1. Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
2. ERATO, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchisi, Saitama 332-0012, Japan
3. Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, 1230 York Avenue, New York, New York 10021, USA

Correspondence to: Shigeaki Kato^1,2 Correspondence and requests for materials should be addressed to S.K. (Email: uskato@mail.ecc.u-tokyo.ac.jp).

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 events^{3, 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 -N-acetylglucosamine (O-GlcNAc) in response to serum glucose levels regulates diverse cellular processes^{7, 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 RAR (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 RAR 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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