Role of DNA methylation in lupus

摘要 表观遗传失调在狼疮发病机制中起重要作用。我们 最近描述了一种对幼稚的CD4T细胞的促炎表观遗传重新编程 狼疮患者疾病活跃度增加。我们的数据表明，表观遗传调控 EZH2可能参与了这些表观遗传学的改变。事实上，我们显示EZH2在 调节EZH2的miR-26a和miR-101均为 监管下调。这两种微小RNA都被证明对葡萄糖浓度敏感， 我们发现抑制糖酵解可以恢复狼疮中这两种微RNA的表达。 CD4T细胞。我们假设狼疮CD4T细胞糖酵解增加，导致 通过下调miR-26a和miR-101上调EZH2。此外，我们还提供证据 狼疮CD4T细胞中EZH2的过度表达上调JAM-A，JAM-A介导的是 T细胞黏附。我们建议确定EZH2过度表达的机制解释 狼疮CD4T细胞及其与糖酵解增加和mTORC1的关系 发信号。我们还将确定完整的基因和信号转导途径。 EZH2在狼疮CD4T细胞中的过表达以确定新的治疗靶点。此外, 鉴于我们的数据表明狼疮患者CD4T细胞黏附增加的现象被消除 在体外抑制EZH2之后，体内抑制EZH2显著提高了存活率 并改善MRL/LPR狼疮易感小鼠的狼疮样疾病，我们建议使用基因 在小鼠模型中研究靶向CD4T细胞Ezh2缺失效应的方法 狼疮的症状。EZH2抑制剂目前正在对一些恶性肿瘤进行试验，因此， 我们的结果将为靶向EZH2或我们将识别的EZH2调控基因铺平道路 狼疮患者。

Abstract Epigenetic dysregulation plays an important role in the pathogenesis of lupus. We recently described a pro-inflammatory epigenetic reprogramming of naïve CD4+ T cells upon increased disease activity in lupus patients. Our data suggest that the epigenetic regulator EZH2 might be mediating these epigenetic changes. Indeed, we show that EZH2 is increased in CD4+ T cells from lupus patients, and that both miR-26a and miR-101 which regulate EZH2 are downregulated. Both microRNAs have been shown to be sensitive to glucose concentrations, and we show that inhibiting glycolysis restores the expression of these two microRNAs in lupus CD4+ T cells. We hypothesize that increased glycolysis in lupus CD4+ T cells, results in upregulation of EZH2 via downregulating miR-26a and miR-101. Further, we provide evidence that EZH2 overexpression in lupus CD4+ T cells upregulates JAM-A which mediates increased T cell adhesion. We propose to determine a mechanistic explanation of EZH2 overexpression in lupus CD4+ T cells and how this might be linked to increased glycolysis and mTORC1 signaling. We will also identify the complete repertoire of genes and pathways dysregulated by EZH2 overexpression in lupus CD4+ T cells to identify novel therapeutic targets. In addition, given our data suggesting abrogation of increased CD4+ T cells adhesion in lupus patients following EZH2 inhibition in vitro, and that EZH2 inhibition in vivo significantly improves survival and ameliorates lupus-like disease in MRL/lpr lupus-prone mice, we propose to use genetic approaches to characterize the effects of targeted CD4+ T cell Ezh2 deletion in a murine model of lupus. EZH2 inhibitors are currently being trialed for a number of malignancies, and therefore, our results will pave the way for targeting EZH2, or EZH2-regulated genes we will identify, in lupus patients.