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

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Fujiki R, Chikanishi T, Hashiba W, Ito H, Takada I, Roeder RG, Kitagawa H, Kato S

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

Nature. 2009 May 21;459(7245):455-9. doi: 10.1038/nature07954. Epub 2009 Apr 19.

PubMed ID

19377461 [ View in PubMed

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Abstract

The post-translational modifications of histone tails generate a 'histone code' that defines local and global chromatin states. The resultant regulation of gene function is thought to govern cell fate, proliferation and differentiation. Reversible histone modifications such as methylation are under mutual controls to organize chromosomal events. Among the histone modifications, methylation of specific lysine and arginine residues seems to be critical for chromatin configuration and control of gene expression. Methylation of histone H3 lysine 4 (H3K4) changes chromatin into a transcriptionally active state. Reversible modification of proteins by beta-N-acetylglucosamine (O-GlcNAc) in response to serum glucose levels regulates diverse cellular processes. 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 RARalpha (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 RARalpha 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.

DrugBank Data that Cites this Article

Polypeptides

Name	UniProt ID
Retinoic acid receptor alpha	P10276	Details
Serine/threonine-protein phosphatase PP1-gamma catalytic subunit	P36873	Details
Serine/threonine-protein phosphatase PP1-alpha catalytic subunit	P62136	Details
Actin, cytoplasmic 1	P60709	Details
Serine/threonine-protein kinase 38	Q15208	Details