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

A Retraction to this article was published on 11 December 2013


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.

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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.


  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 

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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.

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Correspondence to Shigeaki Kato.

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

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