Genetic variants alter T-bet binding and gene expression in mucosal inflammatory disease.
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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2017-02-01
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| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1006587 |
| _version_ | 1818445818530627584 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Katrina Soderquest |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T19:37:52Z |
| format | Article |
| id | doaj.art-1b047c1f9aaf46738e2b7b4684f706e9 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-14T19:37:52Z |
| publishDate | 2017-02-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-1b047c1f9aaf46738e2b7b4684f706e92022-12-21T22:49:50ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042017-02-01132e100658710.1371/journal.pgen.1006587Genetic variants alter T-bet binding and gene expression in mucosal inflammatory disease.Katrina SoderquestArnulf HertweckClaudia GiambartolomeiStephen HendersonRami MohamedRimma GoldbergEsperanza PeruchaLude FrankeJavier HerreroVincent PlagnolRichard G JennerGraham M LordThe 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.https://doi.org/10.1371/journal.pgen.1006587 |
| spellingShingle | 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 Genetic variants alter T-bet binding and gene expression in mucosal inflammatory disease. PLoS Genetics |
| title | Genetic variants alter T-bet binding and gene expression in mucosal inflammatory disease. |
| title_full | Genetic variants alter T-bet binding and gene expression in mucosal inflammatory disease. |
| title_fullStr | Genetic variants alter T-bet binding and gene expression in mucosal inflammatory disease. |
| title_full_unstemmed | Genetic variants alter T-bet binding and gene expression in mucosal inflammatory disease. |
| title_short | Genetic variants alter T-bet binding and gene expression in mucosal inflammatory disease. |
| title_sort | genetic variants alter t bet binding and gene expression in mucosal inflammatory disease |
| url | https://doi.org/10.1371/journal.pgen.1006587 |
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