Identification of a novel component of the self-renewal circuitry conserved in mouse and human ESCs

Thursday, October 11, 2012 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center, Building 45	NIEHS	STEMCELL-10

* FARE Award Winner

Authors

• X Zheng
• R Dumitru
• B Lackford
• J Freudenberg
• A Singh
• T Archer
• R Jothi
• G Hu

Abstract

To systematically study embryonic stem cell (ESC) self-renewal and pluripotency, we have previously carried out a genome-wide RNAi screen in mouse ESCs and identified a list of novel genes important for self-renewal. Here we show that three components of the Ccr4-Not complex, Cnot1, Cnot2, and Cnot3, are required for maintaining mouse ESC identity and prevent differentiation into the extraembryonic lineages. They are highly expressed in ESCs and down regulated during differentiation, and they are also enriched in the inner cell mass of the blastocyst stage embryos. Cnot1, Cnot2, and Cnot3 do not impinge on other known self-renewal transcription factors or pathways. Instead, they maintain self-renewal by repressing the expression of early trophectoderm transcription factors such as Cdx2. Importantly, Cnot1, Cnot2, and Cnot3 are also required for the maintenance of human ESCs, and silencing them in human cells mainly lead to trophectoderm 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, and our approach illustrates the power of RNAi and forward genetics for the systematic study of ESC biology.

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