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.
TNFAIP3 functions as a key negative regulator of the inflammatory signaling pathways governed by NF-kB. Genetic variants in TNFAIP3 are associated with SLE and many other autoimmune diseases and influence TNFAIP3 expression. The experiments proposed in this project will characterize the functional mechanisms that regulate TNFAIP3 expression in the context of SLE risk variants providing key insights that may lead to novel therapies for autoimmune diseases.
|Pelikan, Richard C; Kelly, Jennifer A; Fu, Yao et al. (2018) Enhancer histone-QTLs are enriched on autoimmune risk haplotypes and influence gene expression within chromatin networks. Nat Commun 9:2905|
|Patel, Zubin; Lu, Xiaoming; Miller, Daniel et al. (2018) A plausibly causal functional lupus-associated risk variant in the STAT1-STAT4 locus. Hum Mol Genet :|
|Fu, Yao; Tessneer, Kandice L; Li, Chuang et al. (2018) From association to mechanism in complex disease genetics: the role of the 3D genome. Arthritis Res Ther 20:216|
|Wang, Chih-Chuan; Ortiz-González, Xilma R; Yum, Sabrina W et al. (2018) ?IV Spectrinopathies Cause Profound Intellectual Disability, Congenital Hypotonia, and Motor Axonal Neuropathy. Am J Hum Genet 102:1158-1168|
|Zhao, Jian; Ma, Jianyang; Deng, Yun et al. (2017) A missense variant in NCF1 is associated with susceptibility to multiple autoimmune diseases. Nat Genet 49:433-437|
|Demirci, F Yesim; Wang, Xingbin; Kelly, Jennifer A et al. (2016) Identification of a New Susceptibility Locus for Systemic Lupus Erythematosus on Chromosome 12 in Individuals of European Ancestry. Arthritis Rheumatol 68:174-83|
|Wang, S; Wen, F; Tessneer, K L et al. (2016) TALEN-mediated enhancer knockout influences TNFAIP3 gene expression and mimics a molecular phenotype associated with systemic lupus erythematosus. Genes Immun 17:165-70|
|Ward, Julie M; Ratliff, Michelle L; Dozmorov, Mikhail G et al. (2016) Human effector B lymphocytes express ARID3a and secrete interferon alpha. J Autoimmun 75:130-140|
|Liu, Ke; Kurien, Biji T; Zimmerman, Sarah L et al. (2016) X Chromosome Dose and Sex Bias in Autoimmune Diseases: Increased Prevalence of 47,XXX in Systemic Lupus Erythematosus and Sjögren's Syndrome. Arthritis Rheumatol 68:1290-1300|
|Lu, Xiaoming; Zoller, Erin E; Weirauch, Matthew T et al. (2015) Lupus Risk Variant Increases pSTAT1 Binding and Decreases ETS1 Expression. Am J Hum Genet 96:731-9|
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