Dynamic association of MLL1, H3K4 trimethylation with chromatin and Hox gene expression during the cell cycle
Dynamic association of MLL1, H3K4 trimethylation with chromatin and Hox gene expression during the cell cycle
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DOI：
10.1111/j.1742-4658.2009.06895.x
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发表时间：
2009-03-01
期刊：
影响因子：
5.4
通讯作者：
Mandal, Subhrangsu S.
中科院分区：
文献类型：
--
作者：
Mishra, Bibhu P.;Ansari, Khairul I.;Mandal, Subhrangsu S.
混合谱系白血病 (MLL) 是组蛋白 H3 赖氨酸 4 (H3K4) 特异性甲基化酶，在调节人类基因表达中发挥着关键作用。由于染色质凝聚、松弛和差异基因表达是纠正细胞周期进展的关键，我们分析了 MLL 和 H3K4 三甲基化在细胞周期不同阶段的动态关联。有趣的是，MLL1通常与转录活性染色质（G1期）相关，它从浓缩的有丝分裂染色质中解离出来，并在末期结束时细胞核开始松弛时返回。相比之下，通常也与常染色质（G1 期）相关的 H3K4 三甲基化标记在整个细胞周期中仍然保持相关性，甚至与浓缩染色质相关。 MLL1 和 H3K4 三甲基化的整体水平在细胞周期中不受影响，并且 H3Ser28 磷酸化仅在有丝分裂期间观察到。有趣的是，MLL 靶标同源盒 (Hox) 基因（HoxA5、HoxA7 和 HoxA10）在细胞周期中差异表达，并且 MLL1 和 H3K4 三甲基化水平的招募在这些 Hox 基因的启动子中作为其表达的函数进行调节。此外，MLL1 的下调会导致细胞周期停滞在 G2/M 期。 H3K4三甲基化标记在特定启动子处的波动，但在全局水平上没有波动，表明存在于G1期的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，旧的标记被删除并引入新的标记。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，并在与细胞周期调节相关的 Hox 基因的差异表达中发挥关键作用。
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.