Role of DNA methylation in lupus

摘要 表观遗传失调在狼疮的发病机制中起重要作用。我们 最近描述了一种幼稚CD 4 + T细胞的促炎性表观遗传重编程， 狼疮患者的疾病活动性增加。我们的数据表明表观遗传调节因子 EZH 2可能介导这些表观遗传变化。事实上，我们表明，EZH 2增加， 因此，本研究证实了来自狼疮患者的CD 4 + T细胞，并且调节EZH 2的miR-26 a和miR-101两者都是有效的。 下调。这两种microRNA都对葡萄糖浓度敏感， 我们发现，抑制糖酵解可以恢复狼疮中这两种microRNA的表达， CD 4 + T细胞。我们假设狼疮CD 4 + T细胞糖酵解增加，导致 通过下调miR-26 a和miR-101上调EZH 2。此外，我们还提供了证据， 狼疮CD 4 + T细胞中EZH 2过表达上调JAM-A，JAM-A介导增加的免疫应答， T细胞粘附。我们建议确定EZH 2过度表达的机制解释， 狼疮CD 4 + T细胞及其与糖酵解和mTORC 1增加的关系 信号我们还将鉴定出由以下因素引起的失调的基因和通路的完整库： EZH 2在狼疮CD 4 + T细胞中的过表达以鉴定新的治疗靶点此外，本发明还提供了一种方法， 鉴于我们的数据表明狼疮患者中CD 4 + T细胞粘附增加的消除 在体外EZH 2抑制后，并且体内EZH 2抑制显著改善存活 并改善MRL/lpr狼疮易感小鼠的狼疮样疾病，我们建议使用遗传 在小鼠模型中表征靶向CD 4 + T细胞Ezh 2缺失的作用的方法 狼疮EZH 2抑制剂目前正在试验用于许多恶性肿瘤，因此， 我们的结果将为靶向EZH 2或我们将识别的EZH 2调节基因铺平道路 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.