Genetic variants alter T-bet binding and gene expression in mucosal inflammatory disease
| Autor: | Katrina, Soderquest, Arnulf, Hertweck, Claudia, Giambartolomei, Stephen, Henderson, Rami, Mohamed, Rimma, Goldberg, Esperanza, Perucha, Lude, Franke, Javier, Herrero, Vincent, Plagnol, Richard G, Jenner, Graham M, Lord |
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| Přispěvatelé: | Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL) |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
CD4-Positive T-Lymphocytes
Cancer Research Gene Expression Regulatory Sequences Nucleic Acid QH426-470 White Blood Cells Spectrum Analysis Techniques Crohn Disease Animal Cells Medicine and Health Sciences Genetics(clinical) SYSTEMIC-LUPUS-ERYTHEMATOSUS Cells Cultured Mice Knockout T Cells CELIAC-DISEASE Genomics Regulatory T cells Flow Cytometry DISTAL REGULATORY ELEMENTS CROHNS-DISEASE ULCERATIVE-COLITIS Spectrophotometry Perspective Cytophotometry Cellular Types Protein Binding Cell Binding Cell Physiology SUSCEPTIBILITY LOCI Immune Cells Blotting Western Immunology INNATE LYMPHOID-CELLS Gastroenterology and Hepatology Research and Analysis Methods Polymorphism Single Nucleotide Genome-Wide Association Studies Genetics Animals Humans Genetic Predisposition to Disease Gene Regulation T Helper Cells Interleukin-18 Receptor beta Subunit GENOME-WIDE ASSOCIATION Molecular Biology Ecology Evolution Behavior and Systematics Binding Sites Blood Cells Inflammatory Bowel Disease Biology and Life Sciences Computational Biology Human Genetics Cell Biology Th1 Cells Genome Analysis Celiac Disease TRANSCRIPTION FACTOR-BINDING Colitis Ulcerative IMMUNE-SYSTEM T-Box Domain Proteins Genome-Wide Association Study |
| Zdroj: | PLoS Genetics, Vol 13, Iss 2, p e1006587 (2017) Soderquest, K, Hertweck, A, Giambartolomei, C, Henderson, S, Mohamed, R, Goldberg, R, Perucha, E, Franke, L, Herrero, J, Plagnol, V, Jenner, R G & Lord, G M 2017, ' Genetic variants alter T-bet binding and gene expression in mucosal inflammatory disease ', PL o S Genetics, vol. 13, no. 2, e1006587 . https://doi.org/10.1371/journal.pgen.1006587 PLoS genetics, 13(2):e1006587. PUBLIC LIBRARY SCIENCE Soderquest, K, Hertweck, A, Giambartolomei, C, Henderson, S, Mohamed, R, Goldberg, R, Perucha, E, Franke, L, Herrero, J, Plagnol, V, Jenner, R G & Lord, G M 2017, ' Genetic variants alter T-bet binding and gene expression in mucosal inflammatory disease ', PLoS Genetics, vol. 13, no. 2, e1006587 . https://doi.org/10.1371/journal.pgen.1006587 PLoS Genetics |
| ISSN: | 1553-7404 1553-7390 |
| DOI: | 10.1371/journal.pgen.1006587 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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