RETRACTED: GlcNAcylation of a histone methyltransferase in retinoic-acid-induced granulopoiesis (Retracted Article)

被引:137
作者
Fujiki, Ryoji [1 ,2 ]
Chikanishi, Toshihiro [1 ,2 ]
Hashiba, Waka [1 ]
Ito, Hiroaki [1 ]
Takada, Ichiro [1 ]
Roeder, Robert G. [3 ]
Kitagawa, Hirochika [1 ]
Kato, Shigeaki [1 ,2 ]
机构
[1] Univ Tokyo, Inst Mol & Cellular Biosci, Bunkyo Ku, Tokyo 1130032, Japan
[2] Japan Sci & Technol Agcy, ERATO, Kawaguchi, Saitama 3320012, Japan
[3] Rockefeller Univ, Biochem & Mol Biol Lab, New York, NY 10021 USA
关键词
O-GLCNAC TRANSFERASE; TRANSCRIPTIONAL REGULATION; N-ACETYLGLUCOSAMINE; MYELOID-LEUKEMIA; CHROMATIN; COMPLEX; PROTEINS; RECEPTOR; CELLS; GLYCOSYLATION;
D O I
10.1038/nature07954
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The post-translational modifications of histone tails generate a 'histone code' that defines local and global chromatin states(1). The resultant regulation of gene function is thought to govern cell fate, proliferation and differentiation(2). 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 expression(5). Methylation of histone H3 lysine 4 (H3K4) changes chromatin into a transcriptionally active state(6). Reversible modification of proteins by beta-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 alpha (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 RARa 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.
引用
收藏
页码:455 / U179
页数:7
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