The deubiquitinase USP21 maintains the stemness of mouse embryonic stem cells via stabilization of Nanog

Jiali Jin, Jian Liu, Cong Chen, Zhenping Liu, Cong Jiang, Hongshang Chu, Weijuan Pan, Xinbo Wang, Lingqiang Zhang, Bin Li, Cizhong Jiang, Xin Ge, Xin Xie () and Ping Wang ()
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Jiali Jin: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University
Jian Liu: Chinese Academy of Sciences Key Laboratory of Receptor Research, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Cong Chen: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University
Zhenping Liu: Shanghai Tenth People’s Hospital of Tongji University, School of Life Science and Technology, Tongji University
Cong Jiang: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University
Hongshang Chu: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University
Weijuan Pan: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University
Xinbo Wang: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University
Lingqiang Zhang: State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine
Bin Li: Key Laboratory of Molecular Virology and Immunology, Unit of Molecular Immunology, Institute Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
Cizhong Jiang: Shanghai Tenth People’s Hospital of Tongji University, School of Life Science and Technology, Tongji University
Xin Ge: Shanghai Tenth People's Hospital of Tongji University, Tongji University
Xin Xie: Chinese Academy of Sciences Key Laboratory of Receptor Research, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Ping Wang: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: Abstract Nanog is a master pluripotency factor of embryonic stem cells (ESCs). Stable expression of Nanog is essential to maintain the stemness of ESCs. However, Nanog is a short-lived protein and quickly degraded by the ubiquitin-dependent proteasome system. Here we report that the deubiquitinase USP21 interacts with, deubiquitinates and stabilizes Nanog, and therefore maintains the protein level of Nanog in mouse ESCs (mESCs). Loss of USP21 results in Nanog degradation, mESCs differentiation and reduces somatic cell reprogramming efficiency. USP21 is a transcriptional target of the LIF/STAT3 pathway and is downregulated upon differentiation. Moreover, differentiation cues promote ERK-mediated phosphorylation and dissociation of USP21 from Nanog, thus leading to Nanog degradation. In addition, USP21 is recruited to gene promoters by Nanog to deubiquitinate histone H2A at K119 and thus facilitates Nanog-mediated gene expression. Together, our findings provide a regulatory mechanism by which extrinsic signals regulate mESC fate via deubiquitinating Nanog.

Date: 2016
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DOI: 10.1038/ncomms13594

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