Nature Genetics 38, 431 - 440 (2006)
Published online: 5 March 2006; | doi:10.1038/ng1760
The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cellsYuin-Han Loh1, 2, 7, Qiang Wu1, 7, Joon-Lin Chew1, 2, 7, Vinsensius B Vega3, Weiwei Zhang1, 2, Xi Chen1, 2, Guillaume Bourque3, Joshy George3, Bernard Leong3, Jun Liu4, Kee-Yew Wong5, Ken W Sung3, Charlie W H Lee3, Xiao-Dong Zhao4, Kuo-Ping Chiu3, Leonard Lipovich3, Vladimir A Kuznetsov3, Paul Robson2, 5, Lawrence W Stanton5, Chia-Lin Wei4, Yijun Ruan4, Bing Lim5, 6
& Huck-Hui Ng1, 21
Gene Regulation Laboratory, Genome Institute of Singapore, Singapore 138672. 2
Department of Biological Sciences, National University of Singapore, Singapore 117543. 3
Information & Mathematical Sciences Group, Genome Institute of Singapore, Singapore 138672. 4
Cloning and Sequencing Group, Genome Institute of Singapore, Singapore 138672. 5
Stem Cell & Developmental Biology, Genome Institute of Singapore, Singapore 138672. 6
Harvard Institutes of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA. 7
These authors contributed equally to this work.
Correspondence should be addressed to Yijun Ruan ruanyj@gis.a-star.edu.sg or Huck-Hui Ng nghh@gis.a-star.edu.sg Oct4 and Nanog are transcription factors required to maintain the pluripotency and self-renewal of embryonic stem (ES) cells. Using the chromatin immunoprecipitation paired-end ditags method, we mapped the binding sites of these factors in the mouse ES cell genome. We identified 1,083 and 3,006 high-confidence binding sites for Oct4 and Nanog, respectively. Comparative location analyses indicated that Oct4 and Nanog overlap substantially in their targets, and they are bound to genes in different configurations. Using de novo motif discovery algorithms, we defined the cis-acting elements mediating their respective binding to genomic sites. By integrating RNA interference–mediated depletion of Oct4 and Nanog with microarray expression profiling, we demonstrated that these factors can activate or suppress transcription. We further showed that common core downstream targets are important to keep ES cells from differentiating. The emerging picture is one in which Oct4 and Nanog control a cascade of pathways that are intricately connected to govern pluripotency, self-renewal, genome surveillance and cell fate determination.
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