Skip to main content
NCBI home page
Nucleic Acids Research logoLink to Nucleic Acids Research
. 1997 Dec 15;25(24):5095–5102. doi: 10.1093/nar/25.24.5095

Retinoblastoma protein expression facilitates chromatin remodeling at the HLA-DRA promoter.

A Osborne 1, M Tschickardt 1, G Blanck 1
PMCID: PMC147150  PMID: 9396821

Abstract

The major histocompatibility complex (MHC) class II genes encode a series of heterodimeric cell surface glycoproteins that bind peptide antigen. The MHC class II/peptide complex is bound by the T-cell receptor of CD4(+) T cells, thereby stimulating an immune response. The MHC class II genes are coordinately regulated by conserved promoter elements and are inducible by IFN-gamma. Furthermore, IFN-gamma induction of the MHC class II genes in solid human tumor lines requires retinoblastoma protein (Rb). In vivo footprinting analyses of the HLA-DRA gene, which encodes the heavy chain subunit of the human MHC class II molecule, HLA-DR, revealed that Rb facilitates occupancy of multiple HLA-DRA promoter elements. Detecting the effect of Rb on HLA-DRA promoter occupancy in vivo required IFN-gamma treatment. However, use of a variation on the in vivo footprinting technique, nuclei footprinting, which assays for promoter occupancy in isolated nuclei, revealed that expression of Rb facilitates promoter occupancy even in the absence of IFN-gamma. These results indicate that expression of Rb leads to modification of the chromatin environment of the HLA-DRA promoter independently of transcription.

Full Text

The Full Text of this article is available as a PDF (149.0 KB).

Selected References

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

  1. Amaldi I., Reith W., Berte C., Mach B. Induction of HLA class II genes by IFN-gamma is transcriptional and requires a trans-acting protein. J Immunol. 1989 Feb 1;142(3):999–1004. [PubMed] [Google Scholar]
  2. Archer T. K., Lee H. L., Cordingley M. G., Mymryk J. S., Fragoso G., Berard D. S., Hager G. L. Differential steroid hormone induction of transcription from the mouse mammary tumor virus promoter. Mol Endocrinol. 1994 May;8(5):568–576. doi: 10.1210/mend.8.5.8058066. [DOI] [PubMed] [Google Scholar]
  3. Baskar S., Glimcher L., Nabavi N., Jones R. T., Ostrand-Rosenberg S. Major histocompatibility complex class II+B7-1+ tumor cells are potent vaccines for stimulating tumor rejection in tumor-bearing mice. J Exp Med. 1995 Feb 1;181(2):619–629. doi: 10.1084/jem.181.2.619. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Berry D. E., Lu Y., Schmidt B., Fallon P. G., O'Connell C., Hu S. X., Xu H. J., Blanck G. Retinoblastoma protein inhibits IFN-gamma induced apoptosis. Oncogene. 1996 Apr 18;12(8):1809–1819. [PubMed] [Google Scholar]
  5. Blanck G., Lok M., Kok K., Downie E., Korn J. H., Strominger J. L. Gamma-interferon induction of HLA class II mRNAs in dermal fibroblasts studied by RNAse protection analysis. Hum Immunol. 1990 Oct;29(2):150–156. doi: 10.1016/0198-8859(90)90078-4. [DOI] [PubMed] [Google Scholar]
  6. Boss J. M. Regulation of transcription of MHC class II genes. Curr Opin Immunol. 1997 Feb;9(1):107–113. doi: 10.1016/s0952-7915(97)80166-5. [DOI] [PubMed] [Google Scholar]
  7. Bénichou B., Strominger J. L. Class II-antigen-negative patient and mutant B-cell lines represent at least three, and probably four, distinct genetic defects defined by complementation analysis. Proc Natl Acad Sci U S A. 1991 May 15;88(10):4285–4288. doi: 10.1073/pnas.88.10.4285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Carlson M., Laurent B. C. The SNF/SWI family of global transcriptional activators. Curr Opin Cell Biol. 1994 Jun;6(3):396–402. doi: 10.1016/0955-0674(94)90032-9. [DOI] [PubMed] [Google Scholar]
  9. Carson S., Wiles M. V. Far upstream regions of class II MHC Ea are necessary for position-independent, copy-dependent expression of Ea transgene. Nucleic Acids Res. 1993 May 11;21(9):2065–2072. doi: 10.1093/nar/21.9.2065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Chang C. H., Fontes J. D., Peterlin M., Flavell R. A. Class II transactivator (CIITA) is sufficient for the inducible expression of major histocompatibility complex class II genes. J Exp Med. 1994 Oct 1;180(4):1367–1374. doi: 10.1084/jem.180.4.1367. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Chang C. H., Guerder S., Hong S. C., van Ewijk W., Flavell R. A. Mice lacking the MHC class II transactivator (CIITA) show tissue-specific impairment of MHC class II expression. Immunity. 1996 Feb;4(2):167–178. doi: 10.1016/s1074-7613(00)80681-0. [DOI] [PubMed] [Google Scholar]
  12. Chen P. L., Riley D. J., Chen-Kiang S., Lee W. H. Retinoblastoma protein directly interacts with and activates the transcription factor NF-IL6. Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):465–469. doi: 10.1073/pnas.93.1.465. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Chen P. L., Riley D. J., Chen Y., Lee W. H. Retinoblastoma protein positively regulates terminal adipocyte differentiation through direct interaction with C/EBPs. Genes Dev. 1996 Nov 1;10(21):2794–2804. doi: 10.1101/gad.10.21.2794. [DOI] [PubMed] [Google Scholar]
  14. Dunaief J. L., Strober B. E., Guha S., Khavari P. A., Alin K., Luban J., Begemann M., Crabtree G. R., Goff S. P. The retinoblastoma protein and BRG1 form a complex and cooperate to induce cell cycle arrest. Cell. 1994 Oct 7;79(1):119–130. doi: 10.1016/0092-8674(94)90405-7. [DOI] [PubMed] [Google Scholar]
  15. Durand B., Sperisen P., Emery P., Barras E., Zufferey M., Mach B., Reith W. RFXAP, a novel subunit of the RFX DNA binding complex is mutated in MHC class II deficiency. EMBO J. 1997 Mar 3;16(5):1045–1055. doi: 10.1093/emboj/16.5.1045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Fontes J. D., Jabrane-Ferrat N., Toth C. R., Peterlin B. M. Binding and cooperative interactions between two B cell-specific transcriptional coactivators. J Exp Med. 1996 Jun 1;183(6):2517–2521. doi: 10.1084/jem.183.6.2517. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Groudine M., Kohwi-Shigematsu T., Gelinas R., Stamatoyannopoulos G., Papayannopoulou T. Human fetal to adult hemoglobin switching: changes in chromatin structure of the beta-globin gene locus. Proc Natl Acad Sci U S A. 1983 Dec;80(24):7551–7555. doi: 10.1073/pnas.80.24.7551. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Gunning P., Ponte P., Okayama H., Engel J., Blau H., Kedes L. Isolation and characterization of full-length cDNA clones for human alpha-, beta-, and gamma-actin mRNAs: skeletal but not cytoplasmic actins have an amino-terminal cysteine that is subsequently removed. Mol Cell Biol. 1983 May;3(5):787–795. doi: 10.1128/mcb.3.5.787. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Gönczy P., Reith W., Barras E., Lisowska-Grospierre B., Griscelli C., Hadam M. R., Mach B. Inherited immunodeficiency with a defect in a major histocompatibility complex class II promoter-binding protein differs in the chromatin structure of the HLA-DRA gene. Mol Cell Biol. 1989 Jan;9(1):296–302. doi: 10.1128/mcb.9.1.296. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hobart M., Ramassar V., Goes N., Urmson J., Halloran P. F. IFN regulatory factor-1 plays a central role in the regulation of the expression of class I and II MHC genes in vivo. J Immunol. 1997 May 1;158(9):4260–4269. [PubMed] [Google Scholar]
  21. Jabrane-Ferrat N., Fontes J. D., Boss J. M., Peterlin B. M. Complex architecture of major histocompatibility complex class II promoters: reiterated motifs and conserved protein-protein interactions. Mol Cell Biol. 1996 Sep;16(9):4683–4690. doi: 10.1128/mcb.16.9.4683. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kara C. J., Glimcher L. H. Developmental and cytokine-mediated regulation of MHC class II gene promoter occupancy in vivo. J Immunol. 1993 Jun 1;150(11):4934–4942. [PubMed] [Google Scholar]
  23. 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]
  24. Lu Y., Boss J. M., Hu S. X., Xu H. J., Blanck G. Apoptosis-independent retinoblastoma protein rescue of HLA class II messenger RNA IFN-gamma inducibility in non-small cell lung carcinoma cells. Lack of surface class II expression associated with a specific defect in HLA-DRA induction. J Immunol. 1996 Apr 1;156(7):2495–2502. [PubMed] [Google Scholar]
  25. Lu Y., Ussery G. D., Jacim M., Tschickardt M., Boss J. M., Blanck G. Retinoblastoma protein regulation of surface CD74 (invariant chain) expression in breast carcinoma cells. Mol Immunol. 1994 Dec;31(17):1365–1368. doi: 10.1016/0161-5890(94)90055-8. [DOI] [PubMed] [Google Scholar]
  26. Lu Y., Ussery G. D., Muncaster M. M., Gallie B. L., Blanck G. Evidence for retinoblastoma protein (RB) dependent and independent IFN-gamma responses: RB coordinately rescues IFN-gamma induction of MHC class II gene transcription in noninducible breast carcinoma cells. Oncogene. 1994 Apr;9(4):1015–1019. [PubMed] [Google Scholar]
  27. Moreno C. S., Rogers E. M., Brown J. A., Boss J. M. Regulatory factor X, a bare lymphocyte syndrome transcription factor, is a multimeric phosphoprotein complex. J Immunol. 1997 Jun 15;158(12):5841–5848. [PubMed] [Google Scholar]
  28. Mueller P. R., Salser S. J., Wold B. Constitutive and metal-inducible protein:DNA interactions at the mouse metallothionein I promoter examined by in vivo and in vitro footprinting. Genes Dev. 1988 Apr;2(4):412–427. doi: 10.1101/gad.2.4.412. [DOI] [PubMed] [Google Scholar]
  29. Muncaster M. M., Cohen B. L., Phillips R. A., Gallie B. L. Failure of RB1 to reverse the malignant phenotype of human tumor cell lines. Cancer Res. 1992 Feb 1;52(3):654–661. [PubMed] [Google Scholar]
  30. Ostrand-Rosenberg S., Thakur A., Clements V. Rejection of mouse sarcoma cells after transfection of MHC class II genes. J Immunol. 1990 May 15;144(10):4068–4071. [PubMed] [Google Scholar]
  31. Riley J. L., Westerheide S. D., Price J. A., Brown J. A., Boss J. M. Activation of class II MHC genes requires both the X box region and the class II transactivator (CIITA). Immunity. 1995 May;2(5):533–543. doi: 10.1016/1074-7613(95)90033-0. [DOI] [PubMed] [Google Scholar]
  32. Rohde M., Warthoe P., Gjetting T., Lukas J., Bartek J., Strauss M. The retinoblastoma protein modulates expression of genes coding for diverse classes of proteins including components of the extracellular matrix. Oncogene. 1996 Jun 6;12(11):2393–2401. [PubMed] [Google Scholar]
  33. Seidl C., Saraiya C., Osterweil Z., Fu Y. P., Lee J. S. Genetic complexity of regulatory mutants defective for HLA class II gene expression. J Immunol. 1992 Mar 1;148(5):1576–1584. [PubMed] [Google Scholar]
  34. Sekaly R. P., Tonnelle C., Strubin M., Mach B., Long E. O. Cell surface expression of class II histocompatibility antigens occurs in the absence of the invariant chain. J Exp Med. 1986 Nov 1;164(5):1490–1504. doi: 10.1084/jem.164.5.1490. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Silvennoinen O., Ihle J. N., Schlessinger J., Levy D. E. Interferon-induced nuclear signalling by Jak protein tyrosine kinases. Nature. 1993 Dec 9;366(6455):583–585. doi: 10.1038/366583a0. [DOI] [PubMed] [Google Scholar]
  36. Steimle V., Durand B., Barras E., Zufferey M., Hadam M. R., Mach B., Reith W. A novel DNA-binding regulatory factor is mutated in primary MHC class II deficiency (bare lymphocyte syndrome). Genes Dev. 1995 May 1;9(9):1021–1032. doi: 10.1101/gad.9.9.1021. [DOI] [PubMed] [Google Scholar]
  37. 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]
  38. Steimle V., Siegrist C. A., Mottet A., Lisowska-Grospierre B., Mach B. Regulation of MHC class II expression by interferon-gamma mediated by the transactivator gene CIITA. Science. 1994 Jul 1;265(5168):106–109. doi: 10.1126/science.8016643. [DOI] [PubMed] [Google Scholar]
  39. Strober B. E., Dunaief J. L., Guha, Goff S. P. Functional interactions between the hBRM/hBRG1 transcriptional activators and the pRB family of proteins. Mol Cell Biol. 1996 Apr;16(4):1576–1583. doi: 10.1128/mcb.16.4.1576. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Ting J. P. Current concepts in DRA gene regulation. Immunol Res. 1993;12(1):65–77. doi: 10.1007/BF02918369. [DOI] [PubMed] [Google Scholar]
  41. Tonnelle C., DeMars R., Long E. O. DO beta: a new beta chain gene in HLA-D with a distinct regulation of expression. EMBO J. 1985 Nov;4(11):2839–2847. doi: 10.1002/j.1460-2075.1985.tb04012.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Tschickardt M. E., Lu Y., Jacim M., Ussery G. D., Steimle V., Mach B., Blanck G. RB and a novel E2F-1 binding protein in MHC class II deficient B-cell lines and normal IFN-gamma induction of the class IL transactivator CIITA in class II non-inducible RB-defective tumor lines. Int J Cancer. 1995 Aug 9;62(4):461–465. doi: 10.1002/ijc.2910620417. [DOI] [PubMed] [Google Scholar]
  43. 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]
  44. Wright K. L., Vilen B. J., Itoh-Lindstrom Y., Moore T. L., Li G., Criscitiello M., Cogswell P., Clarke J. B., Ting J. P. CCAAT box binding protein NF-Y facilitates in vivo recruitment of upstream DNA binding transcription factors. EMBO J. 1994 Sep 1;13(17):4042–4053. doi: 10.1002/j.1460-2075.1994.tb06721.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Zhou H., Glimcher L. H. Human MHC class II gene transcription directed by the carboxyl terminus of CIITA, one of the defective genes in type II MHC combined immune deficiency. Immunity. 1995 May;2(5):545–553. doi: 10.1016/1074-7613(95)90034-9. [DOI] [PubMed] [Google Scholar]

Articles from Nucleic Acids Research are provided here courtesy of Oxford University Press

RESOURCES