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

项目名称： 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

项目编号： No.81502734

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： 廖洁月

作者单位： 中南大学

项目金额： 18万元

中文摘要： 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。

中文关键词： 组蛋白甲基转移酶；；SETD3；系统性红斑狼疮(SLE)；CD4+T；细胞

英文摘要： 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.

英文关键词： Histone methyltransferanse; SETD3;systemic lupus erythematosus(SLE);CD4+T cell