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      Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells.

      Nature genetics

      genetics, Up-Regulation, Transfection, Transcription, Genetic, metabolism, biosynthesis, Transcription Factors, cytology, Stem Cells, RNA, Messenger, Octamer Transcription Factor-3, Mice, Genes, Reporter, Genes, Regulator, Gene Expression Regulation, Developmental, Down-Regulation, DNA-Binding Proteins, Clone Cells, Cell Lineage, Cell Line, Cell Division, Cell Differentiation, Animals

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          Abstract

          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 cells and is essential for the initial formation of a pluripotent founder cell population in the mammalian embryo. 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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          Journal
          10.1038/74199
          10742100

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