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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.

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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.

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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.

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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

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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). https://doi.org/10.1038/nature07954

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