Genetic variants alter T-bet binding and gene expression in mucosal inflammatory disease
نویسندگان
چکیده
The polarization of CD4+ T cells into distinct T helper cell lineages is essential for protective immunity against infection, but aberrant T cell polarization can cause autoimmunity. The transcription factor T-bet (TBX21) specifies the Th1 lineage and represses alternative T cell fates. Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) that may be causative for autoimmune diseases. The majority of these polymorphisms are located within non-coding distal regulatory elements. It is considered that these genetic variants contribute to disease by altering the binding of regulatory proteins and thus gene expression, but whether these variants alter the binding of lineage-specifying transcription factors has not been determined. Here, we show that SNPs associated with the mucosal inflammatory diseases Crohn's disease, ulcerative colitis (UC) and celiac disease, but not rheumatoid arthritis or psoriasis, are enriched at T-bet binding sites. Furthermore, we identify disease-associated variants that alter T-bet binding in vitro and in vivo. ChIP-seq for T-bet in individuals heterozygous for the celiac disease-associated SNPs rs1465321 and rs2058622 and the IBD-associated SNPs rs1551398 and rs1551399, reveals decreased binding to the minor disease-associated alleles. Furthermore, we show that rs1465321 is an expression quantitative trait locus (eQTL) for the neighboring gene IL18RAP, with decreased T-bet binding associated with decreased expression of this gene. These results suggest that genetic polymorphisms may predispose individuals to mucosal autoimmune disease through alterations in T-bet binding. Other disease-associated variants may similarly act by modulating the binding of lineage-specifying transcription factors in a tissue-selective and disease-specific manner.
منابع مشابه
Genetic polymorphisms in the promoter region of catalase gene, creates new potential PAX-6 and STAT4 response elements
Catalase (CAT, OMIM: 115500) is an endogenous antioxidant enzyme and genetic variations in the regulatory regions of the CAT gene may alter the CAT enzyme activity and subsequently may alter the risk of oxidative stress related disease. In this study, potential influence(s) of the A-21T (rs7943316) and C-262T (rs1001179) genetic polymorphisms in the CAT promoter region, using the ALGGEN-PROMO.v...
متن کاملExpression of an epitope-based recombinant vaccine against Foot and Mouth Disease (FMDV) in tobacco plant (Nicotiana tabacum)
Regarding high potential of green plants for development of recombinant vaccines, this research was conducted to evaluate expression of a novel recombinant vaccines against Foot and Mouth Disease (FMDV) in tobacco plant. For this purpose, a synthetic gene encoding 129-169 amino acids of foot and mouth disease virus capsid protein VP1 was transferred to tobacco plant via Agrobacterium-mediated g...
متن کاملFusion of Cholera toxin B subunit (ctxB) with Shigella dysenteriae type I toxin B subunit (stxB), Cloning and Expression that in E. coli
Background and Objective: Shiga toxin (STx) is the main virulence factor in Shigella Dysenteriae type I and is composed of an enzymatic subunit STxA monomer and a receptor-binding STxB homopentamer. Shigella toxin B subunit (STxB) is a non-toxic homopentameric protein responsible for toxin binding and internalization into target cells by interacting with glycolipid (Gb3). Cholera toxi...
متن کاملIncreased Expression of Two Alternative Spliced Variants of CD1d Molecule in Human Gastric Cancer
Background: CD1d presents glycolipid antigens to invariant natural killer T (iNKT) cells. The role of CD1d in the development of peptic ulcer and gastric cancer has not been revealed, yet. Objective: To clarify the expression of alternatively spliced variants of CD1d in peptic ulcer and gastric cancer. Methods: Patients with dyspepsia were selected and divided into three groups of non-ulcer dys...
متن کاملReview on the role of host genetic factors in the susceptibility to SARS-CoV-2
Background: Severe acute respiratory system Cov-2 pandemic has affected the world populations for more than one year. Different incidence and severity of this viral disease among various age range and individuals with different background disease may indicate the pivotal role of host genetic factors in their prevalence and mortality rate. In this regards, present study was performed to review t...
متن کامل