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      Transcriptional Activation by Oct4 Is Sufficient for the Maintenance and Induction of Pluripotency

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          Summary

          Oct4 is an essential regulator of pluripotency in vivo and in vitro in embryonic stem cells, as well as a key mediator of the reprogramming of somatic cells into induced pluripotent stem cells. It is not known whether activation and/or repression of specific genes by Oct4 is relevant to these functions. Here, we show that fusion proteins containing the coding sequence of Oct4 or Xlpou91 (the Xenopus homolog of Oct4) fused to activating regions, but not those fused to repressing regions, behave as Oct4, suppressing differentiation and promoting maintenance of undifferentiated phenotypes in vivo and in vitro. An Oct4 activation domain fusion supported embryonic stem cell self-renewal in vitro at lower concentrations than that required for Oct4 while alleviating the ordinary requirement for the cytokine LIF. At still lower levels of the fusion, LIF dependence was restored. We conclude that the necessary and sufficient function of Oct4 in promoting pluripotency is to activate specific target genes.

          Abstract

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          Highlights

          ► Function of Oct4 as an activator is sufficient to induce and maintain pluripotency ► When Oct4 is converted to a strong activator, it supports pluripotency more effectively ► When Oct4 is converted to a repressor, it induces differentiation

          Abstract

          Oct4 is a key transcription factor involved in both the maintenance of embryonic stem cells (ESCs) and the reprogramming of somatic cells to an ESC-like pluripotent state (induced pluripotent stem cells; iPSCs). How does Oct4 support and induce these states? Here, Brickman and colleagues show that activation of a network of gene expression by Oct4 is sufficient to both maintain and reprogram pluripotent cell states.

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          Most cited references38

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          Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells.

          G Martin (1981)
          This report describes the establishment directly from normal preimplantation mouse embryos of a cell line that forms teratocarcinomas when injected into mice. The pluripotency of these embryonic stem cells was demonstrated conclusively by the observation that subclonal cultures, derived from isolated single cells, can differentiate into a wide variety of cell types. Such embryonic stem cells were isolated from inner cell masses of late blastocysts cultured in medium conditioned by an established teratocarcinoma stem cell line. This suggests that such conditioned medium might contain a growth factor that stimulates the proliferation or inhibits the differentiation of normal pluripotent embryonic cells, or both. This method of obtaining embryonic stem cells makes feasible the isolation of pluripotent cells lines from various types of noninbred embryo, including those carrying mutant genes. The availability of such cell lines should made possible new approaches to the study of early mammalian development.
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            Establishment in culture of pluripotential cells from mouse embryos.

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              Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells.

              Embryonic stem (ES) cells undergo extended proliferation while remaining poised for multilineage differentiation. A unique network of transcription factors may characterize self-renewal and simultaneously suppress differentiation. We applied expression cloning in mouse ES cells to isolate a self-renewal determinant. Nanog is a divergent homeodomain protein that directs propagation of undifferentiated ES cells. Nanog mRNA is present in pluripotent mouse and human cell lines, and absent from differentiated cells. In preimplantation embryos, Nanog is restricted to founder cells from which ES cells can be derived. Endogenous Nanog acts in parallel with cytokine stimulation of Stat3 to drive ES cell self-renewal. Elevated Nanog expression from transgene constructs is sufficient for clonal expansion of ES cells, bypassing Stat3 and maintaining Oct4 levels. Cytokine dependence, multilineage differentiation, and embryo colonization capacity are fully restored upon transgene excision. These findings establish a central role for Nanog in the transcription factor hierarchy that defines ES cell identity.
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                Author and article information

                Journal
                Cell Rep
                Cell Rep
                Cell Reports
                Cell Press
                2211-1247
                23 February 2012
                23 February 2012
                : 1
                : 2
                : 99-109
                Affiliations
                [1 ]MRC Centre for Regenerative Medicine - Institute for Stem Cell Research, School of Biological Sciences, 5 Little France Drive, University of Edinburgh, EH16 4UU Edinburgh, UK
                [2 ]Laboratory of Genetics, National Institute on Aging, NIH Biomedical Research Centre, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224, USA
                [3 ]Molecular Biology Program, Memorial Sloan Kettering Cancer Center, 430E 67th St, New York, NY 10065, USA
                [4 ]Center for Cell Engineering, Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
                [5 ]The Danish Stem Cell Centre - DanStem, University of Copenhagen, 3B Blegdamsvej, DK-2200 Copenhagen N
                Author notes
                []Corresponding author joshua.brickman@ 123456sund.ku.dk
                [∗∗ ]Corresponding author m-ptashne@ 123456mskcc.org
                [6]

                Present address: The Wellcome Trust Centre for Stem Cell Research, University of Cambridge, Tennis Court Road, CB2 1QR Cambridge, UK

                [7]

                Present address: Division of Hematology, University of Washington, 1705 NE Pacific St., Box 357710, Seattle, WA 98195, USA

                Article
                S2211-1247(11)00012-X
                10.1016/j.celrep.2011.12.002
                3778438
                22832160
                2fa7abbe-21a1-46a2-918a-aed0aa93397f
                © 2012 The Authors

                This document may be redistributed and reused, subject to certain conditions.

                History
                : 17 October 2011
                : 19 November 2011
                : 15 December 2011
                Categories
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                Cell biology
                Cell biology

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