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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.
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