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Gene Review

HLA-DRA  -  major histocompatibility complex, class II...

Homo sapiens

Synonyms: HLA class II histocompatibility antigen, DR alpha chain, HLA-DRA1, MHC class II antigen DRA, MLRW
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Disease relevance of HLA-DRA


High impact information on HLA-DRA

  • CIITA coordinates multiple histone acetylation modifications at the HLA-DRA promoter [6].
  • Multiple regulatory elements in the hXBP-1 promoter lie 3' to the transcription start site, including the hX2 site, whose core sequence is an AP-1-like element identical to the hXBP-1 target sequence in the HLA-DRA promoter [7].
  • 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 [8].
  • Thus, Oct-2A and HMG I/Y may synergize to activate HLA-DRA expression in B cells [8].
  • 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 [8].

Chemical compound and disease context of HLA-DRA

  • In addition, we have found that the distribution of these HLA-DRA mRNA binding proteins is different in different cell types; in particular, their pattern of expression in Ntera-2, a human teratocarcinoma cell line, is distinct from that observed in Raji, a human B-lymphoma cell line, and is modulated by growth in retinoic acid [9].

Biological context of HLA-DRA

  • Thus, HDAC-mediated repression of the HLA-DRA promoter occurs following the establishment of an apparent nucleosome-free promoter region and before transcriptionally productive occupancy of the promoter by the required transactivators [1].
  • Transient transfection studies using a fully functional HLA-DRA promoter construct ([-300]DR alpha.CAT) showed that inhibition of endogenous NO synthase activity by N(omega)-monomethyl-l-arginine or addition of exogenous hydrogen peroxide (H(2)O(2)) augmented basal and IFN-gamma-stimulated [-300]DR alpha.CAT activity [10].
  • The histone code associated with the XL boxes and that of the HLA-DRA X box was determined [11].
  • Localization of IFN-gamma receptor in first trimester placenta to trophoblasts but lack of stimulation of HLA-DRA, -DRB, or invariant chain mRNA expression by IFN-gamma [12].
  • Description of a polymorphism in the regulatory region of the HLA-DRA gene [13].

Anatomical context of HLA-DRA


Associations of HLA-DRA with chemical compounds


Physical interactions of HLA-DRA

  • In the case of the HLA-DRA gene, which encodes the HLA-DR heavy chain, previous work has indicated that this loss of inducibility is attributable to Oct-1 binding to the HLA-DRA promoter [20].

Regulatory relationships of HLA-DRA

  • Nuclear run-on assays demonstrated that NO and antioxidants inhibited IFN-gamma-induced HLA-DRA gene transcription [10].
  • In this report, we used Oct-1 antisense transformants to determine that Oct-1 represses the interferon-gamma response of the endogenous HLA-DRA gene [20].
  • Transient cotransfection of a construct in which CIITA is under the control of a constitutive promoter with an HLA-DRA promoter-luciferase reporter plasmid resulted in enhanced luciferase expression in ABI fibroblasts [21].
  • Direct role of NF-kappaB activation in Toll-like receptor-triggered HLA-DRA expression [22].

Other interactions of HLA-DRA

  • Mutation of the octamer element also significantly reduced the ability of HDAC1 to confer repression of inducible HLA-DRA promoter activation [1].
  • Regarding the temporal relationship, a significant increase of whole-blood HLA-DRA, -DMA, -DMB, invariant chain, and CIITA mRNA level was observed in survivors (p = .001), whereas expressions remained low in nonsurvivors [23].
  • We thus investigated the binding capacity of the HLA-G X box in comparison to that of HLA-DRA and HLA-E [24].
  • Chromatin immunoprecipitation experiments localized YY1 to the HLA-DRA gene in Rb-defective tumor cells [1].
  • In vitro DNA-protein binding analyses indicated that Oct-1 prevents HLA-DRA promoter activation by mediating the formation of a complex of proteins, termed DRAN (DRA negative), that blocks NF-Y access to the promoter [20].

Analytical, diagnostic and therapeutic context of HLA-DRA


  1. Histone deacetylase activity represses gamma interferon-inducible HLA-DR gene expression following the establishment of a DNase I-hypersensitive chromatin conformation. Osborne, A., Zhang, H., Yang, W.M., Seto, E., Blanck, G. Mol. Cell. Biol. (2001) [Pubmed]
  2. 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. Lu, Y., Boss, J.M., Hu, S.X., Xu, H.J., Blanck, G. J. Immunol. (1996) [Pubmed]
  3. Suppression of MHC class II expression by human class II trans-activator constructs lacking the N-terminal domain. Yun, S., Gustafsson, K., Fabre, J.W. Int. Immunol. (1997) [Pubmed]
  4. HLA-DMB gene and HLA-DRA promoter region polymorphisms in Australian multiple sclerosis patients. Bennetts, B.H., Teutsch, S.M., Buhler, M.M., Heard, R.N., Stewart, G.J. Hum. Immunol. (1999) [Pubmed]
  5. Anomalous expression of the HLA-DR alpha and beta chains in ovarian and other cancers. Rangel, L.B., Agarwal, R., Sherman-Baust, C.A., Mello-Coelho, V., Pizer, E.S., Ji, H., Taub, D.D., Morin, P.J. Cancer Biol. Ther. (2004) [Pubmed]
  6. CIITA coordinates multiple histone acetylation modifications at the HLA-DRA promoter. Beresford, G.W., Boss, J.M. Nat. Immunol. (2001) [Pubmed]
  7. Transcription factor B cell lineage-specific activator protein regulates the gene for human X-box binding protein 1. Reimold, A.M., Ponath, P.D., Li, Y.S., Hardy, R.R., David, C.S., Strominger, J.L., Glimcher, L.H. J. Exp. Med. (1996) [Pubmed]
  8. Functional roles of the transcription factor Oct-2A and the high mobility group protein I/Y in HLA-DRA gene expression. Abdulkadir, S.A., Krishna, S., Thanos, D., Maniatis, T., Strominger, J.L., Ono, S.J. J. Exp. Med. (1995) [Pubmed]
  9. Control of nucleo-cytoplasmic HLA-DRA mRNA partitioning by interaction of a retention signal with compartmentalized proteins. Del Pozzo, G., Ciullo, M., Autiero, M., Guardiola, J. J. Mol. Biol. (1994) [Pubmed]
  10. Inhibition of major histocompatibility complex class II gene transcription by nitric oxide and antioxidants. Grimm, M., Spiecker, M., De Caterina, R., Shin, W.S., Liao, J.K. J. Biol. Chem. (2002) [Pubmed]
  11. X box-like sequences in the MHC class II region maintain regulatory function. Gomez, J.A., Majumder, P., Nagarajan, U.M., Boss, J.M. J. Immunol. (2005) [Pubmed]
  12. Localization of IFN-gamma receptor in first trimester placenta to trophoblasts but lack of stimulation of HLA-DRA, -DRB, or invariant chain mRNA expression by IFN-gamma. Peyman, J.A., Hammond, G.L. J. Immunol. (1992) [Pubmed]
  13. Description of a polymorphism in the regulatory region of the HLA-DRA gene. Pinet, V., Eliaou, J.F., Clot, J. Hum. Immunol. (1991) [Pubmed]
  14. Tumor HLA-DR expression linked to early intrahepatic recurrence of hepatocellular carcinoma. Matoba, K., Iizuka, N., Gondo, T., Ishihara, T., Yamada-Okabe, H., Tamesa, T., Takemoto, N., Hashimoto, K., Sakamoto, K., Miyamoto, T., Uchimura, S., Hamamoto, Y., Oka, M. Int. J. Cancer (2005) [Pubmed]
  15. HLA-DRA promoter polymorphism and diversity generation within the immune system. Schwiebert, L.M., Hughes, A., Monos, D.S., Ono, S.J. Hum. Genet. (1997) [Pubmed]
  16. 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. Ono, S.J., Liou, H.C., Davidon, R., Strominger, J.L., Glimcher, L.H. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  17. Lack of IFN-gamma-mediated induction of the class II transactivator (CIITA) through promoter methylation is predominantly found in developmental tumor cell lines. van der Stoep, N., Biesta, P., Quinten, E., van den Elsen, P.J. Int. J. Cancer (2002) [Pubmed]
  18. Tumor necrosis factor alpha response elements in the HLA-DRA promoter: identification of a tumor necrosis factor alpha-induced DNA-protein complex in astrocytes. Panek, R.B., Moses, H., Ting, J.P., Benveniste, E.N. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  19. Methylation state of the human HLA-DRA gene in T-lymphocytes and B-lymphocytes of transgenic mice. Lack of methylation at one 5'-GCGC site is not required for gene expression. Feriotto, G., Pozzi, L., Ciucci, A., Camarda, G., Mischiati, C., D'Agnano, I., Gambari, R., Giacomini, P. Eur. J. Biochem. (1993) [Pubmed]
  20. Oct-1 maintains an intermediate, stable state of HLA-DRA promoter repression in Rb-defective cells: an Oct-1-containing repressosome that prevents NF-Y binding to the HLA-DRA promoter. Osborne, A.R., Zhang, H., Fejer, G., Palubin, K.M., Niesen, M.I., Blanck, G. J. Biol. Chem. (2004) [Pubmed]
  21. Introduction of exogenous class II trans-activator in MHC class II-deficient ABI fibroblasts results in incomplete rescue of MHC class II antigen expression. Peijnenburg, A., Gobin, S.J., van Eggermond, M.C., Godthelp, B.C., van Graafeiland, N., van den Elsen, P.J. J. Immunol. (1997) [Pubmed]
  22. Direct role of NF-kappaB activation in Toll-like receptor-triggered HLA-DRA expression. Lee, K.W., Lee, Y., Kim, D.S., Kwon, H.J. Eur. J. Immunol. (2006) [Pubmed]
  23. Messenger RNA expression of major histocompatibility complex class II genes in whole blood from septic shock patients. Pachot, A., Monneret, G., Brion, A., Venet, F., Bohé, J., Bienvenu, J., Mougin, B., Lepape, A. Crit. Care Med. (2005) [Pubmed]
  24. The X1 box of HLA-G promoter is a target site for RFX and Sp1 factors. Rousseau, P., Paul, P., O'Brien, M., Dausset, J., Carosella, E.D., Moreau, P. Hum. Immunol. (2000) [Pubmed]
  25. Characterization of a major histocompatibility complex class II X-box-binding protein enhancing tat-induced transcription directed by the human immunodeficiency virus type 1 long terminal repeat. Mischiati, C., Feriotto, G., Borgatti, M., Giacomini, P., Gambari, R. J. Virol. (2000) [Pubmed]
  26. Analysis of the human HLA-DRA gene upstream region: evidence for a stem-loop array directed by nuclear factors. Mischiati, C., Feriotto, G., Bianchi, N., Rutigliano, C., Giacomini, P., Gambari, R. Biochimie (1999) [Pubmed]
  27. Serial peripheral blood cytotoxic lymphocyte gene expression measurements for prediction of pancreas transplant rejection. Cashion, A.K., Sabek, O.M., Driscoll, C.J., Gaber, L.W., Gaber, A.O. Transplant. Proc. (2006) [Pubmed]
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