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Onecut transcription factor OC2 is a direct target of T-bet in type-1 T-helper cells

Genes & Immunity volume 9, pages 302–308 (2008)Cite this article

Abstract

T-box transcription factor, T-bet, has a central role in the differentiation of T-helper (Th) progenitor cells to Th1 or Th2 effector cells, partly by regulating the expression of genes such as interferon-γ (IFN-γ). However, the direct target genes, especially those mediating the transcriptional network initiated by T-bet, are not yet fully understood. By combining chromatin immunoprecipitation from Th1 cells with human cytosine-phosphate-guanine-island array analysis, Onecut 2 (OC2), which encodes a member of the ONECUT class of transcriptional activators, was identified as a direct target gene of T-bet. OC2 is expressed in Th1 but not Th2 cells and reporter assays showed that T-bet transactivates OC2 transcription through putative T-bet half-sites locating −451 to −347 of OC2 promoter region. Moreover, we found that OC2 binds and transactivates human T-bet promoter. These results suggest that not only cell-extrinsic regulation via the IFN-γ/STAT1 pathway, but also cell-intrinsic transcriptional positive feedback loop between T-bet and OC2 could be involved in Th1 development.

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References

  1. Szabo SJ, Sullivan BM, Peng SL, Glimcher LH . Molecular mechanisms regulating Th1 immune responses. Annu Rev Immunol 2003; 21: 713–758.

    Article  CAS  Google Scholar 

  2. Murphy KM, Reiner SL . The lineage decisions of helper T cells. Nat Rev Immunol 2002; 2: 933–944.

    Article  CAS  Google Scholar 

  3. Wilson V, Conlon FL . The T-box family. Genome Biol 2002; 3: reviews 3008.1–3008.7.

  4. Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH . A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 2000; 100: 655–669.

    Article  CAS  Google Scholar 

  5. Finotto S, Neurath MF, Glickman JN, Qin S, Lehr HA, Green FH et al. Development of spontaneous airway changes consistent with human asthma in mice lacking T-bet. Science 2002; 295: 336–338.

    Article  CAS  Google Scholar 

  6. Szabo SJ, Sullivan BM, Stemmann C, Satoskar AR, Sleckman BP, Glimcher LH . Distinct effects of T-bet in TH1 lineage commitment and IFN-gamma production in CD4 and CD8 T cells. Science 2002; 295: 338–342.

    Article  CAS  Google Scholar 

  7. Lighvani AA, Frucht DM, Jankovic D, Yamane H, Aliberti J, Hissong BD et al. T-bet is rapidly induced by interferon-gamma in lymphoid and myeloid cells. Proc Natl Acad Sci USA 2001; 98: 15137–15142.

    Article  CAS  Google Scholar 

  8. Mullen AC, High FA, Hutchins AS, Lee HW, Villarino AV, Livingston DM et al. Role of T-bet in commitment of TH1 cells before IL-12-dependent selection. Science 2001; 292: 1907–1910.

    Article  CAS  Google Scholar 

  9. Afkarian M, Sedy JR, Yang J, Jacobson NG, Cereb N, Yang SY et al. T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4+ T cells. Nat Immunol 2002; 3: 549–557.

    Article  CAS  Google Scholar 

  10. Mullen AC, Hutchins AS, High FA, Lee HW, Sykes KJ, Chodosh LA et al. Hlx is induced by and genetically interacts with T-bet to promote heritable T(H)1 gene induction. Nat Immunol 2002; 3: 652–658.

    Article  CAS  Google Scholar 

  11. Murakami K, Kojima T, Sakaki Y . Assessment of clusters of transcription factor binding sites in relationship to human promoter, CpG islands and gene expression. BMC Genomics 2004; 5: 16.

    Article  Google Scholar 

  12. Weinmann AS, Yan PS, Oberley MJ, Huang TH, Farnham PJ . Isolating human transcription factor targets by coupling chromatin immunoprecipitation and CpG island microarray analysis. Genes Dev 2002; 16: 235–244.

    Article  CAS  Google Scholar 

  13. Mao DY, Watson JD, Yan PS, Barsyte-Lovejoy D, Khosravi F, Wong WW et al. Analysis of Myc bound loci identified by CpG island arrays shows that Max is essential for Myc-dependent repression. Curr Biol 2003; 13: 882–886.

    Article  CAS  Google Scholar 

  14. Wells J, Yan PS, Cechvala M, Huang T, Farnham PJ . Identification of novel pRb binding sites using CpG microarrays suggests that E2F recruits pRb to specific genomic sites during S phase. Oncogene 2003; 22: 1445–1460.

    Article  CAS  Google Scholar 

  15. Jacquemin P, Lannoy VJ, Rousseau GG, Lemaigre FP . OC-2, a novel mammalian member of the ONECUT class of homeodomain transcription factors whose function in liver partially overlaps with that of hepatocyte nuclear factor-6. J Biol Chem 1999; 274: 2665–2671.

    Article  CAS  Google Scholar 

  16. Cho JY, Grigura V, Murphy TL, Murphy K . Identification of cooperative monomeric Brachyury sites conferring T-bet responsiveness to the proximal IFN-gamma promoter. Int Immunol 2003; 15: 1149–1160.

    Article  CAS  Google Scholar 

  17. Lee DU, Avni O, Chen L, Rao A . A distal enhancer in the interferon-gamma (IFN-gamma) locus revealed by genome sequence comparison. J Biol Chem 2004; 279: 4802–4810.

    Article  CAS  Google Scholar 

  18. Kispert A, Koschorz B, Herrmann BG . The T protein encoded by Brachyury is a tissue-specific transcription factor. EMBO J 1995; 14: 4763–4772.

    Article  CAS  Google Scholar 

  19. Lemaigre FP, Durviaux SM, Truong O, Lannoy VJ, Hsuan JJ, Rousseau GG . Hepatocyte nuclear factor 6, a transcription factor that contains a novel type of homeodomain and a single cut domain. Proc Natl Acad Sci USA 1996; 93: 9460–9464.

    Article  CAS  Google Scholar 

  20. Lannoy VJ, Burglin TR, Rousseau GG, Lemaigre FP . Isoforms of hepatocyte nuclear factor-6 differ in DNA-binding properties, contain a bifunctional homeodomain, and define the new ONECUT class of homeodomain proteins. J Biol Chem 1998; 273: 13552–13562.

    Article  CAS  Google Scholar 

  21. Vanhorenbeeck V, Jacquemin P, Lemaigre FP, Rousseau GG . OC-3, a novel mammalian member of the ONECUT class of transcription factors. Biochem Biophys Res Commune 2002; 292: 848–854.

    Article  CAS  Google Scholar 

  22. Harada R, Berube G, Tamplin OJ, Denis-Larose C, Nepveu A . DNA-binding specificity of the cut repeats from the human cut-like protein. Mol Cell Biol 1995; 15: 129–140.

    Article  CAS  Google Scholar 

  23. Bettelli E, Sullivan B, Szabo SJ, Sobel RA, Glimcher LH, Kuchroo VK . Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis. J Exp Med 2004; 200: 79–87.

    Article  CAS  Google Scholar 

  24. Lieberman LA, Banica M, Reiner SL, Hunter CA . STAT1 plays a critical role in the regulation of antimicrobial effector mechanisms, but not in the development of Th1-type responses during toxoplasmosis. J Immunol 2004; 172: 457–463.

    Article  CAS  Google Scholar 

  25. Clotman F, Jacquemin P, Plumb-Rudewiez N, Pierreux CE, Van der Smissen P, Dietz HC et al. Control of liver cell fate decision by a gradient of TGF beta signaling modulated by Onecut transcription factors. Genes Dev 2005; 19: 1849–1854.

    Article  CAS  Google Scholar 

  26. Vanhorenbeeck V, Jenny M, Cornut JF, Gradwohl G, Lemaigre FP, Rousseau GG et al. Role of the Onecut transcription factors in pancreas morphogenesis and in pancreatic and enteric endocrine differentiation. Dev Biol 2007; 305: 685–694.

    Article  CAS  Google Scholar 

  27. Margagliotti S, Clotman F, Pierreux CE, Beaudry JB, Jacquemin P, Rousseau GG et al. The Onecut transcription factors HNF-6/OC-1 and OC-2 regulate early liver expansion by controlling hepatoblast migration. Dev Biol 2007; 311: 579–589.

    Article  CAS  Google Scholar 

  28. Remboutsika E, Yamamoto K, Harbers M, Schmutz M . The bromodomain mediates transcriptional intermediary factor 1alpha–nucleosome interactions. J Biol Chem 2002; 272: 50318–50325.

    Article  Google Scholar 

  29. Huang TH, Perry MR, Laux DE . Methylation profiling of CpG islands in human breast cancer cells. Hum Mol Genet 1999; 8: 459–470.

    Article  CAS  Google Scholar 

  30. Yamamoto K, Sonoda M, Inokuchi J, Shirasawa S, Sasazuki T . Polycomb group suppressor of zeste 12 links heterochromatin protein 1alpha and enhancer of zeste 2. J Biol Chem 2004; 279: 401–406.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank T Tanaka, T Akinaga, M Goto and M Ohnish for technical help. This work was supported by a Grant-in-Aid for Scientific Research in the priority area of Genome Biology, and by a grant from the 21st Center of Excellence Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Authors and Affiliations

  1. Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

    K Furuno, K Fukuyama, M Sonoda & K Yamamoto

  2. Department of Pediatrics, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan

    K Furuno, K Ikeda & T Hara

  3. Department of Parasitology, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan

    S Hamano

  4. International Medical Center of Japan, Tokyo, Japan

    T Sasazuki

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  1. K Furuno
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Correspondence to K Yamamoto.

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Furuno, K., Ikeda, K., Hamano, S. et al. Onecut transcription factor OC2 is a direct target of T-bet in type-1 T-helper cells. Genes Immun 9, 302–308 (2008). https://doi.org/10.1038/gene.2008.18

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