Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Hubei Clinical Research Center of Emergency and Resuscitation, Emergency Center of Zhongnan Hospital of Wuhan University, Frontier Science Center for Immunology and Metabolism, RNA Institute, Wuhan University, Wuhan, 430072, China.
School of Life Sciences and Biotechnology, Shanghai JiaoTong University, Shanghai, 200240, China.
Adv Sci (Weinh). 2023 Oct;10(30):e2303224. doi: 10.1002/advs.202303224. Epub 2023 Sep 3.
Phosphorylation of Ser10 of histone H3 (H3S10p), together with the adjacent methylation of Lys9 (H3K9me), has been proposed to function as a 'phospho-methyl switch' to regulate mitotic chromatin architecture. Despite of immense understanding of the roles of H3S10 phosphorylation, how H3K9me2 are dynamically regulated during mitosis is poorly understood. Here, it is identified that Plk1 kinase phosphorylates the H3K9me1/2 methyltransferase G9a/EHMT2 at Thr1045 (pT1045) during early mitosis, which attenuates its catalytic activity toward H3K9me2. Cells bearing Thr1045 phosphomimic mutant of G9a (T1045E) show decreased H3K9me2 levels, increased chromatin accessibility, and delayed mitotic progression. By contrast, dephosphorylation of pT1045 during late mitosis by the protein phosphatase PPP2CB reactivates G9a activity and upregulates H3K9me2 levels, correlated with decreased levels of H3S10p. Therefore, the results provide a mechanistic explanation of the essential of a 'phospho-methyl switch' and highlight the importance of Plk1 and PPP2CB-mediated dynamic regulation of G9a activity in chromatin organization and mitotic progression.
组蛋白 H3 第 10 位丝氨酸（H3S10p）的磷酸化，以及紧邻的赖氨酸 9 位（H3K9me）甲基化，被提出作为调节有丝分裂染色质结构的“磷酸化-甲基化开关”。尽管人们对 H3S10 磷酸化的作用有了深入的了解，但 H3K9me2 在有丝分裂期间是如何动态调节的还知之甚少。本研究鉴定到，在有丝分裂早期，Plk1 激酶在 Thr1045 位（pT1045）磷酸化 H3K9me1/2 甲基转移酶 G9a/EHMT2，从而削弱其对 H3K9me2 的催化活性。带有 G9a Thr1045 磷酸模拟突变体（T1045E）的细胞表现出 H3K9me2 水平降低、染色质可及性增加和有丝分裂进程延迟。相比之下，在有丝分裂后期，蛋白磷酸酶 PPP2CB 去磷酸化 pT1045 会重新激活 G9a 活性并上调 H3K9me2 水平，与 H3S10p 水平降低相关。因此，这些结果提供了“磷酸化-甲基化开关”的机制解释，并强调了 Plk1 和 PPP2CB 介导的 G9a 活性动态调节在染色质组织和有丝分裂进程中的重要性。
Zotero 插件
