title: AHR promoter variant modulates its transcription and downstream effectors by allele-specific AHR-SP1 interaction functioning as a genetic marker for vitiligo.
abstract: 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.
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Li
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Pu
authors.initials: P
authors.lastname: Song
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Jian
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Sen
authors.initials: S
authors.lastname: Guo
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Chunying
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
authors.forename: Tianwen
authors.initials: T
authors.lastname: Gao
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D005819:Genetic Markers; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics*; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014820:Vitiligo / Q000235:genetics* / Q000378:metabolism*
chemical_list: D016207:Cytokines; D005819:Genetic Markers; D018336:Receptors, Aryl Hydrocarbon; D016329:Sp1 Transcription Factor