Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1991 Nov 15;88(22):10347–10351. doi: 10.1073/pnas.88.22.10347

Delineation of a previously unrecognized cis-acting element required for HLA class II gene expression.

M Sugawara 1, P D Ponath 1, J Shin 1, Z Yang 1, J L Strominger 1
PMCID: PMC52925  PMID: 1946454

Abstract

The cis-acting DNA sequences that control expression of the HLA-DPA and HLA-DQB promoters have been investigated in detail. A set of recombinant plasmids containing 5' promoter deletions as well as site-directed mutants of the DPA and DQB genes were fused to a reporter gene and transfected into human B and interferon gamma (IFN-gamma)-inducible cells. A previously unrecognized cis element, which is essential both for transcription induced by IFN-gamma in several cell types and for constitutive class II expression in B cells, in addition to the well known X and Y boxes, has been defined. This sequence, which spans nucleotides -107 to -98 and -146 to -137 of the DPA and DQB promoters, respectively, has been called the J element. Some evidence for function of a fourth element, the S element, is also presented.

Full text

PDF
10347

Images in this article

10348Image
on p.10348
10349Image
on p.10349
10349Image
on p.10349
10350Image
on p.10350
10350Image
on p.10350

Selected References

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

  1. Anichini A., Castelli C., Sozzi G., Fossati G., Parmiani G. Differential susceptibility to recombinant interferon-gamma-induced HLA-DQ antigen modulation among clones from a human metastatic melanoma. J Immunol. 1988 Jan 1;140(1):183–191. [PubMed] [Google Scholar]
  2. Basta P. V., Sherman P. A., Ting J. P. Identification of an interferon-gamma response region 5' of the human histocompatibility leukocyte antigen DR alpha chain gene which is active in human glioblastoma multiforme lines. J Immunol. 1987 Feb 15;138(4):1275–1280. [PubMed] [Google Scholar]
  3. Benoist C., Mathis D. Regulation of major histocompatibility complex class-II genes: X, Y and other letters of the alphabet. Annu Rev Immunol. 1990;8:681–715. doi: 10.1146/annurev.iy.08.040190.003341. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. Chen C., Okayama H. High-efficiency transformation of mammalian cells by plasmid DNA. Mol Cell Biol. 1987 Aug;7(8):2745–2752. doi: 10.1128/mcb.7.8.2745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cogswell J. P., Austin J., Ting J. P. The W element is a positive regulator of HLA-DRA transcription in various DR+ cell types. J Immunol. 1991 Feb 15;146(4):1361–1367. [PubMed] [Google Scholar]
  7. 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]
  8. Collins T., Korman A. J., Wake C. T., Boss J. M., Kappes D. J., Fiers W., Ault K. A., Gimbrone M. A., Jr, Strominger J. L., Pober J. S. Immune interferon activates multiple class II major histocompatibility complex genes and the associated invariant chain gene in human endothelial cells and dermal fibroblasts. Proc Natl Acad Sci U S A. 1984 Aug;81(15):4917–4921. doi: 10.1073/pnas.81.15.4917. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. 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]
  10. Dorn A., Durand B., Marfing C., Le Meur M., Benoist C., Mathis D. Conserved major histocompatibility complex class II boxes--X and Y--are transcriptional control elements and specifically bind nuclear proteins. Proc Natl Acad Sci U S A. 1987 Sep;84(17):6249–6253. doi: 10.1073/pnas.84.17.6249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Finn P. W., Kara C. J., Douhan J., 3rd, Van T. T., Folsom V., Glimcher L. H. Interferon gamma regulates binding of two nuclear protein complexes in a macrophage cell line. Proc Natl Acad Sci U S A. 1990 Feb;87(3):914–918. doi: 10.1073/pnas.87.3.914. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Folsom V., Gold D. P., White J., Marrack P., Kappler J., Tonegawa S. Functional and inducible expression of a transfected murine class II major histocompatibility complex gene. Proc Natl Acad Sci U S A. 1984 Apr;81(7):2045–2049. doi: 10.1073/pnas.81.7.2045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Freund Y. R., Dedrick R. L., Jones P. P. cis-acting sequences required for class II gene regulation by interferon gamma and tumor necrosis factor alpha in a murine macrophage cell line. J Exp Med. 1990 Apr 1;171(4):1283–1299. doi: 10.1084/jem.171.4.1283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gillies S. D., Folsom V., Tonegawa S. Cell type-specific enhancer element associated with a mouse MHC gene, E beta. Nature. 1984 Aug 16;310(5978):594–597. doi: 10.1038/310594a0. [DOI] [PubMed] [Google Scholar]
  15. Gorman C. M., Moffat L. F., Howard B. H. Recombinant genomes which express chloramphenicol acetyltransferase in mammalian cells. Mol Cell Biol. 1982 Sep;2(9):1044–1051. doi: 10.1128/mcb.2.9.1044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. 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]
  17. Kunkel T. A. Rapid and efficient site-specific mutagenesis without phenotypic selection. Proc Natl Acad Sci U S A. 1985 Jan;82(2):488–492. doi: 10.1073/pnas.82.2.488. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Mathis D. J., Benoist C. O., Williams V. E., 2nd, Kanter M. R., McDevitt H. O. The murine E alpha immune response gene. Cell. 1983 Mar;32(3):745–754. doi: 10.1016/0092-8674(83)90060-0. [DOI] [PubMed] [Google Scholar]
  19. Miwa K., Doyle C., Strominger J. L. Sequence-specific interactions of nuclear factors with conserved sequences of human class II major histocompatibility complex genes. Proc Natl Acad Sci U S A. 1987 Jul;84(14):4939–4943. doi: 10.1073/pnas.84.14.4939. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Nadler P. I., Klingenstein R. J., Richman L. K., Ahmann G. B. The murine Kupffer cell. II. Accessory cell function in in vitro primary antibody responses, mitogen-induced proliferation, and stimulation of mixed lymphocyte responses. J Immunol. 1980 Dec;125(6):2521–2525. [PubMed] [Google Scholar]
  21. Nezu N., Ryu K., Koide Y., Yoshida T. O. Regulation of HLA class II molecule expressions by IFN-gamma. The signal transduction mechanism in glioblastoma cell lines. J Immunol. 1990 Nov 1;145(9):3126–3135. [PubMed] [Google Scholar]
  22. Okada K., Boss J. M., Prentice H., Spies T., Mengler R., Auffray C., Lillie J., Grossberger D., Strominger J. L. Gene organization of DC and DX subregions of the human major histocompatibility complex. Proc Natl Acad Sci U S A. 1985 May;82(10):3410–3414. doi: 10.1073/pnas.82.10.3410. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Pober J. S., Gimbrone M. A., Jr, Cotran R. S., Reiss C. S., Burakoff S. J., Fiers W., Ault K. A. Ia expression by vascular endothelium is inducible by activated T cells and by human gamma interferon. J Exp Med. 1983 Apr 1;157(4):1339–1353. doi: 10.1084/jem.157.4.1339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Polla B. S., Poljak A., Geier S. G., Nathenson S. G., Ohara J., Paul W. E., Glimcher L. H. Three distinct signals can induce class II gene expression in a murine pre-B-cell line. Proc Natl Acad Sci U S A. 1986 Jul;83(13):4878–4882. doi: 10.1073/pnas.83.13.4878. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. 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]
  26. 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]
  27. Sakurai M., Strominger J. L. B-cell-specific enhancer activity of conserved upstream elements of the class II major histocompatibility complex DQB gene. Proc Natl Acad Sci U S A. 1988 Sep;85(18):6909–6913. doi: 10.1073/pnas.85.18.6909. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Sakurai M., Strominger J. L. Studies of expression of the DQ beta promoter and its 5' deletion derivatives in normal and mutant human B cell lines. Tissue Antigens. 1989 Jul;34(1):64–77. doi: 10.1111/j.1399-0039.1989.tb01718.x. [DOI] [PubMed] [Google Scholar]
  29. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Selden R. F., Howie K. B., Rowe M. E., Goodman H. M., Moore D. D. Human growth hormone as a reporter gene in regulation studies employing transient gene expression. Mol Cell Biol. 1986 Sep;6(9):3173–3179. doi: 10.1128/mcb.6.9.3173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. 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]
  32. 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]
  33. Stingl G., Katz S. I., Clement L., Green I., Shevach E. M. Immunologic functions of Ia-bearing epidermal Langerhans cells. J Immunol. 1978 Nov;121(5):2005–2013. [PubMed] [Google Scholar]
  34. 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]
  35. 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]
  36. Tsang S. Y., Nakanishi M., Peterlin B. M. Mutational analysis of the DRA promoter: cis-acting sequences and trans-acting factors. Mol Cell Biol. 1990 Feb;10(2):711–719. doi: 10.1128/mcb.10.2.711. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Unanue E. R., Beller D. I., Lu C. Y., Allen P. M. Antigen presentation: comments on its regulation and mechanism. J Immunol. 1984 Jan;132(1):1–5. [PubMed] [Google Scholar]
  38. Wang Y., Larsen A. S., Peterlin B. M. A tissue-specific transcriptional enhancer is found in the body of the HLA-DR alpha gene. J Exp Med. 1987 Sep 1;166(3):625–636. doi: 10.1084/jem.166.3.625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Yang Z., Sugawara M., Ponath P. D., Wessendorf L., Banerji J., Li Y., Strominger J. L. Interferon gamma response region in the promoter of the human DPA gene. Proc Natl Acad Sci U S A. 1990 Dec;87(23):9226–9230. doi: 10.1073/pnas.87.23.9226. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Zinkernagel R. M., Doherty P. C. MHC-restricted cytotoxic T cells: studies on the biological role of polymorphic major transplantation antigens determining T-cell restriction-specificity, function, and responsiveness. Adv Immunol. 1979;27:51–177. doi: 10.1016/s0065-2776(08)60262-x. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES