TNFAIP3 (A20) and Susceptibility to Systemic Lupus Erythematosus

TNFAIP3 (A20) 与系统性红斑狼疮的易感性

• 批准号: 8761462
• 负责人: Patrick M Gaffney
• 金额: $ 65.2万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-07 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8761462
• 关键词: Alleles; Antigen-Antibody Complex; Attenuated; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Binding; Bioinformatics; Celiac Disease; Cells; ChIP-seq; Chromatin; Chromatin Loop; Chronic Childhood Arthritis; Collection; Complement; Complex; Control Groups; Crohn' s disease; Data; Development; Enhancers; Ensure; Enzymes; Ethnic Origin; European; Funding; Gene Expression; Generations; Genes; Genetic; Genetic Enhancer Element; Genetic Materials; Genetic Transcription; Genomics; Genotype; Haplotypes; Health; Human; Human Genome; Immune System Diseases; Immune Tolerance; Inflammatory; Insulin-Dependent Diabetes Mellitus; Interferons; Laboratories; Lead; Lupus; Maps; Methods; NF-kappa B; Nature; Nuclear Protein; Organ; Pathway interactions; Positron-Emission Tomography; Predisposition; Process; Production; Proteins; Psoriasis; Regulatory Element; Research; Research Infrastructure; Rheumatoid Arthritis; Risk; Role; Signal Pathway; Signal Transduction; Site; Sjogren' s Syndrome; Systemic Lupus Erythematosus; Systemic Scleroderma; Therapeutic; Transcriptional Regulation; Ubiquitin; Upstream Enhancer; Variant; Work; base; case control; clinically relevant; cohort; deep sequencing; disorder risk; genetic variant; genome wide association study; genome-wide; insight; novel; promoter; public health relevance; research study; risk variant; success; transcription factor

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is characterized by a loss of immunologic tolerance to a multitude of self-antigens. Widespread innate and adaptive immune dysfunction includes interferon pathway dysregulation, high titer autoantibody production, and deficiencies in complement function and immune complex clearance. Inflammatory processes result in systemic end-organ damage. Despite decades of research, the underlying genetic basis of lupus is clearly complex and incompletely understood. Our laboratory identified TNFAIP3, a potent negative regulator of NF-¿B signaling, as an SLE risk gene. In addition to SLE, genetic variants in the region of TNFAIP3 are associated rheumatoid arthritis, psoriasis, Crohn's disease, celiac disease, type 1 diabetes, Sjogren's syndrome, systemic sclerosis and juvenile rheumatoid arthritis suggesting that TNFAIP3 is a master regulator of autoimmunity. Therefore, clarifying the mechanisms that regulate TNFAIP3 expression and function are likely to have broad impact on human health. By fine mapping in SLE cohorts of multiple ethnicities and deep sequencing of TNFAIP3 risk haplotypes, we isolated two functional variants (rs148314165, rs200820567) responsible for association with SLE in the region of TNFAIP3. We showed that rs148314165 and rs200820567 (referred to as the TT>A variants) reside in an enhancer element that binds NF-¿B and SATB1 enabling the interaction of the enhancer with the TNFAIP3 promoter through long-range DNA looping. Impaired binding of NF-¿B to the enhancer harboring the TT>A risk allele, inhibits interaction of the enhancer with the TNFAIP3 promoter resulting in reduced A20 expression. These results reveal a novel functional mechanism by which rs148314165 and rs200820567 attenuate A20 expression and support a causal role for these variants in the predisposition to autoimmune disease. The primary scientific objective of this proposal will be to build upon these discoveries by elucidating mechanisms of TNFAIP3 transcriptional control that influence autoimmune disease risk. In the next funding period we will define the dynamic chromatin state for the TT>A enhancer and other SLE enhancers in primary B cells following stimulation using ChIP-sequencing (Aim 1), characterize the transcription factors and chromatin modifiers that assemble on the TT>A enhancer (Aim 2) and explore the functional effect of a putative novel enhancer 55 kb upstream of the TNFAIP3 promoter (Aim 3). All of these studies will be performed in the context of the SLE risk and nonrisk haplotypes to maximize the clinical relevance of our findings. These studies will serve to clarify new functional mechanisms that regulate TNFAIP3 expression and lay the groundwork for developing of rational therapeutics to restore homeostatic potency of TNFAIP3 in autoimmune disease.

描述（由申请人提供）：系统性红斑狼疮（SLE）的特征是对多种自身抗原的免疫耐受性丧失。广泛的先天性和适应性免疫功能障碍包括干扰素途径失调、高滴度自身抗体产生以及补体功能和免疫复合物清除的缺陷。炎症过程导致全身性终末器官损伤。尽管经过了数十年的研究，狼疮的潜在遗传基础显然是复杂的，而且尚未完全了解。 我们的实验室鉴定了TNFAIP 3，一种NF-B信号的有效负调节因子，作为SLE风险基因。除了SLE之外，TNFAIP 3区域中的遗传变体与类风湿性关节炎、银肩病、克罗恩病、乳糜泻、1型糖尿病、舍格伦综合征、系统性硬化症和幼年类风湿性关节炎相关，表明TNFAIP 3是自身免疫的主要调节剂。因此，阐明调节TNFAIP 3表达和功能的机制可能对人类健康产生广泛影响。通过在多种族SLE队列中的精细定位和TNFAIP 3风险单倍型的深度测序，我们分离出了两个负责TNFAIP 3区域中与SLE相关的功能变体（rs 148314165，rs 200820567）。我们发现rs 148314165和rs 200820567（称为TT>A变体）存在于结合NF-B和SATB 1的增强子元件中，使得增强子与TNFAIP 3启动子能够通过长距离DNA成环相互作用。NF-κ B结合受损B与携带TT>A危险等位基因的增强子的结合，抑制增强子与TNFAIP 3启动子的相互作用，导致A20表达降低。这些结果揭示了rs 148314165和rs 200820567减弱A20表达的新功能机制，并支持这些变体在自身免疫性疾病易感性中的因果作用。 这项提议的主要科学目标将是在这些发现的基础上再接再厉 通过阐明影响自身免疫性疾病风险的TNFAIP 3转录控制机制。在下一个资助期内，我们将使用ChIP测序确定原代B细胞中TT>A增强子和其他SLE增强子在刺激后的动态染色质状态（Aim 1），表征在TT>A增强子上组装的转录因子和染色质修饰剂（Aim 2），并探索TNFAIP 3启动子上游55 kb处推定的新型增强子的功能效应（Aim 3）。所有这些研究将在SLE风险和非风险单倍型的背景下进行，以最大限度地提高我们发现的临床相关性。这些研究将有助于阐明调节TNFAIP 3表达的新功能机制，并为开发合理的治疗方法以恢复TNFAIP 3在自身免疫性疾病中的稳态效力奠定基础。