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Embryonic Stem Cells/Induced Pluripotent Stem Cells
Article first published online: 9 APR 2012
Copyright © 2012 AlphaMed Press
Volume 30, Issue 5, pages 910–922, May 2012
How to Cite
Zheng, X., Dumitru, R., Lackford, B. L., Freudenberg, J. M., Singh, A. P., Archer, T. K., Jothi, R. and Hu, G. (2012), Cnot1, Cnot2, and Cnot3 Maintain Mouse and Human ESC Identity and Inhibit Extraembryonic Differentiation. STEM CELLS, 30: 910–922. doi: 10.1002/stem.1070
Author contributions: G.H.: designed the research; X.Z., R.D., B.L., G.H., and A.S.: performed the research; J.F. and R.J.: performed data analysis; G.H., R.J., and T.A.: interpreted the results; G.H. and X.Z.: wrote the manuscript. R.D., B.L.L., J.M.F. contributed equally to this article.
Disclosure of potential conflicts of interest is found at the end of this article.
First published online in STEM CELLSEXPRESS February 24, 2012.
- Issue published online: 9 APR 2012
- Article first published online: 9 APR 2012
- Accepted manuscript online: 24 FEB 2012 11:24AM EST
- Manuscript Accepted: 29 JAN 2012
- Manuscript Received: 9 NOV 2011
- National Institute of Environmental Health Sciences
- National Institutes of Health Intramural Research Program. Grant Numbers: Z01ES102745, Z01ES071006-11, 1ZIAES102625-02
- Embryonic stem cell;
- Extraembryonic differentiation
Embryonic stem cell (ESC) identity and self-renewal is maintained by extrinsic signaling pathways and intrinsic gene regulatory networks. Here, we show that three members of the Ccr4-Not complex, Cnot1, Cnot2, and Cnot3, play critical roles in maintaining mouse and human ESC identity as a protein complex and inhibit differentiation into the extraembryonic lineages. Enriched in the inner cell mass of blastocysts, these Cnot genes are highly expressed in ESC and downregulated during differentiation. In mouse ESCs, Cnot1, Cnot2, and Cnot3 are important for maintenance in both normal conditions and the 2i/LIF medium that supports the ground state pluripotency. Genetic analysis indicated that they do not act through known self-renewal pathways or core transcription factors. Instead, they repress the expression of early trophectoderm (TE) transcription factors such as Cdx2. Importantly, these Cnot genes are also necessary for the maintenance of human ESCs, and silencing them mainly lead to TE and primitive endoderm differentiation. Together, our results indicate that Cnot1, Cnot2, and Cnot3 represent a novel component of the core self-renewal and pluripotency circuitry conserved in mouse and human ESCs. STEM CELLS 2012;30:910–922