title: A common promoter variant of TBX21 is associated with allele specific binding to Yin-Yang 1 and reduced gene expression.
abstract: T-bet is a key regulator for the lineage commitment in CD4 T helper (Th) 1 cells by activating the hallmark production of interferon-γ, and its expression level is linked to autoimmune, infectious, and allergic diseases. A T to C base substitution has been identified at position -1993 in the TBX21 (encoding T-bet) promoter and has been associated with asthma and systemic lupus erythematosus. This study aimed to investigate the molecular mechanisms responsible for the influence of the T-1993C polymorphism on transcription and its functional effect by luciferase reporter, EMSAs, Chromatin immunoprecipitation assay, and flow cytometric analysis of intracellular T-bet, IFN-γ and IL-4 expression in activated CD4(+) T cells. The presence of a -1993T allele obviously increases promoter activity compared with that of a promoter with a -1993C allele. TBX21 promoter carrying -1993C allele possesses significantly stronger binding affinity to the Yin Yang 1 (YY1) transcription factor than that carrying -1993T allele. YY1 overexpression decreased TBX21 promoter function in a T cell line, demonstrating that this element functions as a repressor. The C to T base exchange relieves the repression mediated by YY1. The individuals carrying -1993C allele were determined to have significantly diminished expression of TBX21 and IFN-γ and increased IL-4 production in cells compared with the individuals carrying -1993T allele (P < 0.05). These findings demonstrate that the TBX21 T-1993C polymorphism represses TBX21 expression and Th1 cytokine production through control of YY1, which might result in the imbalance between Th1 and Th2 immune responses in autoimmune or allergic diseases.
authors.affiliation: Institute of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: J-R
authors.initials: JR
authors.lastname: Li
authors.forename: J-G
authors.initials: JG
authors.lastname: Li
authors.forename: G-H
authors.initials: GH
authors.lastname: Deng
authors.forename: W-L
authors.initials: WL
authors.lastname: Zhao
authors.forename: Y-J
authors.initials: YJ
authors.lastname: Dan
authors.forename: Y-M
authors.initials: YM
authors.lastname: Wang
authors.forename: S
authors.initials: S
authors.lastname: Chen
mesh_terms: D000328:Adult; D000483:Alleles; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D047369:Chromatin Immunoprecipitation; D004247:DNA / Q000737:chemistry / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005434:Flow Cytometry; D014644:Genetic Variation; D006801:Humans; D019169:Jurkat Cells; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D020825:T-Box Domain Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D050986:YY1 Transcription Factor / Q000276:immunology*; D055815:Young Adult; D000098815:T-bet Transcription Factor
chemical_list: D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D050986:YY1 Transcription Factor; C494698:YY1 protein, human; D004247:DNA