Cops2 promotes pluripotency maintenance by Stabilizing Nanog Protein and Repressing Transcription

Weiyu Zhang; Peiling Ni; Chunlin Mou; Yanqin Zhang; Hongchao Guo; Tong Zhao; Yuin-Han Loh; Lingyi Chen

doi:10.1038/srep26804

Cops2 promotes pluripotency maintenance by Stabilizing Nanog Protein and Repressing Transcription

Sci Rep. 2016 May 26:6:26804. doi: 10.1038/srep26804.

Authors

Weiyu Zhang¹, Peiling Ni¹, Chunlin Mou¹, Yanqin Zhang¹, Hongchao Guo^{1

1

2}, Tong Zhao¹, Yuin-Han Loh^{2

3}, Lingyi Chen^{1

4}

Affiliations

¹ State Key Laboratory of Medicinal Chemical Biology, Collaborative Innovation Center for Biotherapy, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Protein Sciences and College of Life Sciences, Nankai University, Tianjin 300071, China.
² Epigenetics and Cell Fates Laboratory, A*STAR Institute of Molecular and Cell Biology, 61 Biopolis Drive Proteos, Singapore 138673, Singapore.
³ Department of Biological Sciences, National University of Singapore, Singapore.
⁴ State Key Laboratory of Molecular Oncology, Cancer Institute/Hospital, Chinese Academy of Medical Sciences, Beijing 100021, China.

Abstract

The COP9 signalosome has been implicated in pluripotency maintenance of human embryonic stem cells. Yet, the mechanism for the COP9 signalosome to regulate pluripotency remains elusive. Through knocking down individual COP9 subunits, we demonstrate that Cops2, but not the whole COP9 signalosome, is essential for pluripotency maintenance in mouse embryonic stem cells. Down-regulation of Cops2 leads to reduced expression of pluripotency genes, slower proliferation rate, G2/M cell cycle arrest, and compromised embryoid differentiation of embryonic stem cells. Cops2 also facilitates somatic cell reprogramming. We further show that Cops2 binds to Nanog protein and prevent the degradation of Nanog by proteasome. Moreover, Cops2 functions as transcriptional corepressor to facilitate pluripotency maintenance. Altogether, our data reveal the essential role and novel mechanisms of Cops2 in pluripotency maintenance.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Animals
COP9 Signalosome Complex / antagonists & inhibitors
COP9 Signalosome Complex / genetics
COP9 Signalosome Complex / metabolism*
COP9 Signalosome Complex / physiology
Cell Self Renewal
Cellular Reprogramming Techniques
Embryoid Bodies
Embryonic Stem Cells / cytology*
Embryonic Stem Cells / metabolism
Gene Expression Regulation, Developmental / physiology*
Gene Knockdown Techniques
Mice
Nanog Homeobox Protein / genetics
Nanog Homeobox Protein / metabolism*
Nuclear Proteins / antagonists & inhibitors
Nuclear Proteins / genetics
Nuclear Proteins / physiology*
Octamer Transcription Factor-3 / antagonists & inhibitors
Octamer Transcription Factor-3 / genetics
Octamer Transcription Factor-3 / physiology
Protein Stability
Proteolysis
RNA Interference
RNA, Small Interfering / genetics
SOXC Transcription Factors / antagonists & inhibitors
SOXC Transcription Factors / genetics
SOXC Transcription Factors / physiology
Sheep / genetics
Transcription Factors / antagonists & inhibitors
Transcription Factors / genetics
Transcription Factors / physiology*
Transcription, Genetic / genetics*

Substances

Cops2 protein, mouse
Nanog Homeobox Protein
Nanog protein, mouse
Nuclear Proteins
Octamer Transcription Factor-3
Pou5f1 protein, mouse
RNA, Small Interfering
SOXC Transcription Factors
Sox4 protein, mouse
Transcription Factors
COP9 Signalosome Complex