Original Article

Cell Research (2008) 18:1177–1189. doi: 10.1038/cr.2008.309; published online 25 November 2008

Yamanaka factors critically regulate the developmental signaling network in mouse embryonic stem cells

Xiaosong Liu1, Jinyan Huang2, Taotao Chen1, Ying Wang1, Shunmei Xin1, Jian Li3, Gang Pei1,2 and Jiuhong Kang1

  1. 1Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
  2. 2Department of Bioinformatics, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
  3. 3Agilent Technologies, Shanghai 200001, China

Correspondence: Jiuhong Kang, Tel: +86-21-54921373; Fax: +86-21-54921011 E-mail: jhkang@sibs.ac.cn

Received 16 June 2008; Revised 12 August 2008; Accepted 1 September 2008.

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Abstract

Yamanaka factors (Oct3/4, Sox2, Klf4, c-Myc) are highly expressed in embryonic stem (ES) cells, and their over-expression can induce pluripotency in both mouse and human somatic cells, indicating that these factors regulate the developmental signaling network necessary for ES cell pluripotency. However, systemic analysis of the signaling pathways regulated by Yamanaka factors has not yet been fully described. In this study, we identified the target promoters of endogenous Yamanaka factors on a whole genome scale using ChIP (chromatin immunoprecipitation)-on-chip in E14.1 mouse ES cells, and we found that these four factors co-occupied 58 promoters. Interestingly, when Oct4 and Sox2 were analyzed as core factors, Klf4 functioned to enhance the core factors for development regulation, whereas c-Myc seemed to play a distinct role in regulating metabolism. The pathway analysis revealed that Yamanaka factors collectively regulate a developmental signaling network composed of 16 developmental signaling pathways, nine of which represent earlier unknown pathways in ES cells, including apoptosis and cell-cycle pathways. We further analyzed data from a recent study examining Yamanaka factors in mouse ES cells. Interestingly, this analysis also revealed 16 developmental signaling pathways, of which 14 pathways overlap with the ones revealed by this study, despite that the target genes and the signaling pathways regulated by each individual Yamanaka factor differ significantly between these two datasets. We suggest that Yamanaka factors critically regulate a developmental signaling network composed of approximately a dozen crucial developmental signaling pathways to maintain the pluripotency of ES cells and probably also to induce pluripotent stem cells.

Keywords:

embryonic stem cell, pluripotency, Yamanaka factor, signal pathway, ChIP-on-chip

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