ES cell cycle progression and differentiation require the action of the histone methyltransferase Dot1L.
ES cell cycle progression and differentiation require the action of the histone methyltransferase Dot1L.
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DOI：
10.1002/stem.86
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发表时间：
2009-07
期刊：
影响因子：
--
通讯作者：
Rasmussen TP
中科院分区：
文献类型：
--
作者：
Barry ER;Krueger W;Jakuba CM;Veilleux E;Ambrosi DJ;Nelson CE;Rasmussen TP
小鼠胚胎干细胞（ESCs）以快速的细胞周期动力学增殖，但不丧失多能性。组蛋白甲基转移酶Dot 1 L负责组蛋白H3在赖氨酸79（H3 K79 me）的甲基化。我们研究了ESCs是否需要Dot 1 L来获得适当的干细胞行为。Dot 1 L缺陷的ESC耐受H3 K79甲基化的几乎完全丧失，而对增殖或形态没有实质性影响。然而，诱导分化后不久，Dot 1 L缺陷细胞停止增殖并停滞在细胞周期的G2/M期，非整倍体水平增加。此外，许多异常的有丝分裂纺锤体发生在Dot 1 L缺陷细胞中。令人惊讶的是，这些有丝分裂和细胞周期缺陷未能触发细胞凋亡，表明小鼠ESC在分化的初始阶段缺乏严格的细胞周期检查点控制。转录组分析表明，Dot 1 L缺陷导致一组选定的基因，包括许多已知的作用，在细胞周期控制和细胞增殖以及内胚层分化的标志物的错误调节。这些数据表明，在ESC分化的早期阶段需要Dot 1 L功能，其中Dot 1 L对于有丝分裂的忠实执行和整个基因组中许多基因的正确转录是必要的。
Mouse embryonic stem cells (ESCs) proliferate with rapid cell cycle kinetics but without loss of pluripotency. The histone methyltransferase Dot1L is responsible for methylation of histone H3 at lysine 79 (H3K79me). We investigated whether ESCs require Dot1L for proper stem cell behavior. ESCs deficient for Dot1L tolerate a nearly complete loss of H3K79 methylation without a substantial impact on proliferation or morphology. However, shortly after differentiation is induced, Dot1L-deficient cells cease proliferating and arrest in G2/M phase of the cell cycle, with increased levels of aneuploidy. In addition, many aberrant mitotic spindles occur in Dot1L-deficient cells. Surprisingly, these mitotic and cell cycle defects fail to trigger apoptosis, indicating that mouse ESCs lack stringent cell cycle checkpoint control during initial stages of differentiation. Transcriptome analysis indicates that Dot1L deficiency causes the mis-regulation of a select set of genes, including many with known roles in cell cycle control and cellular proliferation as well as markers of endoderm differentiation. The data indicate a requirement for Dot1L function for early stages of ESC differentiation where Dot1L is necessary for faithful execution of mitosis and proper transcription of many genes throughout the genome.
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