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The role of upstream stimulatory factor 1 in the transcriptional regulation of the human TBX21 promoter mediated by the T-1514C polymorphism associated with systemic lupus erythematosus

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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. Previously, two single nucleotide polymorphisms (SNPs) in the TBX21 promoter, T-1993C and T-1514C, have been shown by statistic studies to associate with systemic lupus erythematosus (SLE). The effect of −1993 SNP on the Yin Yang 1 transcription factor-mediated promoter activity has been already indicated. This study aimed to investigate roles of the T-1514C SNP on TBX21 transcription and its functional effect by luciferase reporter, electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP) assay, and flow cytometric analysis of intracellular T-bet, IFN-γ, and IL-4 expression in activated CD4+ T cells. The TBX21 promoter carrying −1514C possessed significantly lower transcriptional activity than that of −1514T and was markedly downregulated by the overexpression of upstream stimulatory factor 1 (USF-1) when compared with the promoter carrying −1514T. EMSA indicated that the transcription factor USF-1 was bound to the −1514C allele probe with the affinity higher than that to the −1514T allele probe. ChIP assay suggested that USF-1 bound around −1514 of TBX21 genomic DNA in vivo in the human T cell line Jurkat with −1514C/T. The individuals carrying −1514C allele were determined to have significantly diminished expression of T-bet and IFN-γ and increased IL-4 production in CD4+ T cells compared with those of −1514T allele. The findings demonstrate that the T-1514C polymorphism affects TBX21 gene expression and Th1 cytokine production by binding USF-1 to the SNP site.

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Abbreviations

bp:

Base pair

EMSA:

Electrophoretic mobility shift assay

IFN-γ:

Interferon-γ

IL-4:

Interleukin-4

PCR-RFLP:

Polymerase chain reaction–restriction fragment length polymorphism

SNP:

Single nucleotide polymorphism

SD:

Standard deviation

Th cells:

T helper cells

T-bet:

T-box expressed in T cells

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Acknowledgments

This study is supported by the Chinese National Natural Science Foundation grants (no. 30972595).

Conflicts of interest

We declare that we have no conflict of interest to disclose.

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Authors and Affiliations

  1. Institute of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China

    Junggang Li & Song Chen

  2. Medical Team, Force 75135 of Chinese People’s Liberation Army, Guigang Municipality, Guangxi, 537103, China

    Jirong Li

  3. Department of Dermatology, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China

    Yi You

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  1. Junggang Li
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  2. Jirong Li
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  3. Yi You
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  4. Song Chen
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Corresponding author

Correspondence to Song Chen.

Additional information

Junggang Li and Jirong Li contributed equally to this work.

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Li, J., Li, J., You, Y. et al. The role of upstream stimulatory factor 1 in the transcriptional regulation of the human TBX21 promoter mediated by the T-1514C polymorphism associated with systemic lupus erythematosus. Immunogenetics 64, 361–370 (2012). https://doi.org/10.1007/s00251-011-0597-6

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  • DOI: https://doi.org/10.1007/s00251-011-0597-6

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