Abstract
Fli1 is a member of the Ets family of transcription factors and is preferentially expressed in hematopoietic cell lineages. Its expression level is linked to the pathogenesis of lupus. In this study, we identified mechanisms involved in the transcriptional regulation of the mouse and human Fli1 promoters. We show that the Fli1 promoter is upregulated by Ets factors Ets1, Ets2, Fli1 and Elf1 either alone or in combination with GATA factors, but is inhibited by Tel. In vitro binding studies show that Elf1, Tel and Fli1 in T cells bind the three Ets-binding sites in the murine Fli1 proximal promoter. We identified transcription factor-binding sites in the human Fli1 promoter region that function in T cells in a similar manner to those in the mouse promoter. Furthermore, we show similar binding of Ets factors to the endogenous mouse and human Fli1 promoters in T cells and knocking down Ets1 results in an upregulation of Fli1 expression. Together, these results suggest that the human and mouse genes are regulated similarly and that Ets1 may be important in preventing the overexpression of Fli1 in T cells. This report lays the groundwork for identifying targets for manipulating Fli1 expression as a possible therapeutic approach.
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References
Ben-David Y, Giddens EB, Bernstein A . Identification and mapping of a common proviral integration site Fli-1 in erythroleukemia cells induced by Friend murine leukemia virus. Proc Natl Acad Sci USA 1990; 87: 1332–1336.
Ben-David Y, Giddens EB, Letwin K, Bernstein A . Erythroleukemia induction by Friend murine leukemia virus: insertional activation of a new member of the ets gene family, Fli-1, closely linked to c-ets-1. Genes Dev 1991; 5: 908–918.
Melet F, Motro B, Rossi DJ, Zhang L, Bernstein A . Generation of a novel Fli-1 protein by gene targeting leads to a defect in thymus development and a delay in Friend virus-induced erythroleukemia. Mol Cell Biol 1996; 16: 2708–2718.
Watson DK, Smyth FE, Thompson DM, Cheng JQ, Testa JR, Papas TS et al. The ERGB/Fli-1 gene: isolation and characterization of a new member of the family of human ETS transcription factors. Cell Growth Differ 1992; 3: 705–713.
Anderson MK, Hernandez-Hoyos G, Diamond RA, Rothenberg EV . Precise developmental regulation of Ets family transcription factors during specification and commitment to the T cell lineage. Development 1999; 126: 3131–3148.
Gilkeson GS . Glomerular binding antibodies in systemic lupus erythematosus. Lupus: Molecular and Cellular Pathogenesis 1999; 7: 448–470.
Oates JC, Gilkeson GS . Mediators of injury in lupus nephritis. Curr Opin Rheumatol 2002; 14: 498–503.
Georgiou P, Markoulakou IG, Green P, Dantis V, Romano-Spica S, Kottardid JA . Expression of Ets family of genes in systemic lupus erythematosus and Sjogren's syndrome. Int J Oncol 1996; 9: 9–18.
Zhang XK, Gallant S, Molano I, Moussa OM, Ruiz P, Spyropoulos DD et al. Decreased expression of the Ets family transcription factor Fli-1 markedly prolongs survival and significantly reduces renal disease in MRL/lpr mice. J Immunol 2004; 173: 6481–6489.
Zhang L, Eddy A, Teng YT, Fritzler M, Kluppel M, Melet F et al. An immunological renal disease in transgenic mice that overexpress Fli-1, a member of the Ets family of transcription factor genes. Mol Cell Biol 1995; 15: 6961–6970.
Nowling TK, Fulton JD, Chike-Harris K, Gilkeson GS . Ets factors and a newly identified polymorphism regulate Fli1 promoter activity in lymphocytes. Mol Immunol 2008; 45: 1–12.
Brudno M, Do CB, Cooper GM, Kim MF, Davydov E, Green ED et al. LAGAN and Multi-LAGAN: efficient tools for large-scale multiple alignment of genomic DNA. Genome Res 2003; 13: 721–731.
Henkel G, Brown MA PU . 1 and GATA: components of a mast cell-specific interleukin 4 intronic enhancer. Proc Natl Acad Sci USA 1994; 91: 7737–7741.
Hollenhorst PC, Jones DA, Graves BJ . Expression profiles frame the promoter specificity dilemma of the ETS family of transcription factors. Nucleic Acids Res 2004; 32: 5693–5702.
Kwiatkowski BA, Bastian LS, Bauer Jr TR, Tsai S, Zielinska-Kwiatkowska AG, Hickstein DD . The ets family member Tel binds to the Fli-1 oncoprotein and inhibits its transcriptional activity. J Biol Chem 1998; 273: 17525–17530.
Galson DL, Hensold JO, Bishop TR, Schalling M, D’Andrea AD, Jones C et al. Mouse beta-globin DNA-binding protein B1 is identical to a proto-oncogene, the transcription factor Spi-1/PU 1 and is restricted in expression to hematopoietic cells and the testis. Mol Cell Biol 1993; 13: 2929–2941.
Chen ML, Kuo CL . A conserved sequence block in the murine and human T cell receptor Jalpha loci interacts with developmentally regulated nucleoprotein complexes in vitro and associates with GATA-3 and octamer-binding factors in vivo. Eur J Immunol 2001; 31: 1696–1705.
Lavenu-Bombled C, Trainor CD, Makeh I, Romeo PH, Max-Audit I . Interleukin-13 gene expression is regulated by GATA-3 in T cells: role of a critical association of a GATA and two GATG motifs. J Biol Chem 2002; 277: 18313–18321.
Lee GM, Donaldson LW, Pufall MA, Kang HS, Pot I, Graves BJ et al. The structural and dynamic basis of Ets-1 DNA binding autoinhibition. J Biol Chem 2005; 280: 7088–7099.
Tenbrock K, Juang YT, Kyttaris VC, Tsokos GC . Altered signal transduction in SLE T cells. Rheumatology (Oxford) 2007; 46: 1525–1530.
Lelievre E, Lionneton F, Mattot V, Spruyt N, Soncin F . Ets-1 regulates fli-1 expression in endothelial cells. Identification of ETS binding sites in the fli-1 gene promoter. J Biol Chem 2002; 277: 25143–25151.
Wang D, John SA, Clements JL, Percy DH, Barton KP, Garrett-Sinha LA . Ets-1 deficiency leads to altered B cell differentiation, hyperresponsiveness to TLR9 and autoimmune disease. Int Immunol 2005; 17: 1179–1191.
Clements JL, John SA, Garrett-Sinha LA . Impaired generation of CD8+ thymocytes in Ets-1-deficient mice. J Immunol 2006; 177: 905–912.
Tsokos GC, Nambiar MP, Juang YT . Activation of the Ets transcription factor Elf-1 requires phosphorylation and glycosylation: defective expression of activated Elf-1 is involved in the decreased TCR zeta chain gene expression in patients with systemic lupus erythematosus. Ann N Y Acad Sci 2003; 987: 240–245.
Lopez RG, Carron C, Oury C, Gardellin P, Bernard O, Ghysdael J . TEL is a sequence-specific transcriptional repressor. J Biol Chem 1999; 274: 30132–30138.
Szabo SJ, Sullivan BM, Peng SL, Glimcher LH . Molecular mechanisms regulating Th1 immune responses. Annu Rev Immunol 2003; 21: 713–758.
Blumenthal SG, Aichele G, Wirth T, Czernilofsky AP, Nordheim A, Dittmer J . Regulation of the human interleukin-5 promoter by Ets transcription factors. Ets1 and Ets2, but not Elf-1, cooperate with GATA3 and HTLV-I Tax1. J Biol Chem 1999; 274: 12910–12916.
Zheng W, Flavell RA . The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4T cells. Cell 1997; 89: 587–596.
Landry JR, Kinston S, Knezevic K, Donaldson IJ, Green AR, Gottgens B . Fli1, Elf1, and Ets1 regulate the proximal promoter of the LMO2 gene in endothelial cells. Blood 2005; 106: 2680–2687.
Acknowledgements
This work was supported by NIH grants DK072306 and AR053376. The authors thank Dr Angie Rizzino, Dr Dennis Watson and Dr Maria Trojanowska for their kind gifts of Ets and GATA expression vectors. A special thanks also goes to Dr Gary Gilkeson for critical reading of the paper and providing valuable comments.
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Svenson, J., Chike-Harris, K., Amria, M. et al. The mouse and human Fli1 genes are similarly regulated by Ets factors in T cells. Genes Immun 11, 161–172 (2010). https://doi.org/10.1038/gene.2009.73
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DOI: https://doi.org/10.1038/gene.2009.73
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