The transcription repressor, ZEB1, cooperates with CtBP2 and HDAC1 to suppress IL-2 gene activation in T cells

• Published in: International immunology 2009-03, Vol.21 (3), p.227-235
• Main Authors: Wang, Jun, Lee, Seungsoo, Teh, Charis En-Yi, Bunting, Karen, Ma, Lina, Shannon, M. Frances
• Format: Article
• Language: English
• Subjects: Animals; Binding Sites - immunology; Cell Line, Tumor; cytokines; DNA-Binding Proteins - immunology; DNA-Binding Proteins - metabolism; Feedback, Physiological - genetics; Feedback, Physiological - immunology; Histone Deacetylase 1; Histone Deacetylases - immunology; Histone Deacetylases - metabolism; Homeodomain Proteins - genetics; Homeodomain Proteins - immunology; Homeodomain Proteins - metabolism; Homeostasis - immunology; Interleukin-2 - genetics; Interleukin-2 - immunology; Interleukin-2 - metabolism; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - immunology; Kruppel-Like Transcription Factors - metabolism; Mice; Mice, Inbred C57BL; Phosphoproteins - immunology; Phosphoproteins - metabolism; Promoter Regions, Genetic - immunology; Protein Binding; Protein Interaction Domains and Motifs - immunology; Repressor Proteins - genetics; Repressor Proteins - immunology; Repressor Proteins - metabolism; T cells; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Transcriptional Activation - genetics; Transcriptional Activation - immunology; transcriptional regulation; Transfection; Transgenes; Zinc Finger E-box-Binding Homeobox 1
• ISSN: 0953-8178; 1460-2377
• DOI: 10.1093/intimm/dxn143

Activation of T cells leads to the induction of many cytokine genes that are required for appropriate immune responses, including IL-2, a key cytokine for T cell proliferation and homeostasis. The activating transcription factors such as nuclear factor of activated T cells, nuclear factor κB/Rel and activated protein-1 family members that regulate inducible IL-2 gene expression have been well documented. However, negative regulation of the IL-2 gene is less studied. Here we examine the role of zinc finger E-box-binding protein (ZEB) 1, a homeodomain/Zn finger transcription factor, as a repressor of IL-2 gene transcription. We show here that ZEB1 is expressed in non-stimulated and stimulated T cells and using chromatin immunoprecipitation assays we show that ZEB1 binds to the IL-2 promoter. Over-expression of ZEB1 can repress IL-2 promoter activity, as well as endogenous IL-2 mRNA production in EL-4 T cells, and this repression is dependent on the ZEB-binding site at −100. ZEB1 cooperates with the co-repressor C-terminal-binding protein (CtBP) 2 and with histone deacetylase 1 to repress the IL-2 promoter and this cooperation depends on the ZEB-binding site in the promoter as well as the Pro-X-Asp-Leu-Ser protein–protein interaction domain in CtBP2. Thus, ZEB1 may function to recruit a repressor complex to the IL-2 promoter.