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Yin-Yang 1 and Yin-Yang 2 exert opposing effects on the promoter activity of interleukin 4

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Abstract

Interleukin (IL)-4 acts on T cells as a growth and activation factor, and promotes the differentiation of type 2 T helper cells. In T cells, expression of the gene encoding IL-4 is regulated by inducible or constitutive factors. Yin-Yang (YY)-1 is one of constitutive transcription factors binding to the IL-4 promoter. The recently identified YY2 protein is similar to YY1, with both sharing high levels of homology in their zinc finger motifs. However, the role of YY2 in T cells is unclear. YY1 and YY2 were constitutively expressed in EL4 T cells, and their expression was not dependent on stimulation. IL-4 promoter (−741/+56 fragment) activity was enhanced by YY1, but inhibited by YY2. The enhanced IL-4 promoter activity by YY1 was reduced by simultaneous expression of YY2. In addition, the DNA binding affinity of YY1 to the IL-4 promoter was adversely affected by YY2. Our results suggest that YY1 and YY2 exert opposing effects on the IL-4 promoter as they compete for the same DNA binding sites.

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References

  • Atchison, L., A. Ghias, F. Wilkinson, N. Bonini, and M.L. Atchison. 2003. Transcription factor YY1 functions as a PcG protein in vivo. EMBO Journal 22: 1347–1358.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Austen, M., B. Luscher, and J.M. Luscher-Firzlaff. 1997. Characterization of the transcriptional regulator YY1. The bipartite transactivation domain is independent of interaction with the TATA box-binding protein, transcription factor IIB, TAFII55, or cAMP-responsive element-binding protein (CPB)-binding protein. Journal of Biological Chemistry 272: 1709–1717.

    Article  CAS  PubMed  Google Scholar 

  • Barbulescu, K., C. Becker, J.F. Schlaak, E. Schmitt, K.H.M.Z. Buschenfelde, and M.F. Neurath. 1998. IL-12 and IL-18 differentially regulate the transcriptional activity of the human IFN-gamma promoter in primary CD4+T lymphocytes. The Journal of Immunology 160: 3642–3647.

    CAS  PubMed  Google Scholar 

  • Brown, M.A., and J. Hural. 1997. Functions of IL-4 and control of its expression. Critical Reviews in Immunology 17: 1–32.

    Article  CAS  PubMed  Google Scholar 

  • Brown, J.L., D. Mucci, M. Whiteley, M.L. Dirksen, and J.A. Kassis. 1998. The Drosophila Polycomb group gene pleiohomeotic encodes a DNA binding protein with homology to the transcription factor YY1. Molecular Cell 1: 1057–1064.

    Article  CAS  PubMed  Google Scholar 

  • Brusselle, G.G., J.C. Kips, J.H. Tavernier, J.G. Van Der Heyden, C.A. Cuvelier, R.A. Pauwels, and H. Bluethmann. 1994. Attenuation of allergic airway inflammation in IL-4 deficient mice. Clinical and Experimental Allergy 24: 73–80.

    Article  CAS  PubMed  Google Scholar 

  • Chung, S.W., B.Y. Kang, and T.S. Kim. 2003. Inhibition of interleukin-4 production in CD4+T cells by peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands: involvement of physical association between PPAR-gamma and the nuclear factor of activated T cells transcription factor. Molecular Pharmacology 64: 1169–1179.

    Article  CAS  PubMed  Google Scholar 

  • Donohoe, M.E., X. Zhang, L. Mcginnis, J. Biggers, E. Li, and Y. Shi. 1999. Targeted disruption of mouse Yin Yang 1 transcription factor results in peri-implantation lethality. Molecular and Cellular Biology 19: 7237–7244.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Galvin, K.M., and Y. Shi. 1997. Multiple mechanisms of transcriptional repression by YY1. Molecular and Cellular Biology 17: 3723–3732.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gordon, S.J., S. Saleque, and B.K. Birshtein. 2003. Yin Yang 1 is a lipopolysaccharide-inducible activator of the murine 3′ Igh enhancer, hs3. The Journal of Immunology 170: 5549–5557.

    Article  CAS  PubMed  Google Scholar 

  • Gordon, S., G. Akopyan, H. Garban, and B. Bonavida. 2006. Transcription factor YY1: structure, function, and therapeutic implications in cancer biology. Oncogene 25: 1125–1142.

    Article  CAS  PubMed  Google Scholar 

  • Gronroos, E., A.A. Terentiev, T. Punga, and J. Ericsson. 2004. YY1 inhibits the activation of the p53 tumor suppressor in response to genotoxic stress. Proceedings of the National Academy of Sciences USA 101: 12165–12170.

    Article  Google Scholar 

  • Guo, J., V. Casolaro, E. Seto, W.M. Yang, C. Chang, M.C. Seminario, J. Keen, and S.N. Georas. 2001. Yin-Yang 1 activates interleukin-4 gene expression in T cells. Journal of Biological Chemistry 276: 48871–48878.

    Article  CAS  PubMed  Google Scholar 

  • Guo, J., X. Lin, M.A. Williams, Q. Hamid, and S.N. Georas. 2008. Yin-Yang 1 regulates effector cytokine gene expression and T(H)2 immune responses. Journal of Allergy and Clinical Immunology 122: 195–201.

    Article  CAS  PubMed  Google Scholar 

  • He, Y., J. Dupree, J. Wang, J. Sandoval, J. Li, H. Liu, Y. Shi, K.A. Nave, and P. Casaccia-Bonnefil. 2007. The transcription factor Yin Yang 1 is essential for oligodendrocyte progenitor differentiation. Neuron 55: 217–230.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hiromura, M., C.H. Choi, N.A. Sabourin, H. Jones, D. Bachvarov, and A. Usheva. 2003. YY1 is regulated by O-linked N-acetylglucosaminylation (O-glcNAcylation). Journal of Biological Chemistry 278: 14046–14052.

    Article  CAS  PubMed  Google Scholar 

  • Ho, I.C., M.R. Hodge, J.W. Rooney, and L.H. Glimcher. 1996. The proto-oncogene c-maf is responsible for tissue-specific expression of interleukin-4. Cell 85: 973–983.

    Article  CAS  PubMed  Google Scholar 

  • Hwang, S.S., Y.U. Kim, S. Lee, S.W. Jang, M.K. Kim, B.H. Koh, W. Lee, J. Kim, A. Souabni, M. Busslinger, and G.R. Lee. 2013. Transcription factor YY1 is essential for regulation of the Th2 cytokine locus and for Th2 cell differentiation. Proceedings of the National Academy of Sciences USA 110: 276–281.

    Article  CAS  Google Scholar 

  • Kaplan, M.H., U. Schindler, S.T. Smiley, and M.J. Grusby. 1996. Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity 4: 313–319.

    Article  CAS  PubMed  Google Scholar 

  • Kiani, A., F.J. Garcia-Cozar, I. Habermann, S. Laforsch, T. Aebischer, G. Ehninger, and A. Rao. 2001. Regulation of interferon-gamma gene expression by nuclear factor of activated T cells. Blood 98: 1480–1488.

    Article  CAS  PubMed  Google Scholar 

  • Kim, J.D., C. Faulk, and J. Kim. 2007. Retroposition and evolution of the DNA-binding motifs of YY1, YY2 and REX1. Nucleic Acids Research 35: 3442–3452.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mordvinov, V.A., G.T. Schwenger, R. Fournier, M.L. De Boer, S.E. Peroni, A.D. Singh, S. Karlen, J.W. Holland, and C.J. Sanderson. 1999. Binding of YY1 and Oct1 to a novel element that downregulates expression of IL-5 in human T cells. Journal of Allergy and Clinical Immunology 103: 1125–1135.

    Article  CAS  PubMed  Google Scholar 

  • Mosmann, T.R., and R.L. Coffman. 1989. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annual Review of Immunology 7: 145–173.

    Article  CAS  PubMed  Google Scholar 

  • Mosmann, T.R., H. Cherwinski, M.W. Bond, M.A. Giedlin, and R.L. Coffman. 1986. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. The Journal of Immunology 136: 2348–2357.

    CAS  PubMed  Google Scholar 

  • Nguyen, N., X. Zhang, N. Olashaw, and E. Seto. 2004. Molecular cloning and functional characterization of the transcription factor YY2. Journal of Biological Chemistry 279: 25927–25934.

    Article  CAS  PubMed  Google Scholar 

  • Oei, S.L., and Y. Shi. 2001. Poly(ADP-ribosyl)ation of transcription factor Yin Yang 1 under conditions of DNA damage. Biochemical and Biophysical Research Communications 285: 27–31.

    Article  CAS  PubMed  Google Scholar 

  • Parronchi, P., D. Macchia, M.P. Piccinni, P. Biswas, C. Simonelli, E. Maggi, M. Ricci, A.A. Ansari, and S. Romagnani. 1991. Allergen- and bacterial antigen-specific T-cell clones established from atopic donors show a different profile of cytokine production. Proceedings of the National Academy of Sciences USA 88: 4538–4542.

    Article  CAS  Google Scholar 

  • Parronchi, P., M. De Carli, R. Manetti, C. Simonelli, M.P. Piccinni, D. Macchia, E. Maggi, G. Del Prete, M. Ricci, and S. Romagnani. 1992. Aberrant interleukin (IL)-4 and IL-5 production in vitro by CD4+ helper T cells from atopic subjects. European Journal of Immunology 22: 1615–1620.

    Article  CAS  PubMed  Google Scholar 

  • Petkova, V., M.J. Romanowski, I. Sulijoadikusumo, D. Rohne, P. Kang, T. Shenk, and A. Usheva. 2001. Interaction between YY1 and the retinoblastoma protein. Regulation of cell cycle progression in differentiated cells. Journal of Biological Chemistry 276: 7932–7936.

    Article  CAS  PubMed  Google Scholar 

  • Pisaneschi, G., S. Ceccotti, M.L. Falchetti, S. Fiumicino, F. Carnevali, and E. Beccari. 1994. Characterization of FIII/YY1, a Xenopus laevis conserved zinc-finger protein binding to the first exon of L1 and L14 ribosomal protein genes. Biochemical and Biophysical Research Communications 205: 1236–1242.

    Article  CAS  PubMed  Google Scholar 

  • Ranger, A.M., M.R. Hodge, E.M. Gravallese, M. Oukka, L. Davidson, F.W. Alt, F.C. De La Brousse, T. Hoey, M. Grusby, and L.H. Glimcher. 1998. Delayed lymphoid repopulation with defects in IL-4-driven responses produced by inactivation of NF-ATc. Immunity 8: 125–134.

    Article  CAS  PubMed  Google Scholar 

  • Rezai-Zadeh, N., X. Zhang, F. Namour, G. Fejer, Y.D. Wen, Y.L. Yao, I. Gyory, K. Wright, and E. Seto. 2003. Targeted recruitment of a histone H4-specific methyltransferase by the transcription factor YY1. Genes & Development 17: 1019–1029.

    Article  CAS  Google Scholar 

  • Seto, E., B. Lewis, and T. Shenk. 1993. Interaction between transcription factors Sp1 and YY1. Nature 365: 462–464.

    Article  CAS  PubMed  Google Scholar 

  • Shi, Y., E. Seto, L.S. Chang, and T. Shenk. 1991. Transcriptional repression by YY1, a human GLI-Krüppel-related protein, and relief of repression by adenovirus E1A protein. Cell 67: 377–388.

    Article  CAS  PubMed  Google Scholar 

  • Shi, Y., J.S. Lee, and K.M. Galvin. 1997. Everything you have ever wanted to know about Yin Yang 1. Biochimica et Biophysica Acta 1332: F49–F66.

    CAS  PubMed  Google Scholar 

  • Shrivastava, A., S. Saleque, G.V. Kalpana, S. Artandi, S.P. Goff, and K. Calame. 1993. Inhibition of transcriptional regulator Yin-Yang-1 by association with c-Myc. Science 262: 1889–1892.

    Article  CAS  PubMed  Google Scholar 

  • Sokol, C.L., G.M. Barton, A.G. Farr, and R. Medzhitov. 2008. A mechanism for the initiation of allergen-induced T helper type 2 responses. Nature Immunology 9: 310–318.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Song, Z., V. Casolaro, R. Chen, S.N. Georas, D. Monos, and S.J. Ono. 1996. Polymorphic nucleotides within the human IL-4 promoter that mediate overexpression of the gene. The Journal of Immunology 156: 424–429.

    CAS  PubMed  Google Scholar 

  • Swain, S.L. 1993. IL4 dictates T-cell differentiation. Research in Immunology 144: 616–620.

    Article  CAS  PubMed  Google Scholar 

  • Sweetser, M.T., T. Hoey, Y.L. Sun, W.M. Weaver, G.A. Price, and C.B. Wilson. 1998. The roles of nuclear factor of activated T cells and ying-yang 1 in activation-induced expression of the interferon-gamma promoter in T cells. Journal of Biological Chemistry 273: 34775–34783.

    Article  CAS  PubMed  Google Scholar 

  • Thomas, M.J., and E. Seto. 1999. Unlocking the mechanisms of transcription factor YY1: are chromatin modifying enzymes the key? Gene 236: 197–208.

    Article  CAS  PubMed  Google Scholar 

  • Wang, J., M.F. Shannon, and I.G. Young. 2006. A role for Ets1, synergizing with AP-1 and GATA-3 in the regulation of IL-5 transcription in mouse Th2 lymphocytes. International Immunology 18: 313–323.

    Article  CAS  PubMed  Google Scholar 

  • Wang, X., Y. Feng, L. Xu, Y. Chen, Y. Zhang, D. Su, G. Ren, J. Lu, and B. Huang. 2008. YY1 restrained cell senescence through repressing the transcription of p16. Biochimica et Biophysica Acta 1783: 1876–1883.

    Article  CAS  PubMed  Google Scholar 

  • Wilkinson, F.H., K. Park, and M.L. Atchison. 2006. Polycomb recruitment to DNA in vivo by the YY1 REPO domain. Proceedings of the National Academy of Sciences USA 103: 19296–19301.

    Article  CAS  Google Scholar 

  • Yant, S.R., W. Zhu, D. Millinoff, J.L. Slightom, M. Goodman, and D.L. Gumucio. 1995. High affinity YY1 binding motifs: identification of two core types (ACAT and CCAT) and distribution of potential binding sites within the human beta globin cluster. Nucleic Acids Research 23: 4353–4362.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yao, Y.L., W.M. Yang, and E. Seto. 2001. Regulation of transcription factor YY1 by acetylation and deacetylation. Molecular and Cellular Biology 21: 5979–5991.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ye, J., M. Cippitelli, L. Dorman, J.R. Ortaldo, and H.A. Young. 1996. The nuclear factor YY1 suppresses the human gamma interferon promoter through two mechanisms: inhibition of AP1 binding and activation of a silencer element. Molecular and Cellular Biology 16: 4744–4753.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang, D.H., L. Cohn, P. Ray, K. Bottomly, and A. Ray. 1997. Transcription factor GATA-3 is differentially expressed in murine Th1 and Th2 cells and controls Th2-specific expression of the interleukin-5 gene. Journal of Biological Chemistry 272: 21597–21603.

    Article  CAS  PubMed  Google Scholar 

  • Zhou, Q., R.W. Gedrich, and D.A. Engel. 1995. Transcriptional repression of the c-fos gene by YY1 is mediated by a direct interaction with ATF/CREB. Journal of Virology 69: 4323–4330.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2010-0006261).

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Correspondence to Kwang Youl Lee or Bok Yun Kang.

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Lee, S.H., Cho, YC., Jeong, H.M. et al. Yin-Yang 1 and Yin-Yang 2 exert opposing effects on the promoter activity of interleukin 4. Arch. Pharm. Res. 39, 547–554 (2016). https://doi.org/10.1007/s12272-015-0622-7

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