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.

  • Letter
  • Published:

GlcNAcylation of a histone methyltransferase in retinoic-acid-induced granulopoiesis

Nature volume 459, pages 455–459 (2009)Cite this article

A Retraction to this article was published on 11 December 2013

Abstract

The post-translational modifications of histone tails generate a ‘histone code’ that defines local and global chromatin states1. The resultant regulation of gene function is thought to govern cell fate, proliferation and differentiation2. Reversible histone modifications such as methylation are under mutual controls to organize chromosomal events3,4. Among the histone modifications, methylation of specific lysine and arginine residues seems to be critical for chromatin configuration and control of gene expression5. Methylation of histone H3 lysine 4 (H3K4) changes chromatin into a transcriptionally active state6. Reversible modification of proteins by β-N-acetylglucosamine (O-GlcNAc) in response to serum glucose levels regulates diverse cellular processes7,8,9. However, the epigenetic impact of protein GlcNAcylation is unknown. Here we report that nuclear GlcNAcylation of a histone lysine methyltransferase (HKMT), MLL5, by O-GlcNAc transferase facilitates retinoic-acid-induced granulopoiesis in human HL60 promyelocytes through methylation of H3K4. MLL5 is biochemically identified in a GlcNAcylation-dependent multi-subunit complex associating with nuclear retinoic acid receptor RARα (also known as RARA), serving as a mono- and di-methyl transferase to H3K4. GlcNAcylation at Thr 440 in the MLL5 SET domain evokes its H3K4 HKMT activity and co-activates RARα in target gene promoters. Increased nuclear GlcNAcylation by means of O-GlcNAc transferase potentiates retinoic-acid-induced HL60 granulopoiesis and restores the retinoic acid response in the retinoic-acid-resistant HL60-R2 cell line. Thus, nuclear MLL5 GlcNAcylation triggers cell lineage determination of HL60 through activation of its HKMT activity.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: MLL5 acts as a co-activator of RARα.
Figure 2: Purification of the HKMT-active MLL5 complex.
Figure 3: MLL5 is a GlcNAcylation-dependent HKMT.
Figure 4: GlcNAcylation of MLL5 facilitates RA-induced granulopoiesis.

Similar content being viewed by others

References

  1. Strahl, B. D. & Allis, C. D. The language of covalent histone modifications. Nature 403, 41–45 (2000)

    Article  ADS  CAS  Google Scholar 

  2. Bernstein, B. E., Meissner, A. & Lander, E. S. The mammalian epigenome. Cell 128, 669–681 (2007)

    Article  CAS  Google Scholar 

  3. Sarma, K. & Reinberg, D. Histone variants meet their match. Nature Rev. Mol. Cell Biol. 6, 139–149 (2005)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. Zhang, Y. & Reinberg, D. Transcription regulation by histone methylation: interplay between different covalent modifications of the core histone tails. Genes Dev. 15, 2343–2360 (2001)

    Article  CAS  Google Scholar 

  6. Mikkelsen, T. S. et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448, 553–560 (2007)

    Article  ADS  CAS  Google Scholar 

  7. Hart, G. W., Housley, M. P. & Slawson, C. Cycling of O-linked β-N-acetylglucosamine on nucleocytoplasmic proteins. Nature 446, 1017–1022 (2007)

    Article  ADS  CAS  Google Scholar 

  8. Jackson, S. P. & Tjian, R. O-glycosylation of eukaryotic transcription factors: implications for mechanisms of transcriptional regulation. Cell 55, 125–133 (1988)

    Article  CAS  Google Scholar 

  9. Kelly, W. G. & Hart, G. W. Glycosylation of chromosomal proteins: localization of O-linked N-acetylglucosamine in Drosophila chromatin. Cell 57, 243–251 (1989)

    Article  CAS  Google Scholar 

  10. Chambon, P. A decade of molecular biology of retinoic acid receptors. FASEB J. 10, 940–954 (1996)

    Article  CAS  Google Scholar 

  11. Collins, S. J. The role of retinoids and retinoic acid receptors in normal hematopoiesis. Leukemia 16, 1896–1905 (2002)

    Article  CAS  Google Scholar 

  12. Nakamura, T. et al. ALL-1 is a histone methyltransferase that assembles a supercomplex of proteins involved in transcriptional regulation. Mol. Cell 10, 1119–1128 (2002)

    Article  CAS  Google Scholar 

  13. Dou, Y. et al. Physical association and coordinate function of the H3 K4 methyltransferase MLL1 and the H4 K16 acetyltransferase MOF. Cell 121, 873–885 (2005)

    Article  CAS  Google Scholar 

  14. Emerling, B. M. et al. MLL5, a homolog of Drosophila trithorax located within a segment of chromosome band 7q22 implicated in myeloid leukemia. Oncogene 21, 4849–4854 (2002)

    Article  CAS  Google Scholar 

  15. 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 

  16. Lee, M. G. et al. Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination. Science 318, 447–450 (2007)

    Article  ADS  CAS  Google Scholar 

  17. Cho, Y. W. et al. PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4 methyltransferase complex. J. Biol. Chem. 282, 20395–20406 (2007)

    Article  CAS  Google Scholar 

  18. Mori, J. et al. Characterization of two novel retinoic acid-resistant cell lines derived from HL-60 cells following long-term culture with all-trans-retinoic acid. Jpn. J. Cancer Res. 90, 660–668 (1999)

    Article  CAS  Google Scholar 

  19. Wysocka, J. et al. 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 

  20. Si, J., Mueller, L. & Collins, S. J. CaMKII regulates retinoic acid receptor transcriptional activity and the differentiation of myeloid leukemia cells. J. Clin. Invest. 117, 1412–1421 (2007)

    Article  CAS  Google Scholar 

  21. Yang, X. et al. Phosphoinositide signalling links O-GlcNAc transferase to insulin resistance. Nature 451, 964–969 (2008)

    Article  ADS  CAS  Google Scholar 

  22. Dentin, R. et al. Hepatic glucose sensing via the CREB coactivator CRTC2. Science 319, 1402–1405 (2008)

    Article  ADS  CAS  Google Scholar 

  23. Kitagawa, H. et al. The chromatin-remodeling complex WINAC targets a nuclear receptor to promoters and is impaired in Williams syndrome. Cell 113, 905–917 (2003)

    Article  CAS  Google Scholar 

  24. Ohtake, F. et al. Dioxin receptor is a ligand-dependent E3 ubiquitin ligase. Nature 446, 562–566 (2007)

    Article  ADS  CAS  Google Scholar 

  25. Takada, I. et al. A histone lysine methyltransferase activated by non-canonical Wnt signalling suppresses PPAR-gamma transactivation. Nature Cell Biol. 9, 1273–1285 (2007)

    Article  CAS  Google Scholar 

  26. Fujiki, R. et al. Ligand-induced transrepression by VDR through association of WSTF with acetylated histones. EMBO J. 24, 3881–3894 (2005)

    Article  CAS  Google Scholar 

  27. Wells, L. et al. O-GlcNAc transferase is in a functional complex with protein phosphatase 1 catalytic subunits. J. Biol. Chem. 279, 38466–38470 (2004)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank A. Miyajima and S. Saito for cell lines, P. Chambon, T. Kitamura and S. Suzuki for experimental materials, H. Akaishi for technical support, and M. Yamaki for manuscript preparation. This work was supported in part by priority areas from the Ministry of Education, Culture, Sports, Science and Technology (to H.K. and S.K.).

Author Contributions S.K. planned the project and analysed the experiments together with R.F., R.G.R. and H.K. R.F., T.C., W.H., H.I. and I.T. conducted the experiments. The manuscript was written by S.K. and R.F., and all authors commented on it.

Author information

Authors and Affiliations

  1. Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan ,

    Ryoji Fujiki, Toshihiro Chikanishi, Waka Hashiba, Hiroaki Ito, Ichiro Takada, Hirochika Kitagawa & Shigeaki Kato

  2. ERATO, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchisi, Saitama 332-0012, Japan ,

    Ryoji Fujiki, Toshihiro Chikanishi & Shigeaki Kato

  3. Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, 1230 York Avenue, New York, New York 10021, USA ,

    Robert G. Roeder

Authors
  1. Ryoji Fujiki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Toshihiro Chikanishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Waka Hashiba
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hiroaki Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ichiro Takada
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Robert G. Roeder
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hirochika Kitagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shigeaki Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shigeaki Kato.

Supplementary information

Supplementary Information

This file contains a Supplementary Table and Supplementary Figures S1-S31 with Legends. (PDF 2858 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fujiki, R., Chikanishi, T., Hashiba, W. et al. GlcNAcylation of a histone methyltransferase in retinoic-acid-induced granulopoiesis. Nature 459, 455–459 (2009). https://doi.org/10.1038/nature07954

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature07954

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