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Certain and Progressive Methylation of Histone H4 at Lysine 20 during the Cell Cycle

机译:在细胞周期中,组蛋白H4在赖氨酸20处的某些和进行性甲基化

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Methylation of histone H4 at lysine 20 (K20) has been implicated in transcriptional activation, gene silencing, heterochromatin formation, mitosis, and DNA repair. However, little is known about how this modification is regulated or how it contributes to these diverse processes. Metabolic labeling and top-down mass spectrometry reveal that newly synthesized H4 is progressively methylated at K20 during the G2, M, and G1 phases of the cell cycle in a process that is largely inescapable and irreversible. Approximately 98% of new H4 becomes dimethylated within two to three cell cycles, and K20 methylation turnover in vivo is undetectable. New H4 is methylated regardless of prior acetylation, and acetylation occurs predominantly on K20-dimethylated H4, refuting the hypothesis that K20 methylation antagonizes H4 acetylation and represses transcription epigenetically. Despite suggestions that it is required for normal mitosis and cell cycle progression, K20 methylation proceeds normally during colchicine treatment. Moreover, delays in PR-Set7 synthesis and K20 methylation which accompany altered cell cycle progression during sodium butyrate treatment appear to be secondary to histone hyperacetylation or other effects of butyrate since depletion of PR-Set7 did not affect cell cycle progression. Together, our data provide an unbiased perspective of the regulation and function of K20 methylation.
机译:组蛋白H4在赖氨酸20(K20)处的甲基化与转录激活,基因沉默,异染色质形成,有丝分裂和DNA修复有关。但是,对于这种调节是如何调节的或如何对这些不同的过程做出贡献的了解甚少。代谢标记和自上而下的质谱分析表明,在一个过程中,细胞周期的G 2 ,M和G 1 阶段,新合成的H4在K20处逐渐甲基化。这在很大程度上是不可避免的和不可逆转的。大约98%的新H4在2至3个细胞周期内被二甲基化,体内K20甲基化转换率不可检测。不管先前的乙酰化如何,新的H4都会被甲基化,并且乙酰化主要发生在K20-二甲基化的H4上,这驳斥了K20甲基化拮抗H4乙酰化并表观遗传抑制转录的假设。尽管有人建议正常的有丝分裂和细胞周期的进展是必需的,但秋水仙碱治疗期间K20甲基化正常进行。此外,在丁酸钠处理期间伴随细胞周期进程改变而发生的PR-Set7合成和K20甲基化延迟似乎是组蛋白过乙酰化或丁酸盐的其他作用的继发,因为PR-Set7的耗竭并不影响细胞周期进程。总之,我们的数据为K20甲基化的调节和功能提供了公正的视角。

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