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Chromatin remodeling and extragenic transcription at the MHC class II locus control region

Nature Immunology volume 4, pages 132–137 (2003)Cite this article

Abstract

In vivo, a wild-type pattern of major histocompatibility complex (MHC) class II expression requires a locus control region (LCR). Whereas the role of promoter-proximal MHC class II regulatory sequences is well established, the function of the distal LCR remained obscure. We show here that this LCR is bound by the MHC class II-specific transactivators regulatory factor X (RFX) and class II transactivator (CIITA). Binding of these factors induces long-range histone acetylation, RNA polymerase II recruitment and the synthesis of extragenic transcripts within the LCR. The finding that RFX and CIITA regulate the function of the MHC class II LCR reveals an unexpected degree of complexity in the mechanisms controlling MHC class II gene expression.

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Figure 1: Conserved regulatory elements situated upstream of mouse H2-Ea and human HLA-DRA.
Figure 2: The distal HLA-DRA Y'-S' module can function as a transcriptional enhancer.
Figure 3: The MHC class II transactivators RFX and CIITA occupy both the promoter proximal and distal enhancers of human HLA-DRA and murine H2-Ea.
Figure 4: Binding of RFX and CIITA induces a broad pattern of histone acetylation in the HLA-DRA upstream region.
Figure 5: RFX and CIITA recruit TFIID and TFIIB to the promoter, but not to the distal enhancer.
Figure 6: CIITA recruits Pol II to the HLA-DRA upstream region.
Figure 7: CIITA induces extragenic transcripts in the HLA-DRA upstream region.

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References

  1. Cresswell, P. Assembly, transport, and function of MHC class II molecules. Annu. Rev. Immunol. 12, 259–293 (1994).

    Article  CAS  Google Scholar 

  2. Viret, C. & Janeway, C.A.J. MHC and T cell development. Rev. Immunogenet. 1, 91–104 (1999).

    CAS  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. 8, 681–715 (1990).

    Article  CAS  Google Scholar 

  4. Mach, B., Steimle, V., Martinez-Soria, E. & Reith, W. Regulation of MHC class II genes: Lessons from a disease. Annu. Rev. Immunol. 14, 301–331 (1996).

    Article  CAS  Google Scholar 

  5. Reith, W. & Mach, B. The bare lymphocyte syndrome and the regulation of MHC expression. Annu. Rev. Immunol. 19, 331–373 (2001).

    Article  CAS  Google Scholar 

  6. Ting, J.P. & Trowsdale, J. Genetic control of MHC class II expression. Cell 109 (Suppl.), S21–S33 (2002).

    Article  CAS  Google Scholar 

  7. Steimle, V., Otten, L.A., Zufferey, M. & Mach, B. Complementation cloning of an MHC class II transactivator mutated in hereditary MHC class II deficiency. Cell 75, 135–146 (1993).

    Article  CAS  Google Scholar 

  8. Steimle, V. et al. A novel DNA binding regulatory factor is mutated in primary MHC class II deficiency (bare lymphocyte syndrome). Genes Dev. 9, 1021–1032 (1995).

    Article  CAS  Google Scholar 

  9. Durand, B. et al. RFXAP, a novel subunit of the RFX DNA binding complex is mutated in MHC class II deficiency. EMBO J. 16, 1045–1055 (1997).

    Article  CAS  Google Scholar 

  10. Masternak, K. et al. A gene encoding a novel RFX-associated transactivator is mutated in the majority of MHC class II deficiency patients. Nat. Genet. 20, 273–277 (1998).

    Article  CAS  Google Scholar 

  11. Nagarajan, U.M. et al. RFX-B is the gene responsible for the most common cause of the bare lymphocyte syndrome, an MHC class II immunodeficiency. Immunity 10, 153–162 (1999).

    Article  CAS  Google Scholar 

  12. Masternak, K. et al. CIITA is a transcriptional coactivator that is recruited to MHC class II promoters by multiple synergistic interactions with an enhanceosome complex. Genes Dev. 14, 1156–1166 (2000).

    CAS  PubMed Central  Google Scholar 

  13. Masternak, K. & Reith, W. Promoter-specific functions of CIITA and the MHC class II enhanceosome in transcriptional activation. EMBO J. 21, 1379–1388 (2002).

    Article  CAS  Google Scholar 

  14. Brown, J.A., He, X.F., Westerheide, S.D. & Boss, J.M. Characterization of the expressed CIITA allele in the class II MHC transcriptional mutant RJ2.2.5. Immunogenetics 43, 88–91 (1995).

    Article  Google Scholar 

  15. Dorn, A. et al. B cell control region at the 5′ end of a major histocompatibility complex class II gene: sequences and factors. Mol. Cell. Biol. 8, 3975–3987 (1988).

    Article  CAS  Google Scholar 

  16. Carson, S. & Wiles, M.V. Far upstream regions of class II MHC Eα are necessary for position-independent, copy-dependent expression of Eα transgene. Nucleic Acids Res. 21, 2065–2072 (1993).

    Article  CAS  Google Scholar 

  17. Li, Q., Harju, S. & Peterson, K.R. Locus control regions: coming of age at a decade plus. Trends Genet. 15, 403–408 (1999).

    Article  Google Scholar 

  18. Carson, S. DNase I hypersensitive sites flank the mouse class II major histocompatibility complex during B cell development. Nucleic Acids Res. 19, 5007–5014 (1991).

    Article  CAS  Google Scholar 

  19. Feriotto, G. et al. Sequencing of an upstream region of the human HLA-DRA gene containing X' and Y' boxes. Nucleic Acids Res. 23, 1671–1678 (1995).

    Article  CAS  Google Scholar 

  20. Mischiati, C. et al. Analysis of the human HLA-DRA gene upstream region: evidence for a stem-loop array directed by nuclear factors. Biochimie 81, 219–228 (1999).

    Article  CAS  Google Scholar 

  21. Ashe, H.L., Monks, J., Wijgerde, M., Fraser, P. & Proudfoot, N.J. Intergenic transcription and transinduction of the human β-globin locus. Genes Dev. 11, 2494–2509 (1997).

    Article  CAS  Google Scholar 

  22. Gribnau, J., Diderich, K., Pruzina, S., Calzolari, R. & Fraser, P. Intergenic transcription and developmental remodeling of chromatin subdomains in the human β-globin locus. Mol. Cell 5, 377–386 (2000).

    Article  CAS  Google Scholar 

  23. Plant, K.E., Routledge, S.J. & Proudfoot, N.J. Intergenic transcription in the human β-globin gene cluster. Mol. Cell. Biol. 21, 6507–6514 (2001).

    Article  CAS  Google Scholar 

  24. Koch, W., Benoist, C. & Mathis, D. Anatomy of a new B-cell-specific enhancer. Mol. Cell. Biol. 9, 303–311 (1989).

    Article  CAS  Google Scholar 

  25. Forsberg, E.C. & Bresnick, E.H. Histone acetylation beyond promoters: long-range acetylation patterns in the chromatin world. Bioessays 23, 820–830 (2001).

    Article  CAS  Google Scholar 

  26. Elefant, F., Su, Y., Liebhaber, S.A. & Cooke, N.E. Patterns of histone acetylation suggest dual pathways for gene activation by a bifunctional locus control region. EMBO J. 19, 6814–6822 (2000).

    Article  CAS  Google Scholar 

  27. Litt, M.D., Simpson, M., Recillas-Targa, F., Prioleau, M.N. & Felsenfeld, G. Transitions in histone acetylation reveal boundaries of three separately regulated neighboring loci. EMBO J. 20, 2224–2235 (2001).

    Article  CAS  Google Scholar 

  28. Beresford, G.W. & Boss, J.M. CIITA coordinates multiple histone acetylation modifications at the HLA-DRA promoter. Nat. Immunol. 2, 652–657 (2001).

    Article  CAS  Google Scholar 

  29. Wuarin, J. & Schibler, U. Physical isolation of nascent RNA chains transcribed by RNA polymerase II: evidence for cotranscriptional splicing. Mol. Cell. Biol. 14, 7219–7225 (1994).

    Article  CAS  Google Scholar 

  30. Chowdhury, D. & Sen, R. Stepwise activation of the immunoglobulin μ heavy chain gene locus. EMBO J. 20, 6394–6403 (2001).

    Article  CAS  Google Scholar 

  31. Leach, K.M. et al. Reconstitution of human β-globin locus control region hypersensitive sites in the absence of chromatin assembly. Mol. Cell. Biol. 21, 2629–2640 (2001).

    Article  CAS  Google Scholar 

  32. Johnson, K.D., Christensen, H.M., Zhao, B. & Bresnick, E.H. Distinct mechanisms control RNA polymerase II recruitment to a tissue-specific locus control region and a downstream promoter. Mol. Cell 8, 465–471 (2001).

    Article  CAS  Google Scholar 

  33. Bulger, M. & Groudine, M. Looping versus linking: toward a model for long-distance gene activation. Genes Dev. 13, 2465–2477 (1999).

    Article  CAS  Google Scholar 

  34. Blackwood, E.M. & Kadonaga, J.T. Going the distance: a current view of enhancer action. Science 281, 61–63 (1998).

    Article  Google Scholar 

  35. Engel, J.D. & Tanimoto, K. Looping, linking, and chromatin activity: new insights into β-globin locus regulation. Cell 100, 499–502 (2000).

    Article  CAS  Google Scholar 

  36. Schubeler, D., Groudine, M. & Bender, M.A. The murine β-globin locus control region regulates the rate of transcription but not the hyperacetylation of histones at the active genes. Proc. Natl. Acad. Sci. USA 98, 11432–11437 (2001).

    Article  CAS  Google Scholar 

  37. Travers, A. Chromatin modification by DNA tracking. Proc. Natl. Acad. Sci. USA 96, 13634–13637 (1999).

    Article  CAS  Google Scholar 

  38. Orphanides, G. & Reinberg, D. RNA polymerase II elongation through chromatin. Nature 407, 471–475 (2000).

    Article  CAS  Google Scholar 

  39. Wittschieben, B.O. et al. A novel histone acetyltransferase is an integral subunit of elongating RNA polymerase II holoenzyme. Mol. Cell 4, 123–128 (1999).

    Article  CAS  Google Scholar 

  40. Linhoff, M.W., Harton, J.A., Cressman, D.E., Martin, B.K. & Ting, J.P. Two distinct domains within CIITA mediate self-association: involvement of the GTP-binding and leucine-rich repeat domains. Mol. Cell. Biol. 21, 3001–3011 (2001).

    Article  CAS  Google Scholar 

  41. Sisk, T.J., Roys, S. & Chang, C.H. Self-association of CIITA and its transactivation potential. Mol. Cell. Biol. 21, 4919–4928 (2001).

    Article  CAS  Google Scholar 

  42. Accolla, R.S. Human B cell variants immunoselected against a single Ia antigen subset have lost expression in several Ia antigen subsets. J. Exp. Med. 157, 1053–1058 (1983).

    Article  CAS  Google Scholar 

  43. Hume, C.R., Shookster, L.A., Collins, N., O'Reilly, R. & Lee, J.S. Bare lymphocyte syndrome: altered HLA class II expression in B cell lines derived from two patients. Hum. Immunol. 25, 1–11 (1989).

    Article  CAS  Google Scholar 

  44. Tsang, S.Y., Nakanishi, M. & Peterlin, B.M. Mutational analysis of the DRA promoter: cis-acting sequences and trans-acting factors. Mol. Cell. Biol. 10, 711–719 (1990).

    Article  CAS  Google Scholar 

  45. Bontron, S., Ucla, C., Mach, B. & Steimle, V. Efficient repression of endogenous major histocompatibility complex class II expression through dominant negative CIITA mutants isolated by a functional selection strategy. Mol. Cell. Biol. 17, 4249–4258 (1997).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank A. Muhlethaler-Mottet for providing the pDRAprox plasmid; N. Hernandez and J. Svejstrup for providing antibodies; M. Zufferey and S. Landmann for help with cell culture and real-time PCR; and M. Strubin for valuable discussions. This work was supported by grants from the Swiss National Science Foundation and NovImmune SA.

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  1. Krzysztof Masternak

    Present address: NovImmune SA, CH-1211, Geneva, Switzerland

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  1. University of Geneva Medical School, CMU, Geneva, CH-1211, Switzerland

    Krzysztof Masternak, Nicolas Peyraud, Michal Krawczyk, Emmanuèle Barras & Walter Reith

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Masternak, K., Peyraud, N., Krawczyk, M. et al. Chromatin remodeling and extragenic transcription at the MHC class II locus control region. Nat Immunol 4, 132–137 (2003). https://doi.org/10.1038/ni883

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