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Shortened G1 phase of cell cycle and decreased histone H3K27 methylation are associated with AKT-induced enhancement of primordial germ cell reprogramming.
Development, Growth & Differentiation ( IF 2.5 ) Pub Date : 2019-06-14 , DOI: 10.1111/dgd.12621
Asuka Takehara 1, 2, 3 , Yasuhisa Matsui 1, 2, 3, 4
Affiliation  

Primordial germ cells (PGCs) are reprogrammed into pluripotent embryonic germ cells (EGCs) under specific culture conditions, but the detailed mechanisms of PGC reprogramming have not yet been fully clarified. Previous studies have demonstrated that AKT, an important intracellular signaling molecule, promotes reprogramming of PGCs into EGCs. Because AKT likely inhibits p53 functions to enhance PGC reprogramming, and p53 negatively regulates cell cycle progression, we analyzed cell cycle changes in PGCs following AKT activation and found that the ratio of PGCs in the G1/G0 phase was decreased while that of PGCs in the G2/M phase was increased after AKT activation. We also showed that the expression of the CDK inhibitor p27kip1, which prevents the G1‐S transition and is transcriptionally activated by p53, was significantly downregulated by AKT activation. The results suggested that the characteristic cell cycle changes of PGCs by AKT activation are, at least in part, due to decreased expression of p27kip1 . We also investigated changes in histone H3K27 tri-methylation (H3K27me3) by AKT activation in PGCs, because we previously found that decreased H3K27me3 was involved in PGC reprogramming via upregulation of cyclin D1. We observed that AKT activation in PGCs resulted in H3K27 hypomethylation. In addition, DZNeP, an inhibitor of the H3K27 trimethyl transferase Ezh2, stimulated EGC formation. These results together suggested that AKT activation promotes G1-S transition and downregulates H3K27me3 to enhance PGC reprogramming.

中文翻译:

细胞周期的G1期缩短和组蛋白H3K27甲基化降低与AKT诱导的原始生殖细胞重编程增强有关。

在特定的培养条件下,原始生殖细胞(PGC)被重编程为多能胚胎生殖细胞(EGC),但尚未完全阐明PGC重编程的详细机制。先前的研究表明,AKT是一种重要的细胞内信号分子,可促进PGC重新编程为EGC。由于AKT可能抑制p53功能以增强PGC重编程,并且p53负调控细胞周期进程,因此我们分析了AKT激活后PGC中的细胞周期变化,发现G1 / G0期中PGC的比例降低,而P1 / g0期中PGC的比例降低。 AKT激活后,G2 / M期增加。我们还表明,CDK抑制剂p27kip1的表达阻止了G1-S的转变,并被p53转录激活,被AKT激活显着下调。结果表明,通过AKT激活,PGCs的特征性细胞周期变化至少部分是由于p27kip1表达降低。我们还研究了PGC中AKT激活引起的组蛋白H3K27三甲基化(H3K27me3)的变化,因为我们先前发现降低的H3K27me3参与了通过细胞周期蛋白D1上调的PGC重编程。我们观察到PGC中的AKT激活导致H3K27甲基化不足。此外,H3K27三甲基转移酶Ezh2的抑制剂DZNeP刺激了EGC的形成。这些结果共同表明,AKT激活促进G1-S过渡并下调H3K27me3,以增强PGC重编程。由于p27kip1表达降低。我们还研究了PGC中AKT激活引起的组蛋白H3K27三甲基化(H3K27me3)的变化,因为我们先前发现降低的H3K27me3参与了通过细胞周期蛋白D1上调的PGC重编程。我们观察到PGC中的AKT激活导致H3K27甲基化不足。此外,H3K27三甲基转移酶Ezh2的抑制剂DZNeP刺激了EGC的形成。这些结果共同表明,AKT激活促进G1-S过渡并下调H3K27me3,以增强PGC重编程。由于p27kip1表达降低。我们还研究了PGC中AKT激活引起的组蛋白H3K27三甲基化(H3K27me3)的变化,因为我们先前发现降低的H3K27me3参与了通过细胞周期蛋白D1上调的PGC重编程。我们观察到PGC中的AKT激活导致H3K27甲基化不足。此外,H3K27三甲基转移酶Ezh2的抑制剂DZNeP刺激了EGC的形成。这些结果共同表明,AKT激活促进G1-S过渡并下调H3K27me3,以增强PGC重编程。我们观察到PGC中的AKT激活导致H3K27甲基化不足。此外,H3K27三甲基转移酶Ezh2的抑制剂DZNeP刺激了EGC的形成。这些结果共同表明,AKT激活促进G1-S过渡并下调H3K27me3,以增强PGC重编程。我们观察到PGC中的AKT激活导致H3K27甲基化不足。此外,H3K27三甲基转移酶Ezh2的抑制剂DZNeP刺激了EGC的形成。这些结果共同表明,AKT激活促进G1-S过渡并下调H3K27me3,以增强PGC重编程。
更新日期:2019-11-01
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