Role of DNA methylation in lupus

描述(申请人提供)：系统性红斑狼疮是一种累及多个器官系统的慢性复发性自身免疫性疾病。狼疮的病因和发病机制尚不完全清楚。有强有力的证据表明，遗传因素与狼疮发病有关，然而，尽管在定位狼疮易感基因方面取得了巨大的进展，但发现的遗传关联只解释了一小部分狼疮的遗传性。大量文献支持表观遗传失调，尤其是T细胞DNA甲基化缺陷在狼疮发病机制中的作用。事实上，去甲基化的T细胞足以在动物模型中引起狼疮。我们认为，狼疮患者和对照组之间的表观遗传学差异导致了这种疾病的“缺失”遗传性。我们建议使用全基因组方法来确定狼疮患者特定T细胞亚群中与正常对照相比的差异甲基化遗传位点，并对其进行功能表征，该方法的可行性已经在我们自己的初步实验中得到了证实。我们将进一步确定和验证随着时间的推移，DNA甲基化变化与狼疮患者疾病活动的关系。我们假设与狼疮相关的遗传变异将以一种等位基因特异性的方式改变已知的狼疮易感基因座上的DNA甲基化。因此，我们将确定狼疮有效遗传易感基因座的等位基因特异性DNA甲基化变化。我们以前曾报道过MECP2中的SNPs与狼疮的遗传关联。MeCP2(甲基CpG结合蛋白2)是甲基化敏感基因的关键转录调节因子，也被认为在DNA合成过程中招募DNA甲基化酶DNMT1。我们将使用下一代测序对MECP2/IRAK1 LD区块进行重新测序，以确定该基因座的因果变异。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus is a chronic relapsing autoimmune disease that involves multiple organ systems. The etiology and pathogenesis of lupus are incompletely understood. There is a strong evidence for genetic contribution to the pathogenesis of lupus, however, despite the enormous progress in mapping lupus susceptibility genes, only a small fraction of lupus heritability is accounted for by the genetic associations discovered. A large body of literature supports the contention that epigenetic dysregulation, particularly T cell DNA methylation defect, contributes to the pathogenesis of lupus. Indeed, demethylated T cells are sufficient to cause lupus in animal models. We believe that epigenetic differences between lupus patients and controls contribute towards the "missing" heritability of the disease. We propose to determine and functionally characterize differentially methylated genetic loci in specific T cell subsets in lupus patients compared to normal controls, using a genome-wide approach, the feasibility of which has been confirmed in our own preliminary experiments. We will further Identify and validate DNA methylation changes over time in relation to disease activity in lupus patients. We hypothesize that genetic variants associated with lupus will alter DNA methylation in known lupus susceptibility loci in an allele-specific manner. Therefore, we will determine allele specific DNA methylation changes in validated genetic susceptibility loci for lupus. We previously reported the genetic association between SNPs within MECP2 and lupus. MECP2 (methyl-CpG-binding protein 2) is a key transcriptional regulator for methylation sensitive genes, and is also known to recruit the DNA methylation enzyme DNMT1 during DNA synthesis. We will resequence the MECP2/IRAK1 LD block using next generation sequencing to identify the causal variants in this locus.