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.