分子机制，可能为SLE治疗提供新的靶点和途径。

CD4+T细胞分化异常及亚群失衡在系统性红斑狼疮（SLE）病理机制中起重要作用，然而调控CD4+T细胞分化的具体机制尚不清楚。组蛋白甲基化修饰是一种重.要的基因表达调控机制。本项目通过扩大样本检测到SLE患者CD4+ T细胞中组蛋白甲基转移酶SETD3 mRNA和蛋白表达水平较健康对照明显增高。进一步抽取人外周血，分离naïve CD4+T细胞，诱导向Thl,Th2,Thl7,Treg，Tfh分化，SETD3在CD4+T细胞亚群Tfh中表达尤为明显，Tfh细胞是近年发现的一种主要的辅助B细胞产生抗体的CD4+T细胞，通过siRNA下调SETD3的表达，发现Tfh细胞CXCR5表达降低，同时CXCR5基因启动子区组蛋白H3K4me3，H3K36me3甲基化水平下降；通过过表达质粒上调SETD3的表达，发现CXCR5表达增高，同时CXCR5基因启动子区组蛋白H3K4me3，H3K36me3甲基化水平上调。本项目首次证实SETD3通过动态改变组蛋白甲基标志如H3K4,H3K36me3从而调控CD4+T细胞亚群分化，进一步阐明了SLE CD4+T细胞亚群失衡的表观遗传学分子机制，为今后SLE 表观遗传学治疗提供新的靶点和途径。