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Series GSE81881 Query DataSets for GSE81881
Status Public on Jan 24, 2017
Title Genetic variants alter T-bet binding and gene expression in mucosal inflammatory disease
Organism Homo sapiens
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Summary 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.
Overall design Correlation of T-bet binding sites and autoimmune disease associate SNPs
Contributor(s) Soderquest K, Hertweck A, Giambartolomei C, Henderson S, Mohamed R, Goldberg R, Perucha E, Franke L, Herrero J, Plagnol V, Jenner RG, Lord GM
Citation(s) 28187197
Submission date May 25, 2016
Last update date May 15, 2019
Contact name Richard Jenner
Organization name UCL Cancer Institute
Department Cancer Biology
Lab Regulatory Genomics
Street address 72 Huntley Street
City London
ZIP/Postal code WC1E 6BT
Country United Kingdom
Platforms (1)
GPL18573 Illumina NextSeq 500 (Homo sapiens)
Samples (4)
GSM2176974 Homo sapiens Donor 1 Th1 T-bet
GSM2176975 Homo sapiens Donor 1 Th1 Input
GSM2176976 Homo sapiens Donor 2 Th1 T-bet
BioProject PRJNA322847
SRA SRP075698

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Supplementary file Size Download File type/resource
GSE81881_RAW.tar 440.0 Kb (http)(custom) TAR (of BED)
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Raw data are available in SRA
Processed data provided as supplementary file

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