Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

PRDI-BF1 recruits the histone H3 methyltransferase G9a in transcriptional silencing

Nature Immunology volume 5, pages 299–308 (2004)Cite this article

Abstract

PRDI-BF1, the human ortholog of mouse Blimp-1, is a DNA-binding protein involved in postinduction repression of interferon-β gene transcription in response to viral infection. PRDI-BF1 also has an essential function in driving terminal differentiation of B lymphocytes and therein silences multiple genes. Here we show PRDI-BF1 assembles silent chromatin over the interferon-β promoter in the osteosarcoma cell line U2OS through recruitment of the histone H3 lysine methyltransferase G9a. G9a is recruited only when in a complex with PRDI-BF1. G9a catalytic activity is required for the accumulation of methylated histone H3 and transcriptional silencing mediated by PRDI-BF1 in vivo. This establishes a mechanism for the recruitment of G9a, the main mammalian euchromatic methyltransferase, and defines nonembryonic targets of G9a.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: PRDI-BF1 complexes contain histone H3 methyltransferase activity independent of the PR domain.
Figure 2: In vitro reconstitution of the PRDI-BF1 methyltransferase activity.
Figure 3: PRDI-BF1-mediated methyltransferase activity is specific for lysine 9 of histone H3.
Figure 4: Deletion of the first two zinc fingers of PRDI-BF1 abolishes the methyltransferase activity and impairs transcriptional repression without disrupting deacetylase activity.
Figure 5: G9a specifically associates with PRDI-BF1.
Figure 6: PRDI-BF1 binds the IFNB1 promoter in vivo, increases H3-K9 methylation and silences transcription.
Figure 7: Catalytically active G9a silences transcription at the IFNB1 promoter through PRDI-BF1.

Similar content being viewed by others

References

  1. Keller, A.D. & Maniatis, T. Identification and characterization of a novel repressor of β-interferon gene expression. Genes Dev. 5, 868–879 (1991).

    Article  CAS  Google Scholar 

  2. Keller, A.D. & Maniatis, T. Only two of the five zinc fingers of the eukaryotic transcriptional repressor PRDI-BF1 are required for sequence-specific DNA binding. Mol. Cell. Biol. 12, 1940–1949 (1992).

    Article  CAS  Google Scholar 

  3. Calame, K.L., Lin, K.I. & Tunyaplin, C. Regulatory mechanisms that determine the development and function of plasma cells. Annu. Rev. Immunol. 21, 205–230 (2003).

    Article  CAS  Google Scholar 

  4. Angelin-Duclos, C., Cattoretti, G., Lin, K.I. & Calame, K. Commitment of B lymphocytes to a plasma cell fate is associated with Blimp-1 expression in vivo . J. Immunol. 165, 5462–5471 (2000).

    Article  CAS  Google Scholar 

  5. Turner, C.A., Jr., Mack, D.H. & Davis, M.M. Blimp-1, a novel zinc finger-containing protein that can drive the maturation of B lymphocytes into immunoglobulin-secreting cells. Cell 77, 297–306 (1994).

    Article  CAS  Google Scholar 

  6. Messika, E.J. et al. Differential effect of B lymphocyte-induced maturation protein (Blimp-1) expression on cell fate during B cell development. J. Exp. Med. 188, 515–525 (1998).

    Article  CAS  Google Scholar 

  7. Lin, Y., Wong, K. & Calame, K. Repression of c-myc transcription by Blimp-1, an inducer of terminal B cell differentiation. Science 276, 596–599 (1997).

    Article  CAS  Google Scholar 

  8. Shapiro-Shelef, M. et al. Blimp-1 is required for the formation of immunoglobulin secreting plasma cells and pre-plasma memory B cells. Immunity 19, 607–620 (2003).

    Article  CAS  Google Scholar 

  9. Shaffer, A.L. et al. Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program. Immunity 17, 51–62 (2002).

    Article  CAS  Google Scholar 

  10. Lin, K., Angelin-Duclos, C., Kuo, T.C. & Calame, K. Blimp-1-dependent repression of Pax-5 is required for differentiation of B cells to immunoglobulin M-secreting plasma cells. Mol. Cell. Biol. 22, 4771–4780 (2002).

    Article  CAS  Google Scholar 

  11. Piskurich, J.F. et al. BLIMP-I mediates extinction of major histocompatibility class II transactivator expression in plasma cells. Nat. Immunol. 1, 526–532 (2000).

    Article  CAS  Google Scholar 

  12. Ghosh, N., Gyory, I., Wright, G., Wood, J. & Wright, K.L. Positive regulatory domain I binding factor 1 silences class II transactivator expression in multiple myeloma cells. J. Biol. Chem. 276, 15264–15268 (2001).

    Article  CAS  Google Scholar 

  13. Funabiki, T., Kreider, B.L. & Ihle, J.N. The carboxyl domain of zinc fingers of the Evi-1 myeloid transforming gene binds a consensus sequence of GAAGATGAG. Oncogene 9, 1575–1581 (1994).

    CAS  PubMed  Google Scholar 

  14. Xie, M., Shao, G., Buyse, I.M. & Huang, S. Transcriptional repression mediated by the PR domain zinc finger gene RIZ. J. Biol. Chem. 272, 26360–26366 (1997).

    Article  CAS  Google Scholar 

  15. Abel, K.J. et al. Characterization of EZH1, a human homolog of Drosophila enhancer of zeste near BRCA1. Genomics 37, 161–171 (1996).

    Article  CAS  Google Scholar 

  16. Jenuwein, T., Laible, G., Dorn, R. & Reuter, G. SET domain proteins modulate chromatin domains in eu- and heterochromatin. Cell. Mol. Life Sci. 54, 80–93 (1998).

    Article  CAS  Google Scholar 

  17. Firestein, R., Cui, X., Huie, P. & Cleary, M.L. Set domain-dependent regulation of transcriptional silencing and growth control by SUV39H1, a mammalian ortholog of Drosophila Su(var)3-9. Mol. Cell. Biol. 20, 4900–4909 (2000).

    Article  CAS  Google Scholar 

  18. Lachner, M. & Jenuwein, T. The many faces of histone lysine methylation. Curr. Opin. Cell Biol. 14, 286–298 (2002).

    Article  CAS  Google Scholar 

  19. Kouzarides, T. Histone methylation in transcriptional control. Curr. Opin. Genet. Dev. 12, 198–209 (2002).

    Article  CAS  Google Scholar 

  20. Fears, S. et al. Intergenic splicing of MDS1 and EVI1 occurs in normal tissues as well as in myeloid leukemia and produces a new member of the PR domain family. Proc. Natl. Acad. Sci. USA 93, 1642–1647 (1996).

    Article  CAS  Google Scholar 

  21. Liu, L., Shao, G., Steele-Perkins, G. & Huang, S. The retinoblastoma interacting zinc finger gene RIZ produces a PR domain-lacking product through an internal promoter. J. Biol. Chem. 272, 2984–2991 (1997).

    Article  CAS  Google Scholar 

  22. Gyory, I., Fejer, G., Ghosh, N., Seto, E. & Wright, K.L. Identification of a functionally impaired positive regulatory domain I binding factor 1 transcription repressor in myeloma cell lines. J. Immunol. 170, 3125–3133 (2003).

    Article  Google Scholar 

  23. Fichelson, S. et al. Evi-1 expression in leukemic patients with rearrangements of the 3q25-q28 chromosomal region. Leukemia 6, 93–99 (1992).

    CAS  PubMed  Google Scholar 

  24. He, L. et al. RIZ1, but not the alternative RIZ2 product of the same gene, is underexpressed in breast cancer, and forced RIZ1 expression causes G2-M cell cycle arrest and/or apoptosis. Cancer Res. 58, 4238–4244 (1998).

    CAS  PubMed  Google Scholar 

  25. Jiang, G., Liu, L., Buyse, I.M., Simon, D. & Huang, S. Decreased RIZ1 expression but not RIZ2 in hepatoma and suppression of hepatoma tumorigenicity by RIZ1. Int. J. Cancer 83, 541–546 (1999).

    Article  CAS  Google Scholar 

  26. Ren, B., Chee, K.J., Kim, T.H. & Maniatis, T. PRDI-BF1/Blimp-1 repression is mediated by corepressors of the Groucho family of proteins. Genes Dev. 13, 125–137 (1999).

    Article  CAS  Google Scholar 

  27. Chen, G., Fernandez, J., Mische, S. & Courey, A.J. A functional interaction between the histone deacetylase Rpd3 and the corepressor groucho in Drosophila development. Genes Dev. 13, 2218–2230 (1999).

    Article  CAS  Google Scholar 

  28. Yu, J., Angelin-Duclos, C., Greenwood, J., Liao, J. & Calame, K. Transcriptional repression by blimp-1 (PRDI-BF1) involves recruitment of histone deacetylase. Mol. Cell. Biol. 20, 2592–2603 (2000).

    Article  CAS  Google Scholar 

  29. Tachibana, M., Sugimoto, K., Fukushima, T. & Shinkai, Y. Set domain-containing protein, G9a, is a novel lysine-preferring mammalian histone methyltransferase with hyperactivity and specific selectivity to lysines 9 and 27 of histone H3. J. Biol. Chem. 276, 25309–25317 (2001).

    Article  CAS  Google Scholar 

  30. Rea, S. et al. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 406, 593–599 (2000).

    Article  CAS  Google Scholar 

  31. Yang, L. et al. Molecular cloning of ESET, a novel histone H3-specific methyltransferase that interacts with ERG transcription factor. Oncogene 21, 148–152 (2002).

    Article  CAS  Google Scholar 

  32. Schultz, D.C., Ayyanathan, K., Negorev, D., Maul, G.G. & Rauscher, F.J., 3rd. SETDB1: a novel KAP-1-associated histone H3, lysine 9-specific methyltransferase that contributes to HP1-mediated silencing of euchromatic genes by KRAB zinc-finger proteins. Genes Dev. 16, 919–932 (2002).

    Article  CAS  Google Scholar 

  33. Ogawa, H., Ishiguro, K., Gaubatz, S., Livingston, D.M. & Nakatani, Y.A complex with chromatin modifiers that occupies E2F- and Myc-responsive genes in G0 cells. Science 296, 1132–1136 (2002).

    Article  CAS  Google Scholar 

  34. Tachibana, M. et al. G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. Genes Dev. 16, 1779–1791 (2002).

    Article  CAS  Google Scholar 

  35. Peters, A.H. et al. Loss of the Suv39h histone methyltransferases impairs mammalian heterochromatin and genome stability. Cell 107, 323–337 (2001).

    Article  CAS  Google Scholar 

  36. Rice, J.C. et al. Histone methyltransferases direct different degrees of methylation to define distinct chromatin domains. Mol. Cell 12, 1591–1598 (2003).

    Article  CAS  Google Scholar 

  37. Peters, A.H. et al. Partitioning and plasticity of repressive histone methylation states in mammalian chromatin. Mol. Cell 12, 1577–1589 (2003).

    Article  CAS  Google Scholar 

  38. Jenuwein, T. & Allis, C.D. Translating the histone code. Science 293, 1074–1080 (2001).

    Article  CAS  Google Scholar 

  39. Ayyanathan, K. et al. Regulated recruitment of HP1 to a euchromatic gene induces mitotically heritable, epigenetic gene silencing: a mammalian cell culture model of gene variegation. Genes Dev. 17, 1855–1869 (2003).

    Article  CAS  Google Scholar 

  40. Lomvardas, S. & Thanos, D. Modifying gene expression programs by altering core promoter chromatin architecture. Cell 110, 261–271 (2002).

    Article  CAS  Google Scholar 

  41. Zhang, X. et al. Structural basis for the product specificity of histone lysine methyltransferases. Mol. Cell 12, 177–185 (2003).

    Article  Google Scholar 

  42. Zhang, X. et al. Structure of the Neurospora SET domain protein DIM-5, a histone H3 lysine methyltransferase. Cell 111, 117–127 (2002).

    Article  CAS  Google Scholar 

  43. Wang, H. et al. Purification and functional characterization of a histone h3-lysine 4- specific methyltransferase. Mol. Cell 8, 1207–1217 (2001).

    Article  CAS  Google Scholar 

  44. Nishioka, K. et al. Set9, a novel histone H3 methyltransferase that facilitates transcription by precluding histone tail modifications required for heterochromatin formation. Genes Dev. 16, 479–489 (2002).

    Article  CAS  Google Scholar 

  45. Lachner, M., O'Sullivan, R.J. & Jenuwein, T. An epigenetic road map for histone lysine methylation. J. Cell Sci. 116, 2117–2124 (2003).

    Article  CAS  Google Scholar 

  46. Huang, S. Histone methyltransferases, diet nutrients and tumour suppressors. Nat. Rev. Cancer 2, 469–476 (2002).

    Article  CAS  Google Scholar 

  47. Turner, B.M. Memorable transcription. Nat. Cell Biol. 5, 390–393 (2003).

    Article  CAS  Google Scholar 

  48. Vandel, L. et al. Transcriptional repression by the retinoblastoma protein through the recruitment of a histone methyltransferase. Mol. Cell. Biol. 21, 6484–6494 (2001).

    Article  CAS  Google Scholar 

  49. Nielsen, S.J. et al. Rb targets histone H3 methylation and HP1 to promoters. Nature 412, 561–565 (2001).

    Article  CAS  Google Scholar 

  50. Trimarchi, J.M. & Lees, J.A. Sibling rivalry in the E2F family. Nat. Rev. Mol. Cell. Biol. 3, 11–20 (2002).

    Article  CAS  Google Scholar 

  51. Oberley, M.J., Inman, D.R. & Farnham, P.J. E2F6 negatively regulates BRCA1 in human cancer cells without methylation of histone H3 on lysine 9. J. Biol. Chem. 278, 42466–42476 (2003).

    Article  CAS  Google Scholar 

  52. Yang, W.M., Tsai, S.C., Wen, Y.D., Fejer, G. & Seto, E. Functional domains of histone deacetylase-3. J. Biol. Chem. 277, 9447–9454 (2002).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Supported in part by the National Institutes of Health (CA80990), the American Cancer Society (ACS-IRG 032) and the Molecular Biology Core Facility and Molecular Imaging Core Facility at the H. Lee Moffitt Cancer Center and Research Institute.

Author information

Author notes

  1. Ildikó Győry

    Present address: Microbiological Research Group, National Center for Epidemiology, Budapest, H-1529, Hungary

  2. György Fejér

    Present address: Veterinary Medical Research Institute, Hungarian Academy of Sciences, H-1582, Budapest, Hungary

  3. Jian Wu and György Fejér: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, 12902 Magnolia Drive, MRC4East, Tampa, 33612, Florida, USA

    Ildikó Győry & Jian Wu

  2. Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, 12902 Magnolia Drive, MRC4East, Tampa, 33612, Florida, USA

    György Fejér, Edward Seto & Kenneth L Wright

Authors
  1. Ildikó Győry
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jian Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. György Fejér
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Edward Seto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kenneth L Wright
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kenneth L Wright.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Győry, I., Wu, J., Fejér, G. et al. PRDI-BF1 recruits the histone H3 methyltransferase G9a in transcriptional silencing. Nat Immunol 5, 299–308 (2004). https://doi.org/10.1038/ni1046

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni1046

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing