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TNFAIP3 (A20) and Susceptibility to Systemic Lupus Erythematosus

TNFAIP3 (A20) 与系统性红斑狼疮的易感性

基本信息

批准号：
9548564
负责人：
Patrick M Gaffney
金额：
$ 65.36万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9548564
关键词：
Alleles Antigen-Antibody Complex Attenuated Autoantibodies Autoantigens Autoimmune Diseases Autoimmunity B-Lymphocytes Binding Bioinformatics Celiac Disease Cells ChIP-seq Chromatin Chromatin Interaction Analysis by Paired-End Tag Sequencing Chromatin Loop Chromatin Remodeling Factor Chronic Childhood Arthritis Collection Complement Complex Control Groups Crohn&apos s disease Data Development Enhancers Ensure Enzymes Ethnic Origin European Funding Gene Expression Generations Genes Genetic Genetic Enhancer Element Genetic Materials Genetic Transcription Genomic Segment Genomics Genotype Haplotypes Health Human Human Genome Immune System Diseases Immune Tolerance Impairment Inflammatory Insulin-Dependent Diabetes Mellitus Interferons Laboratories Lead Lupus Methods NF-kappa B Nature Nuclear Protein Organ Pathway interactions Predisposition Process Production Proteins Psoriasis Regulatory Element Research Research Infrastructure Rheumatoid Arthritis Risk Role Signal Pathway Signal Transduction Site Sjogren&apos s Syndrome Systemic Lupus Erythematosus Systemic Scleroderma Therapeutic Transcriptional Regulation Ubiquitin Upstream Enhancer Variant Work case control clinically relevant cohort deep sequencing disorder risk experimental study genetic variant genome wide association study genome-wide insight novel novel therapeutics promoter protein complex public health relevance risk variant success transcription factor

项目摘要

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-κB 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-κB and SATB1 enabling the interaction of the enhancer with the TNFAIP3 promoter through long-range DNA looping. Impaired binding of NF-κB 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）的特征是丧失对多种自身抗原的免疫耐受性。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、高滴度自身抗体的产生以及补体功能和免疫复合物清除的缺陷。 Inflammatory processes result in systemic end-organ damage.尽管经过数十年的研究，狼疮的潜在遗传基础显然很复杂且尚未完全了解。我们的实验室将 TNFAIP3（NF-κB 信号传导的有效负调节因子）确定为 SLE 风险基因。除了 SLE 之外，TNFAIP3 区域的遗传变异还与类风湿性关节炎、牛皮癣、克罗恩病、乳糜泻、1 型糖尿病、干燥综合征、系统性硬化症和幼年类风湿性关节炎相关，表明 TNFAIP3 是自身免疫的主要调节因子。因此，阐明调节 TNFAIP3 表达和功能的机制可能会对人类健康产生广泛的影响。通过对多个种族的 SLE 队列进行精细定位和对 TNFAIP3 风险单倍型进行深度测序，我们分离出了两个与 TNFAIP3 区域中的 SLE 相关的功能变异（rs148314165、rs200820567）。我们发现 rs148314165 和 rs200820567（称为 TT>A 变体）驻留在结合 NF-κB 和 SATB1 的增强子元件中，使增强子能够通过长距离 DNA 环与 TNFAIP3 启动子相互作用。 NF-κB 与含有 TT>A 风险等位基因的增强子的结合受损，会抑制增强子与 TNFAIP3 启动子的相互作用，从而导致 A20 表达减少。这些结果揭示了 rs148314165 和 rs200820567 减弱 A20 表达的新功能机制，并支持这些变异在自身免疫性疾病易感性中的因果作用。该提案的主要科学目标是建立在这些发现的基础上通过阐明影响自身免疫性疾病风险的 TNFAIP3 转录控制机制。在下一个资助期间，我们将定义原代 B 细胞中 TT>A 增强子和其他 SLE 增强子在使用 ChIP 测序刺激后的动态染色质状态（目标 1），表征在 TT>A 增强子上组装的转录因子和染色质修饰剂（目标 2），并探索 TNFAIP3 启动子上游 55 kb 的推定新型增强子的功能效应（目标 3）。所有这些研究都将在 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研究结果的临床相关性。这些研究将有助于阐明调节 TNFAIP3 表达的新功能机制，并为开发合理的治疗方法以恢复 TNFAIP3 在自身免疫性疾病中的稳态效力奠定基础。