Genetic variants alter T-bet binding and gene expression in mucosal inflammatory disease

• Published in: PLoS genetics Vol. 13; no. 2; p. e1006587
• Main Authors: Soderquest, Katrina, Hertweck, Arnulf, Giambartolomei, Claudia, Henderson, Stephen, Mohamed, Rami, Goldberg, Rimma, Perucha, Esperanza, Franke, Lude, Herrero, Javier, Plagnol, Vincent, Jenner, Richard G, Lord, Graham M
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 10.02.2017; Public Library of Science (PLoS)
• Subjects: Analysis; Animals; Autoimmune diseases; Binding Sites - genetics; Biology and life sciences; Biomedical research; Blotting, Western; Cancer; CD4-Positive T-Lymphocytes - metabolism; Celiac disease; Celiac Disease - genetics; Celiac Disease - metabolism; Cells, Cultured; Colitis, Ulcerative - genetics; Colitis, Ulcerative - metabolism; Crohn Disease - genetics; Crohn Disease - metabolism; Crohns disease; Deoxyribonucleic acid; DNA; Funding; Gene Expression; Genetic aspects; Genetic Predisposition to Disease - genetics; Genetics; Genome-Wide Association Study - methods; Genomes; Genomics; Grants; Health aspects; Hospitals; Humans; Inflammation; Inflammatory diseases; Interleukin-18 Receptor beta Subunit - genetics; Interleukin-18 Receptor beta Subunit - metabolism; Medical research; Medicine and Health Sciences; Mice, Knockout; Polymorphism, Single Nucleotide; Protein Binding - genetics; Regulatory Sequences, Nucleic Acid - genetics; Research and Analysis Methods; Risk factors; Single nucleotide polymorphisms; T-Box Domain Proteins - genetics; T-Box Domain Proteins - metabolism; Th1 Cells - metabolism; Transcription (Genetics); Transcription factors; University colleges; United States
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1006587

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.