CD4+ T细胞组蛋白修饰异常对CREMα基因表达的调控及其在系统性红斑狼疮发病中的作用

近年来的研究表明CD4+ T细胞CREMα表达升高在系统性红斑狼疮（SLE）的发病中起到至关重要的作用，然而CREMα过度表达的分子机制尚未完全阐明。我们前期实验发现SLE患者CD4+ T细胞CREMα启动子区H3K4me3水平显著高于正常对照，且该区H3K4甲基化酶Set1水平亦显著升高，提示CREMα在SLE CD4+ T细胞中过表达可能与异常的组蛋白修饰相关。因此，我们拟进一步证实正常对照和SLE患者CD4+ T细胞CREMα启动子区H3K4me3和H3K4甲基化酶的水平是否存在差异；在SLE CD4+ T细胞中抑制H3K4甲基化酶的表达，检测对CREMα转录水平、CREMα启动子区H3K4me3、组蛋白乙酰化、DNA甲基化水平以及IL-2、IL-17A水平的影响，以此探讨CREMα在SLE患者CD4+ T细胞中表达升高的原因及具体机制，并有望为SLE的治疗提供新的途径和有效靶点。

In recent years, accumulating evidence has demonstrated that increased CREMα in CD4+ T cells plays an essential role in the pathogenesis of systemic lupus erythematosus (SLE). However, the molecular mechanisms that result in CREMα over expression remain poorly understood. In our previous work, we identified markedly increased histone H3 lysine 4 trimethylation (H3K4me3) enrichment at the CREMα promoter of SLE CD4+ T cells relative to controls. In addition, a striking increase was observed in Set1 (a H3K4 methyltransferase) binding. All these results suggested that aberrant histone modification was involved in over expression of CREMα in SLE CD4+ T cells. Therefore, we plan to further compare the levels of H3K4me3 and H3K4 methyltransferases at the CREMα promoter between normal and SLE CD4+ T cells; And to knock down H3K4 methyltransferases in CD4+ T cells from SLE patients, subsequently to examine the effects on CREMα expression, on the levels of H3K4me3, histone acetylation and DNA methylation at the CREMα promoter, and on the productions of IL-2 and IL-17A. By these ways, we would reveal the causation and detailed mechanism of CREMα increase in SLE CD4+ T cells, and could help provide a novel way and target for effective SLE therapy.