AHR promoter variant modulates its transcription and downstream effectors by allele-specific AHR-SP1 interaction functioning as a genetic marker for vitiligo.
AHR promoter variant modulates its transcription and downstream effectors by allele-specific AHR-SP1 interaction functioning as a genetic marker for vitiligo.
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AHR 启动子变体通过等位基因特异性 AHR-SP1 相互作用调节其转录和下游效应子，充当白癜风的遗传标记
DOI：
10.1038/srep13542
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发表时间：
2015-09-15
影响因子：
4.6
通讯作者：
Gao T
中科院分区：
文献类型：
--
作者：
Wang X;Li K;Liu L;Shi Q;Song P;Jian Z;Guo S;Wang G;Li C;Gao T
白癜风是一种获得性色素脱失障碍，主要由黑素细胞缺陷或自身免疫诱导的黑素细胞破坏引起。芳香烃受体(AHR)是维持黑素细胞动态平衡和免疫过程所必需的，白癜风患者存在AHR异常。我们先前发现AHR−129c T变异的T等位基因是白癜风的保护因子。然而，这种效应背后的生物学特征并不是完全确定的，有必要通过机制研究进一步验证，并在本研究中进行。我们发现，与−129C等位基因相比，−129T等位基因通过促进其与Sp1转录因子(Sp1)的相互作用而促进其转录活性。随后，我们发现白癜风患者外周血中AHR和SP1的转录表达降低，并且AHR水平与病程呈负相关。我们还观察了白癜风患者血清肿瘤坏死因子-α水平升高，血清IL-10和转化生长因子-β1水平下降。进一步的遗传分析表明，-129T携带者的AHR和IL-10水平高于−129C携带者。因此，我们的研究表明，启动子变异体对AHR转录的调控对白癜风有着深远的影响，这不仅加深了我们对AHR功能的理解，也为包括白癜风在内的退行性或自身免疫性疾病的发病机制提供了新的视角。
Vitiligo is an acquired depigmentation disorder largely caused by defective melanocyte- or autoimmunity-induced melanocyte destruction. The aryl hydrocarbon receptor (AHR) is essential for melanocyte homeostasis and immune process and abnormal AHR was observed in vitiligo. We previously identified the T allele of AHR −129C T variant as a protective factor against vitiligo. However, biological characterization underlying such effects is not fully certain, further validation by mechanistic research is warranted and was conducted in the present study. We showed that −129T allele promoted AHR transcriptional activity through facilitating its interaction with SP1 transcription factor (SP1) compared with −129C allele. We subsequently found reduced peripheral AHR and SP1 transcript expressions in vitiligo and a negative correlation of AHR level with disease duration. We also investigated AHR-related cytokines and observed increased serum TNF-α concentration and diminished serum levels of IL-10 and TGF-β1 in vitiligo. Further genetic analysis showed that -129T carriers possessed higher levels of AHR and IL-10 than −129C carriers. Therefore, our study indicates that the modulation of AHR transcription by a promoter variant has a profound influence on vitiligo, not only advancing our understanding on AHR function but also providing novel insight into the pathogenesis of degenerative or autoimmune diseases including vitiligo.