Role of DNA methylation in lupus

DNA 甲基化在狼疮中的作用

基本信息

批准号：
8503129
负责人：
Amr H Sawalha
金额：
$ 37.47万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-25 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8503129
关键词：
Accounting Address Adverse effects Affect Alleles Animal Model Autoimmune Diseases Biological Process CD4 Positive T Lymphocytes Chromatin Chronic CpG Islands DNA Methylation DNA Methyltransferase DNA Modification Methylases DNA Resequencing DNA biosynthesis Defect Disease Disease susceptibility Environment Enzymes Epigenetic Process Etiology Flare Frequencies Gene Expression Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Genome Haplotypes Heritability Human Biology Human Genome IRAK1 gene Individual Interferon Type I Knowledge Literature Lupus Maintenance Maps Mediating Methyl-CpG-Binding Protein 2 Methylation Morbidity - disease rate Pathogenesis Patients Predisposition Promoter Regions Recruitment Activity Relapse Reporting Resolution Risk Role Site Specificity Susceptibility Gene Systemic Lupus Erythematosus T-Lymphocyte T-Lymphocyte Subsets Time Transcriptional Regulation Variant Work base body system falls genetic association genetic variant genome wide association study genome-wide insight mortality next generation sequencing novel novel diagnostics promoter public health relevance research study systemic autoimmune disease transcription factor

项目摘要

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.

描述（由申请人提供）：系统性红斑狼疮是一种涉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对狼疮发病机制的贡献，然而，尽管在绘制狼疮易感基因图谱方面取得了巨大进展，但所发现的遗传关联仅解释了狼疮遗传性的一小部分。大量文献支持表观遗传失调，特别是 T 细胞 DNA 甲基化缺陷，导致狼疮发病机制的论点。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，狼疮患者和对照者之间的表观遗传差异导致了该疾病遗传性的“缺失”。我们建议使用全基因组方法来确定和功能性表征狼疮患者特定 T 细胞亚群中与正常对照相比的差异甲基化遗传位点，其可行性已在我们自己的初步实验中得到证实。我们将进一步识别和验证 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位点的 DNA 甲基化。因此，我们将确定经验证的狼疮遗传易感性位点中等位基因特异性 DNA 甲基化变化。我们之前报道了 MECP2 内的 SNP 与狼疮之间的遗传关联。 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，并且还已知在 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 块进行重新测序，以识别该基因座中的因果变异。