Aurkb/PP1-mediated resetting of Oct4 during the cell cycle determines the identity of embryonic stem cells

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Abstract

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.

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Jihoon Shin

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

Competing interests
The authors declare that no competing interests exist.
Tae Wan Kim

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

Competing interests
The authors declare that no competing interests exist.
Hyunsoo Kim

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

Competing interests
The authors declare that no competing interests exist.
Hye Ji Kim

Department of Biological Sciences, Seoul National University, Seoul, Republic of Korea

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The authors declare that no competing interests exist.
Min Young Suh

Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science, Seoul National University, Seoul, Republic of Korea

Competing interests
The authors declare that no competing interests exist.
Sangho Lee

Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science, Seoul National University, Seoul, Republic of Korea

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The authors declare that no competing interests exist.
Han-Teo Lee

Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul, Republic of Korea

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The authors declare that no competing interests exist.
Sojung Kwak

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

Competing interests
The authors declare that no competing interests exist.
Sang-Eun Lee

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

Competing interests
The authors declare that no competing interests exist.
Jong-Hyuk Lee

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

Competing interests
The authors declare that no competing interests exist.
Hyonchol Jang

Division of Cancer Biology, Research Institute, National Cancer Center, Goyang, Republic of Korea

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The authors declare that no competing interests exist.
Eun-Jung Cho

College of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea

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The authors declare that no competing interests exist.
Hong-Duk Youn

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

For correspondence
hdyoun@snu.ac.kr

Competing interests
The authors declare that no competing interests exist.

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