Shin Jihoon, Kim Tae Wan, Kim Hyunsoo, Kim Hye Ji, Suh Min Young, Lee Sangho, Lee Han-Teo, Kwak Sojung, Lee Sang-Eun, Lee Jong-Hyuk, Jang Hyonchol, Cho Eun-Jung, Youn Hong-Duk
National Creative Research Center for Epigenome Reprogramming Network, Department of Biomedical Sciences, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
Department of Biological Sciences, Seoul National University, Seoul, Republic of Korea.
Elife. 2016 Feb 15;5:e10877. doi: 10.7554/eLife.10877.
Pluripotency transcription programs by core transcription factors (CTFs) might be reset during M/G1 transition to maintain the pluripotency of embryonic stem cells (ESCs). However, little is known about how CTFs are governed during cell cycle progression. Here, we demonstrate that the regulation of Oct4 by Aurora kinase b (Aurkb)/protein phosphatase 1 (PP1) during the cell cycle is important for resetting Oct4 to pluripotency and cell cycle genes in determining the identity of ESCs. Aurkb phosphorylates Oct4(S229) during G2/M phase, leading to the dissociation of Oct4 from chromatin, whereas PP1 binds Oct4 and dephosphorylates Oct4(S229) during M/G1 transition, which resets Oct4-driven transcription for pluripotency and the cell cycle. Aurkb phosphor-mimetic and PP1 binding-deficient mutations in Oct4 alter the cell cycle, effect the loss of pluripotency in ESCs, and decrease the efficiency of somatic cell reprogramming. Our findings provide evidence that the cell cycle is linked directly to pluripotency programs in ESCs.
核心转录因子（CTFs）介导的多能性转录程序可能在M/G1期转换过程中被重置，以维持胚胎干细胞（ESCs）的多能性。然而，关于细胞周期进程中CTFs如何被调控却知之甚少。在此，我们证明细胞周期中极光激酶b（Aurkb）/蛋白磷酸酶1（PP1）对Oct4的调控对于将Oct4重置为多能性以及细胞周期基因以确定ESCs的特性至关重要。Aurkb在G2/M期磷酸化Oct4（S229），导致Oct4从染色质上解离，而PP1在M/G1期转换时结合Oct4并使Oct4（S229）去磷酸化，从而重置Oct4驱动的多能性转录和细胞周期。Oct4中Aurkb磷酸化模拟和PP1结合缺陷突变会改变细胞周期，影响ESCs多能性丧失，并降低体细胞重编程效率。我们的研究结果提供了证据表明细胞周期与ESCs的多能性程序直接相关。
