Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1995 Aug 1;182(2):487–500. doi: 10.1084/jem.182.2.487

Functional roles of the transcription factor Oct-2A and the high mobility group protein I/Y in HLA-DRA gene expression

PMCID: PMC2192141  PMID: 7629508

Abstract

The class II major histocompatibility complex gene HLA-DRA is expressed in B cells, activated T lymphocytes, and in antigen-presenting cells. In addition, HLA-DRA gene expression is inducible in a variety of cell types by interferon-gamma (IFN-gamma). Here we show that the lymphoid- specific transcription factor Oct-2A plays a critical role in HLA-DRA gene expression in class II-positive B cell lines, and that the high mobility group protein (HMG) I/Y binds to multiple sites within the DRA promoter, including the Oct-2A binding site. Coexpression of HMG I/Y and Oct-2 in cell lines lacking Oct-2 results in high levels of HLA-DRA gene expression, and in vitro DNA-binding studies reveal that HMG I/Y stimulates Oct-2A binding to the HLA-DRA promoter. Thus, Oct-2A and HMG I/Y may synergize to activate HLA-DRA expression in B cells. By contrast, Oct-2A is not involved in the IFN-gamma induction of the HLA- DRA gene in HeLa cells, but antisense HMG I/Y dramatically decreases the level of induction. We conclude that distinct sets of transcription factors are involved in the two modes of HLA-DRA expression, and that HMG I/Y may be important for B cell-specific expression, and is essential for IFN-gamma induction.

Full Text

The Full Text of this article is available as a PDF (2.3 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Andersson G., Peterlin B. M. NF-X2 that binds to the DRA X2-box is activator protein 1. Expression cloning of c-Jun. J Immunol. 1990 Nov 15;145(10):3456–3462. [PubMed] [Google Scholar]
  2. Boss J. M., Strominger J. L. Regulation of a transfected human class II major histocompatibility complex gene in human fibroblasts. Proc Natl Acad Sci U S A. 1986 Dec;83(23):9139–9143. doi: 10.1073/pnas.83.23.9139. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Chuvpilo S., Schomberg C., Gerwig R., Heinfling A., Reeves R., Grummt F., Serfling E. Multiple closely-linked NFAT/octamer and HMG I(Y) binding sites are part of the interleukin-4 promoter. Nucleic Acids Res. 1993 Dec 11;21(24):5694–5704. doi: 10.1093/nar/21.24.5694. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cogswell J. P., Basta P. V., Ting J. P. X-box-binding proteins positively and negatively regulate transcription of the HLA-DRA gene through interaction with discrete upstream W and V elements. Proc Natl Acad Sci U S A. 1990 Oct;87(19):7703–7707. doi: 10.1073/pnas.87.19.7703. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Dedrick R. L., Jones P. P. Sequence elements required for activity of a murine major histocompatibility complex class II promoter bind common and cell-type-specific nuclear factors. Mol Cell Biol. 1990 Feb;10(2):593–604. doi: 10.1128/mcb.10.2.593. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Didier D. K., Schiffenbauer J., Woulfe S. L., Zacheis M., Schwartz B. D. Characterization of the cDNA encoding a protein binding to the major histocompatibility complex class II Y box. Proc Natl Acad Sci U S A. 1988 Oct;85(19):7322–7326. doi: 10.1073/pnas.85.19.7322. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Du W., Thanos D., Maniatis T. Mechanisms of transcriptional synergism between distinct virus-inducible enhancer elements. Cell. 1993 Sep 10;74(5):887–898. doi: 10.1016/0092-8674(93)90468-6. [DOI] [PubMed] [Google Scholar]
  8. Eckner R., Birnstiel M. L. Cloning of cDNAs coding for human HMG I and HMG Y proteins: both are capable of binding to the octamer sequence motif. Nucleic Acids Res. 1989 Aug 11;17(15):5947–5959. doi: 10.1093/nar/17.15.5947. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Ephrussi A., Church G. M., Tonegawa S., Gilbert W. B lineage--specific interactions of an immunoglobulin enhancer with cellular factors in vivo. Science. 1985 Jan 11;227(4683):134–140. doi: 10.1126/science.3917574. [DOI] [PubMed] [Google Scholar]
  10. Fashena S. J., Reeves R., Ruddle N. H. A poly(dA-dT) upstream activating sequence binds high-mobility group I protein and contributes to lymphotoxin (tumor necrosis factor-beta) gene regulation. Mol Cell Biol. 1992 Feb;12(2):894–903. doi: 10.1128/mcb.12.2.894. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Glimcher L. H., Kara C. J. Sequences and factors: a guide to MHC class-II transcription. Annu Rev Immunol. 1992;10:13–49. doi: 10.1146/annurev.iy.10.040192.000305. [DOI] [PubMed] [Google Scholar]
  12. Grueneberg D. A., Natesan S., Alexandre C., Gilman M. Z. Human and Drosophila homeodomain proteins that enhance the DNA-binding activity of serum response factor. Science. 1992 Aug 21;257(5073):1089–1095. doi: 10.1126/science.257.5073.1089. [DOI] [PubMed] [Google Scholar]
  13. Hatzopoulos A. K., Stoykova A. S., Erselius J. R., Goulding M., Neuman T., Gruss P. Structure and expression of the mouse Oct2a and Oct2b, two differentially spliced products of the same gene. Development. 1990 Jun;109(2):349–362. doi: 10.1242/dev.109.2.349. [DOI] [PubMed] [Google Scholar]
  14. Hooft van Huijsduijnen R., Li X. Y., Black D., Matthes H., Benoist C., Mathis D. Co-evolution from yeast to mouse: cDNA cloning of the two NF-Y (CP-1/CBF) subunits. EMBO J. 1990 Oct;9(10):3119–3127. doi: 10.1002/j.1460-2075.1990.tb07509.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hume C. R., Lee J. S. Congenital immunodeficiencies associated with absence of HLA class II antigens on lymphocytes result from distinct mutations in trans-acting factors. Hum Immunol. 1989 Dec;26(4):288–309. doi: 10.1016/0198-8859(89)90007-4. [DOI] [PubMed] [Google Scholar]
  16. Kappes D., Strominger J. L. Human class II major histocompatibility complex genes and proteins. Annu Rev Biochem. 1988;57:991–1028. doi: 10.1146/annurev.bi.57.070188.005015. [DOI] [PubMed] [Google Scholar]
  17. Kara C. J., Glimcher L. H. In vivo footprinting of MHC class II genes: bare promoters in the bare lymphocyte syndrome. Science. 1991 May 3;252(5006):709–712. doi: 10.1126/science.1902592. [DOI] [PubMed] [Google Scholar]
  18. Kaufman J. F., Auffray C., Korman A. J., Shackelford D. A., Strominger J. The class II molecules of the human and murine major histocompatibility complex. Cell. 1984 Jan;36(1):1–13. doi: 10.1016/0092-8674(84)90068-0. [DOI] [PubMed] [Google Scholar]
  19. King D. P., Jones P. P. Induction of Ia and H-2 antigens on a macrophage cell line by immune interferon. J Immunol. 1983 Jul;131(1):315–318. [PubMed] [Google Scholar]
  20. Liou H. C., Boothby M. R., Glimcher L. H. Distinct cloned class II MHC DNA binding proteins recognize the X box transcription element. Science. 1988 Oct 7;242(4875):69–71. doi: 10.1126/science.3140376. [DOI] [PubMed] [Google Scholar]
  21. Lucey D. R., Nicholson-Weller A., Weller P. F. Mature human eosinophils have the capacity to express HLA-DR. Proc Natl Acad Sci U S A. 1989 Feb;86(4):1348–1351. doi: 10.1073/pnas.86.4.1348. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Matis L. A., Glimcher L. H., Paul W. E., Schwartz R. H. Magnitude of response of histocompatibility-restricted T-cell clones is a function of the product of the concentrations of antigen and Ia molecules. Proc Natl Acad Sci U S A. 1983 Oct;80(19):6019–6023. doi: 10.1073/pnas.80.19.6019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Miwa K., Strominger J. L. The HLA-DQ beta gene upstream region contains an immunoglobulin-like octamer motif that binds cell-type specific nuclear factors. Nucleic Acids Res. 1987 Oct 12;15(19):8057–8067. doi: 10.1093/nar/15.19.8057. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Müller M. M., Ruppert S., Schaffner W., Matthias P. A cloned octamer transcription factor stimulates transcription from lymphoid-specific promoters in non-B cells. Nature. 1988 Dec 8;336(6199):544–551. doi: 10.1038/336544a0. [DOI] [PubMed] [Google Scholar]
  25. Ono S. J., Bazil V., Levi B. Z., Ozato K., Strominger J. L. Transcription of a subset of human class II major histocompatibility complex genes is regulated by a nucleoprotein complex that contains c-fos or an antigenically related protein. Proc Natl Acad Sci U S A. 1991 May 15;88(10):4304–4308. doi: 10.1073/pnas.88.10.4304. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Ono S. J., Bazil V., Sugawara M., Strominger J. L. An isotype-specific trans-acting factor is defective in a mutant B cell line that expresses HLA-DQ, but not -DR or -DP. J Exp Med. 1991 Mar 1;173(3):629–637. doi: 10.1084/jem.173.3.629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Ono S. J., Issa-Chergui B., Colle E., Guttmann R. D., Seemayer T. A., Fuks A. IDDM in BB rats. Enhanced MHC class I heavy-chain gene expression in pancreatic islets. Diabetes. 1988 Oct;37(10):1411–1418. [PubMed] [Google Scholar]
  28. Ono S. J., Liou H. C., Davidon R., Strominger J. L., Glimcher L. H. Human X-box-binding protein 1 is required for the transcription of a subset of human class II major histocompatibility genes and forms a heterodimer with c-fos. Proc Natl Acad Sci U S A. 1991 May 15;88(10):4309–4312. doi: 10.1073/pnas.88.10.4309. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Oñate S. A., Prendergast P., Wagner J. P., Nissen M., Reeves R., Pettijohn D. E., Edwards D. P. The DNA-bending protein HMG-1 enhances progesterone receptor binding to its target DNA sequences. Mol Cell Biol. 1994 May;14(5):3376–3391. doi: 10.1128/mcb.14.5.3376. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Parslow T. G., Blair D. L., Murphy W. J., Granner D. K. Structure of the 5' ends of immunoglobulin genes: a novel conserved sequence. Proc Natl Acad Sci U S A. 1984 May;81(9):2650–2654. doi: 10.1073/pnas.81.9.2650. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Phares W., Franza B. R., Jr, Herr W. The kappa B enhancer motifs in human immunodeficiency virus type 1 and simian virus 40 recognize different binding activities in human Jurkat and H9 T cells: evidence for NF-kappa B-independent activation of the kappa B motif. J Virol. 1992 Dec;66(12):7490–7498. doi: 10.1128/jvi.66.12.7490-7498.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Pober J. S., Collins T., Gimbrone M. A., Jr, Cotran R. S., Gitlin J. D., Fiers W., Clayberger C., Krensky A. M., Burakoff S. J., Reiss C. S. Lymphocytes recognize human vascular endothelial and dermal fibroblast Ia antigens induced by recombinant immune interferon. Nature. 1983 Oct 20;305(5936):726–729. doi: 10.1038/305726a0. [DOI] [PubMed] [Google Scholar]
  33. Pujol-Borrell R., Todd I., Doshi M., Bottazzo G. F., Sutton R., Gray D., Adolf G. R., Feldmann M. HLA class II induction in human islet cells by interferon-gamma plus tumour necrosis factor or lymphotoxin. Nature. 1987 Mar 19;326(6110):304–306. doi: 10.1038/326304a0. [DOI] [PubMed] [Google Scholar]
  34. Reith W., Barras E., Satola S., Kobr M., Reinhart D., Sanchez C. H., Mach B. Cloning of the major histocompatibility complex class II promoter binding protein affected in a hereditary defect in class II gene regulation. Proc Natl Acad Sci U S A. 1989 Jun;86(11):4200–4204. doi: 10.1073/pnas.86.11.4200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Reith W., Herrero-Sanchez C., Kobr M., Silacci P., Berte C., Barras E., Fey S., Mach B. MHC class II regulatory factor RFX has a novel DNA-binding domain and a functionally independent dimerization domain. Genes Dev. 1990 Sep;4(9):1528–1540. doi: 10.1101/gad.4.9.1528. [DOI] [PubMed] [Google Scholar]
  36. Reith W., Siegrist C. A., Durand B., Barras E., Mach B. Function of major histocompatibility complex class II promoters requires cooperative binding between factors RFX and NF-Y. Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):554–558. doi: 10.1073/pnas.91.2.554. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Scheidereit C., Cromlish J. A., Gerster T., Kawakami K., Balmaceda C. G., Currie R. A., Roeder R. G. A human lymphoid-specific transcription factor that activates immunoglobulin genes is a homoeobox protein. Nature. 1988 Dec 8;336(6199):551–557. doi: 10.1038/336551a0. [DOI] [PubMed] [Google Scholar]
  38. Servenius B., Rask L., Peterson P. A. Class II genes of the human major histocompatibility complex. The DO beta gene is a divergent member of the class II beta gene family. J Biol Chem. 1987 Jun 25;262(18):8759–8766. [PubMed] [Google Scholar]
  39. Sherman P. A., Basta P. V., Heguy A., Wloch M. K., Roeder R. G., Ting J. P. The octamer motif is a B-lymphocyte-specific regulatory element of the HLA-DR alpha gene promoter. Proc Natl Acad Sci U S A. 1989 Sep;86(17):6739–6743. doi: 10.1073/pnas.86.17.6739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Sherman P. A., Basta P. V., Ting J. P. Upstream DNA sequences required for tissue-specific expression of the HLA-DR alpha gene. Proc Natl Acad Sci U S A. 1987 Jun;84(12):4254–4258. doi: 10.1073/pnas.84.12.4254. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Song Z., Krishna S., Thanos D., Strominger J. L., Ono S. J. A novel cysteine-rich sequence-specific DNA-binding protein interacts with the conserved X-box motif of the human major histocompatibility complex class II genes via a repeated Cys-His domain and functions as a transcriptional repressor. J Exp Med. 1994 Nov 1;180(5):1763–1774. doi: 10.1084/jem.180.5.1763. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Steimle V., Otten L. A., Zufferey M., Mach B. Complementation cloning of an MHC class II transactivator mutated in hereditary MHC class II deficiency (or bare lymphocyte syndrome). Cell. 1993 Oct 8;75(1):135–146. [PubMed] [Google Scholar]
  43. Stimac E., Lyons S., Pious D. Transcription of HLA class II genes in the absence of B-cell-specific octamer-binding factor. Mol Cell Biol. 1988 Sep;8(9):3734–3739. doi: 10.1128/mcb.8.9.3734. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Strauss F., Varshavsky A. A protein binds to a satellite DNA repeat at three specific sites that would be brought into mutual proximity by DNA folding in the nucleosome. Cell. 1984 Jul;37(3):889–901. doi: 10.1016/0092-8674(84)90424-0. [DOI] [PubMed] [Google Scholar]
  45. Tanaka M., Lai J. S., Herr W. Promoter-selective activation domains in Oct-1 and Oct-2 direct differential activation of an snRNA and mRNA promoter. Cell. 1992 Feb 21;68(4):755–767. doi: 10.1016/0092-8674(92)90150-b. [DOI] [PubMed] [Google Scholar]
  46. Thanos D., Maniatis T. The high mobility group protein HMG I(Y) is required for NF-kappa B-dependent virus induction of the human IFN-beta gene. Cell. 1992 Nov 27;71(5):777–789. doi: 10.1016/0092-8674(92)90554-p. [DOI] [PubMed] [Google Scholar]
  47. Thanos D., Mavrothalassitis G., Papamatheakis J. Multiple regulatory regions on the 5' side of the mouse E alpha gene. Proc Natl Acad Sci U S A. 1988 May;85(9):3075–3079. doi: 10.1073/pnas.85.9.3075. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Ting J. P. Current concepts in DRA gene regulation. Immunol Res. 1993;12(1):65–77. doi: 10.1007/BF02918369. [DOI] [PubMed] [Google Scholar]
  49. Tsang S. Y., Nakanishi M., Peterlin B. M. B-cell-specific and interferon-gamma-inducible regulation of the HLA-DR alpha gene. Proc Natl Acad Sci U S A. 1988 Nov;85(22):8598–8602. doi: 10.1073/pnas.85.22.8598. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Vilen B. J., Cogswell J. P., Ting J. P. Stereospecific alignment of the X and Y elements is required for major histocompatibility complex class II DRA promoter function. Mol Cell Biol. 1991 May;11(5):2406–2415. doi: 10.1128/mcb.11.5.2406. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Wegner M., Zastrow G., Klavinius A., Schwender S., Müller F., Luksza H., Hoppe J., Wienberg J., Grummt F. Cis-acting sequences from mouse rDNA promote plasmid DNA amplification and persistence in mouse cells: implication of HMG-I in their function. Nucleic Acids Res. 1989 Dec 11;17(23):9909–9932. doi: 10.1093/nar/17.23.9909. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Wright K. L., Ting J. P. In vivo footprint analysis of the HLA-DRA gene promoter: cell-specific interaction at the octamer site and up-regulation of X box binding by interferon gamma. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7601–7605. doi: 10.1073/pnas.89.16.7601. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Yang-Yen H. F., Chambard J. C., Sun Y. L., Smeal T., Schmidt T. J., Drouin J., Karin M. Transcriptional interference between c-Jun and the glucocorticoid receptor: mutual inhibition of DNA binding due to direct protein-protein interaction. Cell. 1990 Sep 21;62(6):1205–1215. doi: 10.1016/0092-8674(90)90396-v. [DOI] [PubMed] [Google Scholar]
  54. Zeleznik-Le N. J., Itoh-Lindstrom Y., Clarke J. B., Moore T. L., Ting J. P. The B cell-specific nuclear factor OTF-2 positively regulates transcription of the human class II transplantation gene, DRA. J Biol Chem. 1992 Apr 15;267(11):7677–7682. [PubMed] [Google Scholar]
  55. Zhao K., Käs E., Gonzalez E., Laemmli U. K. SAR-dependent mobilization of histone H1 by HMG-I/Y in vitro: HMG-I/Y is enriched in H1-depleted chromatin. EMBO J. 1993 Aug;12(8):3237–3247. doi: 10.1002/j.1460-2075.1993.tb05993.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. de Préval C., Lisowska-Grospierre B., Loche M., Griscelli C., Mach B. A trans-acting class II regulatory gene unlinked to the MHC controls expression of HLA class II genes. Nature. 1985 Nov 21;318(6043):291–293. doi: 10.1038/318291a0. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES