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Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells | Nature Genetics
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Cell fate during development is defined by transcription factors that act as molecular switches to activate or repress specific gene expression programmes. The POU transcription factor Oct-3/4 (encoded by Pou5f1) is a candidate regulator in pluripotent and germline cells1,2,3,4 and is essential for the initial formation of a pluripotent founder cell population in the mammalian embryo5. Here we use conditional expression and repression in embryonic stem (ES) cells to determine requirements for Oct-3/4 in the maintenance of developmental potency. Although transcriptional determination has usually been considered as a binary on-off control system, we found that the precise level of Oct-3/4 governs three distinct fates of ES cells. A less than twofold increase in expression causes differentiation into primitive endoderm and mesoderm. In contrast, repression of Oct-3/4 induces loss of pluripotency and dedifferentiation to trophectoderm. Thus a critical amount of Oct-3/4 is required to sustain stem-cell self-renewal, and up- or downregulation induce divergent developmental programmes. Our findings establish a role for Oct-3/4 as a master regulator of pluripotency that controls lineage commitment and illustrate the sophistication of critical transcriptional regulators and the consequent importance of quantitative analyses.
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nature portfolio permissions reprints privacy policy author information authors genome research advertising social media nature s345 nature 344 nature 336 nature 343 nature crispr/cas-based toolkit time-lapse recording facilities vertebrate oct4/pou5 functions pou-domain transcription factor protein-protein interactions facilitated personal data japan data protection springerlink instant access transcription factor expressed mouse development colin pluripotent stem cells factor binding sites embryonic stem cells specific spatial arrangement privacy oct-3/4 induces loss oct-4 transcription factor expand oct4 binding sustain stem-cell permissions controls lineage commitment osteopontin preimplantation enhancer mouse embryonic cells early stem cells lif-deficient cells hybrid cell extinction extra-embryonic membranes content oct-4 european economic area institutional subscriptions read tetracycline-responsive promoters dicistronic targeting constructs endodermally derived tissues progressive lineage analysis neural crest derivatives signalling mechanisms regulating mitotic bookmarking redundancy
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