Genetic variants alter T-bet binding and gene expression in mucosal inflammatory disease.
Genetic variants alter T-bet binding and gene expression in mucosal inflammatory disease.
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DOI：
10.1371/journal.pgen.1006587
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发表时间：
2017-02
期刊：
影响因子：
4.5
通讯作者：
Lord GM
中科院分区：
文献类型：
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作者：
Soderquest K;Hertweck A;Giambartolomei C;Henderson S;Mohamed R;Goldberg R;Perucha E;Franke L;Herrero J;Plagnol V;Jenner RG;Lord GM
CD4 + T细胞极化成不同的T辅助细胞谱系对于针对感染的保护性免疫是必不可少的，但异常的T细胞极化可引起自身免疫。转录因子T-bet（TBX21）指定Th1谱系并抑制备选T细胞命运。全基因组关联研究已经确定了可能导致自身免疫性疾病的单核苷酸多态性（SNP）。这些多态性大多位于非编码远端调控元件内。人们认为这些遗传变异通过改变调节蛋白的结合从而改变基因表达而导致疾病，但这些变异是否改变谱系特异性转录因子的结合尚未确定。在这里，我们表明，与粘膜炎性疾病克罗恩病，溃疡性结肠炎（UC）和乳糜泻，但不是类风湿性关节炎或牛皮癣，SNPs富集在T-bet结合位点。此外，我们确定了疾病相关的变体，改变T-bet结合在体外和体内。在乳糜泻相关SNPs rs1465321和rs2058622以及IBD相关SNPs rs1551398和rs1551399杂合的个体中，T-bet的ChIP-seq显示与次要疾病相关等位基因的结合减少。此外，我们发现，rs1465321是一个表达数量性状位点（eQTL）的相邻基因IL 18 RAP，减少T-bet结合与该基因的表达减少。这些结果表明，遗传多态性可能通过改变T-bet结合使个体易患粘膜自身免疫性疾病。其他疾病相关的变异体可以类似地通过以组织选择性和疾病特异性方式调节谱系特异性转录因子的结合来起作用。迄今为止的研究已经确定了许多在患有特定疾病的人中更常见的遗传变异。然而，在反映多种遗传和环境因素的情况下，很难确切地知道任何特定的遗传变异是否和为什么是致病性的，以及可能导致这种情况的机制。这些变体通常在蛋白质编码外显子之外，而不是落在调节基因表达的区域。在这些情况下，遗传变异可能会改变转录因子结合和随后的基因表达。在这项研究中，我们研究了遗传变异如何影响T-bet与DNA的结合，作为免疫反应中的关键转录调节机制。不能有效地建立这种反应可能导致对感染或癌症的易感性增加，而太强或错误靶向的反应可能导致不受控制的/慢性炎症和自身免疫性疾病。我们已经发现，T-bet结合位点特异性地富集在与粘膜自身炎性疾病UC、克罗恩病和乳糜泻相关的遗传变体中。我们还确定了改变T-bet结合和基因表达的遗传变异。因此，这一发现确定了一种分子机制，通过这种机制，遗传变异可能与粘膜自身免疫性疾病风险增加有关。
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. Research to date has identified many genetic variants that are more common in people with a particular disease. However, in conditions that reflect multiple genetic and environmental factors, it is difficult to know with certainty if and why any particular genetic variant is causative and the mechanism that may underlie this. Such variants are often outside of protein-coding exons, instead falling in regions that regulate gene expression. In these cases, the genetic variation may alter transcription factor binding and subsequent gene expression. In this study, we have examined how genetic variation affects T-bet binding to DNA, as a key transcriptional regulatory mechanism in the immune response. An inability to mount this response effectively can result in increased susceptibility to infections or cancer, while a response that is too strong, or wrongly targeted, can result in uncontrolled/chronic inflammatory and autoimmune conditions. We have found that T-bet binding sites are specifically enriched in genetic variants associated with the mucosal autoinflammatory diseases UC, Crohn’s disease and celiac disease. We also identify genetic variants that alter T-bet binding and gene expression. This discovery thus identifies a molecular mechanism through which genetic variants can be associated with increased risk of mucosal autoimmune disease.