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.

Methylation of histone H3R2 by PRMT6 and H3K4 by an MLL complex are mutually exclusive

Nature volume 449, pages 933–937 (2007)Cite this article

Abstract

Eukaryotic genomes are organized into active (euchromatic) and inactive (heterochromatic) chromatin domains. Post-translational modifications of histones (or ‘marks’) are key in defining these functional states, particularly in promoter regions1,2. Mutual regulatory interactions between these marks—and the enzymes that catalyse them—contribute to the shaping of this epigenetic landscape, in a manner that remains to be fully elucidated1,2. We previously observed that asymmetric di-methylation of histone H3 arginine 2 (H3R2me2a) counter-correlates with di- and tri- methylation of H3 lysine 4 (H3K4me2, H3K4me3) on human promoters3. Here we show that the arginine methyltransferase PRMT6 catalyses H3R2 di-methylation in vitro and controls global levels of H3R2me2a in vivo. H3R2 methylation by PRMT6 was prevented by the presence of H3K4me3 on the H3 tail. Conversely, the H3R2me2a mark prevented methylation of H3K4 as well as binding to the H3 tail by an ASH2/WDR5/MLL-family methyltransferase complex4,5,6,7. Chromatin immunoprecipitation showed that H3R2me2a was distributed within the body and at the 3′ end of human genes, regardless of their transcriptional state, whereas it was selectively and locally depleted from active promoters, coincident with the presence of H3K4me3. Hence, the mutual antagonism between H3R2 and H3K4 methylation, together with the association of MLL-family complexes with the basal transcription machinery8, may contribute to the localized patterns of H3K4 tri-methylation characteristic of transcriptionally poised or active promoters in mammalian genomes1,2,3,9,10.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

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

Figure 1: H3R2me2a is present on inactive promoters, and within genes independently from the expression status.
Figure 2: H3R2 methylation by PRMT6 is prevented by H3K4me3.
Figure 3: H3R2me2a excludes binding of WDR5 to the H3 tail.
Figure 4: H3R2me2a and MLL complex subunits are counter-correlated on chromatin.

References

  1. Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007)

    Article  CAS  Google Scholar 

  2. Li, B., Carey, M. & Workman, J. L. The role of chromatin during transcription. Cell 128, 707–719 (2007)

    Article  CAS  Google Scholar 

  3. Guccione, E. et al. Myc-binding-site recognition in the human genome is determined by chromatin context. Nature Cell Biol. 8, 764–770 (2006)

    Article  CAS  Google Scholar 

  4. Tenney, K. & Shilatifard, A. A. COMPASS in the voyage of defining the role of trithorax/MLL-containing complexes: linking leukemogensis to covalent modifications of chromatin. J. Cell. Biochem. 95, 429–436 (2005)

    Article  CAS  Google Scholar 

  5. Wysocka, J., Myers, M. P., Laherty, C. D., Eisenman, R. N. & Herr, W. Human Sin3 deacetylase and trithorax-related Set1/Ash2 histone H3–K4 methyltransferase are tethered together selectively by the cell-proliferation factor HCF-1. Genes Dev. 17, 896–911 (2003)

    Article  CAS  Google Scholar 

  6. Hughes, C. M. et al. Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus. Mol. Cell 13, 587–597 (2004)

    Article  CAS  Google Scholar 

  7. Steward, M. M. et al. Molecular regulation of H3K4 trimethylation by ASH2L, a shared subunit of MLL complexes. Nature Struct. Mol. Biol. 13, 852–854 (2006)

    Article  CAS  Google Scholar 

  8. Hampsey, M. & Reinberg, D. Tails of intrigue: phosphorylation of RNA polymerase II mediates histone methylation. Cell 113, 429–432 (2003)

    Article  CAS  Google Scholar 

  9. Bernstein, B. E. et al. Genomic maps and comparative analysis of histone modifications in human and mouse. Cell 120, 169–181 (2005)

    Article  CAS  Google Scholar 

  10. Kouskouti, A. & Talianidis, I. Histone modifications defining active genes persist after transcriptional and mitotic inactivation. EMBO J. 24, 347–357 (2005)

    Article  CAS  Google Scholar 

  11. Bedford, M. T. & Richard, S. Arginine methylation: an emerging regulator of protein function. Mol. Cell 18, 263–272 (2005)

    Article  CAS  Google Scholar 

  12. Krause, C. D. et al. Protein arginine methyltransferases: evolution and assessment of their pharmacological and therapeutic potential. Pharmacol. Ther. 113, 50–87 (2007)

    Article  CAS  Google Scholar 

  13. Maurer-Stroh, S. et al. The Tudor domain 'Royal Family': Tudor, plant Agenet, Chromo, PWWP and MBT domains. Trends Biochem. Sci. 28, 69–74 (2003)

    Article  CAS  Google Scholar 

  14. Sims, R. J. & Reinberg, D. Histone H3 Lys 4 methylation: caught in a bind? Genes Dev. 20, 2779–2786 (2006)

    Article  CAS  Google Scholar 

  15. Strahl, B. D. et al. Methylation of histone H4 at arginine 3 occurs in vivo and is mediated by the nuclear receptor coactivator PRMT1. Curr. Biol. 11, 996–1000 (2001)

    Article  CAS  Google Scholar 

  16. Huang, S., Litt, M. & Felsenfeld, G. Methylation of histone H4 by arginine methyltransferase PRMT1 is essential in vivo for many subsequent histone modifications. Genes Dev. 19, 1885–1893 (2005)

    Article  CAS  Google Scholar 

  17. Daujat, S. et al. Crosstalk between CARM1 methylation and CBP acetylation on histone H3. Curr. Biol. 12, 2090–2097 (2002)

    Article  CAS  Google Scholar 

  18. Bauer, U. M., Daujat, S., Nielsen, S. J., Nightingale, K. & Kouzarides, T. Methylation at arginine 17 of histone H3 is linked to gene activation. EMBO Rep. 3, 39–44 (2002)

    Article  CAS  Google Scholar 

  19. Covic, M. et al. Arginine methyltransferase CARM1 is a promoter-specific regulator of NF-κB-dependent gene expression. EMBO J. 24, 85–96 (2005)

    Article  CAS  Google Scholar 

  20. Schurter, B. T. et al. Methylation of histone H3 by coactivator-associated arginine methyltransferase 1. Biochemistry 40, 5747–5756 (2001)

    Article  CAS  Google Scholar 

  21. Torres-Padilla, M. E., Parfitt, D. E., Kouzarides, T. & Zernicka-Goetz, M. Histone arginine methylation regulates pluripotency in the early mouse embryo. Nature 445, 214–218 (2007)

    Article  ADS  CAS  Google Scholar 

  22. Wysocka, J. et al. WDR5 associates with histone H3 methylated at K4 and is essential for H3 K4 methylation and vertebrate development. Cell 121, 859–872 (2005)

    Article  CAS  Google Scholar 

  23. Couture, J. F., Collazo, E. & Trievel, R. C. Molecular recognition of histone H3 by the WD40 protein WDR5. Nat. Struct. Mol. Biol. 13, 698–703 (2006)

    Article  CAS  Google Scholar 

  24. Han, Z. et al. Structural basis for the specific recognition of methylated histone H3 lysine 4 by the WD-40 protein WDR5. Mol. Cell 22, 137–144 (2006)

    Article  CAS  Google Scholar 

  25. Ruthenburg, A. J. et al. Histone H3 recognition and presentation by the WDR5 module of the MLL1 complex. Nature Struct. Mol. Biol. 13, 704–712 (2006)

    Article  CAS  Google Scholar 

  26. Schuetz, A. et al. Structural basis for molecular recognition and presentation of histone H3 by WDR5. EMBO J. 25, 4245–4252 (2006)

    Article  CAS  Google Scholar 

  27. Dou, Y. et al. Regulation of MLL1 H3K4 methyltransferase activity by its core components. Nature Struct. Mol. Biol. 13, 713–719 (2006)

    Article  CAS  Google Scholar 

  28. Kirmizis, A. et al. Arginine methylation at histone H3R2 controls deposition of H3K4 trimethylation. Nature doi: 10.1038/nature06160 (this issue)

  29. Frank, S. R., Schroeder, M., Fernandez, P., Taubert, S. & Amati, B. Binding of c-Myc to chromatin mediates mitogen-induced acetylation of histone H4 and gene activation. Genes Dev. 15, 2069–2082 (2001)

    Article  CAS  Google Scholar 

  30. Pajic, A. et al. Cell cycle activation by c-myc in a burkitt lymphoma model cell line. Int. J. Cancer 87, 787–793 (2000)

    Article  CAS  Google Scholar 

  31. Xie, B., Invernizzi, C. F., Richard, S. & Wainberg, M. A. Arginine methylation of the human immunodeficiency virus type 1 Tat protein by PRMT6 negatively affects Tat interactions with both cyclin T1 and the Tat transactivation region. J. Virol. 81, 4226–4234 (2007)

    Article  CAS  Google Scholar 

  32. Pavri, R. et al. Histone H2B monoubiquitination functions cooperatively with FACT to regulate elongation by RNA polymerase II. Cell 125, 703–717 (2006)

    Article  CAS  Google Scholar 

  33. Rigaut, G. et al. A generic protein purification method for protein complex characterization and proteome exploration. Nature Biotechnol. 17, 1030–1032 (1999)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank G. Natoli, G. I. Dellino and all the members of our group for discussions; T. Kouzarides for PRMT4/CARM1 expression vectors and for communicating unpublished data; S. Richard, M. Wainberg and C. Invernizzi for PRMT6 vectors; D. Reinberg and P. Trojer for the Flag–ASH2 vector; and P. G. Pelicci for continuous support. This work was supported by a fellowship from the Italian Federation for Cancer Research (FIRC) to E.G., by grants from the Italian Association for Cancer Research (AIRC) to B.A. and by a grant from the Deutsche Forschungsgemeinschaft (DFG) to B.L.

Author Contributions E.G. and B.A. conceived the work and designed the experiments. B.A. supervised the project and wrote the manuscript. E.G. and F.M. performed ChIP, E.G. and C.B. performed biochemical experiments, and F.C. constructed expression vectors. M.C. performed the statistical analysis of ChIP data. H.S. and B.L. purified the TAP–ASH2 complex.

Author information

Authors and Affiliations

  1. Department of Experimental Oncology, European Institute of Oncology (IEO), IFOM-IEO Campus, Milan 20139, Italy

    Ernesto Guccione, Christian Bassi, Fabio Casadio, Francesca Martinato, Matteo Cesaroni & Bruno Amati

  2. Division of Biochemistry and Molecular Biology, Institute of Biochemistry, RWTH Aachen University Hospital, 52074 Aachen, Germany

    Henning Schuchlautz & Bernhard Lüscher

Authors
  1. Ernesto Guccione
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christian Bassi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fabio Casadio
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Francesca Martinato
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Matteo Cesaroni
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Henning Schuchlautz
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bernhard Lüscher
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bruno Amati
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bruno Amati.

Ethics declarations

Competing interests

Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Supplementary information

Supplementary Information

The file contains Supplementary Figures 1-6 with Legends and additional references. (PDF 4741 kb)

Supplementary Information

The file contains Supplementary Table 1 with genomic coordinates and primers used in this work. (XLS 146 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Guccione, E., Bassi, C., Casadio, F. et al. Methylation of histone H3R2 by PRMT6 and H3K4 by an MLL complex are mutually exclusive. Nature 449, 933–937 (2007). https://doi.org/10.1038/nature06166

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature06166

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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