title: Genetic variants alter T-bet binding and gene expression in mucosal inflammatory disease.
abstract: 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.
authors.affiliation: Department of Experimental Immunobiology, King's College London, London, United Kingdom.|NIHR Biomedical Research Centre at Guy's and St Thomas' Hospital and King's College London, London, United Kingdom.
authors.forename: Katrina
authors.initials: K
authors.lastname: Soderquest
authors.affiliation: UCL Cancer Institute, University College London, London, United Kingdom.
authors.forename: Arnulf
authors.initials: A
authors.lastname: Hertweck
authors.affiliation: UCL Genetics Institute, University College London, London, United Kingdom.
authors.forename: Claudia
authors.identifier: 0000-0002-9982-7280
authors.initials: C
authors.lastname: Giambartolomei
authors.affiliation: UCL Cancer Institute, University College London, London, United Kingdom.
authors.forename: Stephen
authors.identifier: 0000-0002-9032-3828
authors.initials: S
authors.lastname: Henderson
authors.affiliation: Department of Experimental Immunobiology, King's College London, London, United Kingdom.|NIHR Biomedical Research Centre at Guy's and St Thomas' Hospital and King's College London, London, United Kingdom.|The Francis Crick Institute, London, United Kingdom.
authors.forename: Rami
authors.initials: R
authors.lastname: Mohamed
authors.affiliation: Department of Experimental Immunobiology, King's College London, London, United Kingdom.|NIHR Biomedical Research Centre at Guy's and St Thomas' Hospital and King's College London, London, United Kingdom.
authors.forename: Rimma
authors.initials: R
authors.lastname: Goldberg
authors.affiliation: Department of Experimental Immunobiology, King's College London, London, United Kingdom.
authors.forename: Esperanza
authors.initials: E
authors.lastname: Perucha
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
authors.affiliation: UCL Cancer Institute, University College London, London, United Kingdom.
authors.forename: Javier
authors.initials: J
authors.lastname: Herrero
authors.affiliation: UCL Genetics Institute, University College London, London, United Kingdom.
authors.forename: Vincent
authors.identifier: 0000-0002-5597-9215
authors.initials: V
authors.lastname: Plagnol
authors.affiliation: UCL Cancer Institute, University College London, London, United Kingdom.
authors.forename: Richard G
authors.identifier: 0000-0002-2946-6811
authors.initials: RG
authors.lastname: Jenner
authors.affiliation: Department of Experimental Immunobiology, King's College London, London, United Kingdom.|NIHR Biomedical Research Centre at Guy's and St Thomas' Hospital and King's College London, London, United Kingdom.
authors.forename: Graham M
authors.initials: GM
authors.lastname: Lord
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002446:Celiac Disease / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D003093:Colitis, Ulcerative / Q000235:genetics* / Q000378:metabolism; D003424:Crohn Disease / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D053728:Interleukin-18 Receptor beta Subunit / Q000235:genetics / Q000378:metabolism; D018345:Mice, Knockout; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D020825:T-Box Domain Proteins / Q000235:genetics* / Q000378:metabolism; D018417:Th1 Cells / Q000378:metabolism; D000098815:T-bet Transcription Factor
chemical_list: C115629:IL18RAP protein, human; D053728:Interleukin-18 Receptor beta Subunit; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor