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还不完全清楚。有一个强有力的证据表明遗传因素对狼疮的发病机制有贡献，然而，尽管在狼疮易感基因定位方面取得了巨大进展，但发现的遗传关联仅占狼疮遗传性的一小部分。大量的文献支持这样的论点，即表观遗传失调，特别是T细胞DNA甲基化缺陷，有助于狼疮的发病机制。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差异有助于疾病的遗传性“缺失”。我们建议使用全基因组方法确定和功能表征狼疮患者与正常对照组相比特定T细胞亚群中差异甲基化的遗传位点，其可行性已在我们自己的初步实验中得到证实。我们将进一步确定和验证DNA甲基化随时间的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等位基因特异性方式改变已知狼疮易感基因座的DNA甲基化。因此，我们将确定等位基因特异性DNA甲基化的变化，在验证遗传易感性位点的狼疮。我们先前报道了MECP 2内SNP与狼疮之间的遗传关联。MECP 2（methyl-CpG-binding protein 2）是甲基化敏感基因的关键转录调节因子，并且已知在DNA合成期间募集DNA甲基化酶DNMT 1。我们将使用下一代测序对MECP 2/IRAK 1 LD块进行重新测序，以鉴定该基因座中的致病变体。

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.