GlcNAcylation of a histone methyltransferase in retinoic-acid-induced granulopoiesis (Retracted Article)
GlcNAcylation of a histone methyltransferase in retinoic-acid-induced granulopoiesis (Retracted Article)
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DOI：
10.1038/nature07954
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发表时间：
2009-05-21
期刊：
影响因子：
64.8
通讯作者：
Kato, Shigeaki
中科院分区：
文献类型：
--
作者：
Fujiki, Ryoji;Chikanishi, Toshihiro;Kato, Shigeaki
组蛋白尾巴的翻译后修饰产生了定义局部和全局染色质状态的“组蛋白代码”（1）。认为基因功能的调节被认为控制细胞命运，增殖和分化（2）。可逆的组蛋白修饰（例如甲基化）在相互控制下组织染色体事件（3,4）。在组蛋白的修饰中，特异性赖氨酸和精氨酸残基的甲基化似乎对于染色质构型和基因表达的控制至关重要（5）。组蛋白H3赖氨酸4（H3K4）的甲基化将染色质变成转录活性状态（6）。 β-N-乙酰葡萄糖胺（O-GLCNAC）对血清葡萄糖水平的反应可逆修饰蛋白质可调节多种细胞过程（7,8,9）。然而，蛋白质Glcnacylation的表观遗传影响尚不清楚。在这里，我们报告说，通过O-GLCNAC转移酶，组蛋白赖氨酸甲基转移酶（HKMT），MLL5的核Glcnacylation通过HL60 PromyElopytes促进了视黄酸性酸诱导的粒细胞的粒细胞，这促进了通过H3K4的甲基化。 MLL5在Glcnacylation依赖性的多亚基复合物中与核视黄酸受体RAR Alpha（也称为RARA）相关的生化鉴定，作为单甲基转移酶与H3K4。 MLL5设定域中THR 440处的Glcnacylation唤起其H3K4 HKMT活性，并在靶基因启动子中共同激活RARA。通过O-GLCNAC转移酶增强了视黄酸诱导的HL60粒植物的增强核glcnacylation，并恢复了耐氨基酸酸HL60-R2细胞系中的视黄酸反应。因此，核MLL5 Glcnacylation通过激活其HKMT活性触发了HL60的细胞谱系测定。
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.