Fig. 4. A transcription factor network to control ES cell self-renewal and differentiation. (A) Transcriptional regulation of the mouse Oct3/4 gene. There are four evolutionally conserved regions (CR1-4) that contain multiple transcription factor (TF) binding sites. The TFs that bind to these sites are shown above and either activate (red) or repress (blue) transcription. DE, distal enhancer; PE, proximal enhancer; PP, proximal promoter. (B) Transcription factor networks for pluripotent stem cells (green), trophectoderm (yellow) and primitive (extraembryonic) endoderm (blue). Positive-feedback loops between Oct3/4, Sox2 and Nanog maintain their expression to promote continuous ES cell self-renewal. Cdx2 is autoregulated and forms a reciprocal inhibitory loop with Oct3/4, which acts to establish their mutually exclusive expression patterns. A similar regulatory loop, not yet confirmed, might exist for Nanog and Gata6. A combination of positive-feedback loops and reciprocal inhibitory loops converts continuous input parameters into a bimodal probability distribution, resulting in a clear segregation of these cell lineages (see text for details). Coup-tfs and Gcnf act as a negative-feedback system to repress Oct3/4 completely.