Mishra Bibhu P, Ansari Khairul I, Mandal Subhrangsu S
Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington 76019, TX, USA.
FEBS J. 2009 Mar;276(6):1629-40. doi: 10.1111/j.1742-4658.2009.06895.x. Epub 2009 Feb 7.
Mixed lineage leukemias (MLLs) are histone H3 at lysine 4 (H3K4)-specific methylases that play a critical role in regulating gene expression in humans. As chromatin condensation, relaxation and differential gene expression are keys to correct cell cycle progression, we analyzed the dynamic association of MLL and H3K4 trimethylation at different stages of the cell cycle. Interestingly, MLL1, which is normally associated with transcriptionally active chromatins (G1 phase), dissociates from condensed mitotic chromatin and returns at the end of telophase when the nucleus starts to relax. In contrast, H3K4 trimethylation mark, which is also normally associated with euchromatins (in G1), remains associated, even with condensed chromatin, throughout the cell cycle. The global levels of MLL1 and H3K4 trimethylation are not affected during the cell cycle, and H3Ser28 phosphorylation is only observed during mitosis. Interestingly, MLL target homeobox-containing (Hox) genes (HoxA5, HoxA7 and HoxA10) are differentially expressed during the cell cycle, and the recruitment of MLL1 and H3K4 trimethylation levels are modulated in the promoter of these Hox genes as a function of their expression. In addition, down-regulation of MLL1 results in cell cycle arrest at the G2/M phase. The fluctuation of H3K4 trimethylation marks at specific promoters, but not at the global level, indicates that H3K4 trimethylation marks that are present in the G1 phase may not be the same as the marks in other phases of the cell cycle; rather, old marks are removed and new marks are introduced. In conclusion, our studies demonstrate that MLL1 and H3K4 methylation have distinct dynamics during the cell cycle and play critical roles in the differential expression of Hox genes associated with cell cycle regulation.
混合谱系白血病（MLL）是赖氨酸4（H3K4）特异性组蛋白甲基转移酶，在调节人类基因表达中起关键作用。由于染色质凝聚、松弛和基因差异表达是正确细胞周期进程的关键，我们分析了细胞周期不同阶段MLL与H3K4三甲基化的动态关联。有趣的是，通常与转录活性染色质（G1期）相关的MLL1从凝聚的有丝分裂染色质上解离，并在末期结束时当细胞核开始松弛时返回。相反，同样通常与常染色质（G1期）相关的H3K4三甲基化标记，在整个细胞周期中即使与凝聚的染色质也保持关联。MLL1和H3K4三甲基化的整体水平在细胞周期中不受影响，并且仅在有丝分裂期间观察到H3Ser28磷酸化。有趣的是，MLL靶标含同源框（Hox）基因（HoxA5、HoxA7和HoxA10）在细胞周期中差异表达，并且MLL1的募集和H3K4三甲基化水平在这些Hox基因的启动子中根据其表达而受到调节。此外，MLL1的下调导致细胞周期在G2/M期停滞。特定启动子处而非整体水平的H3K4三甲基化标记的波动表明，G1期存在的H3K4三甲基化标记可能与细胞周期其他阶段的标记不同；相反，旧标记被去除，新标记被引入。总之，我们的研究表明，MLL1和H3K4甲基化在细胞周期中具有不同的动态变化，并在与细胞周期调节相关的Hox基因差异表达中起关键作用。
