Transcription Elongation Factor Tcea3 Regulates the Pluripotent Differentiation Potential of Mouse Embryonic Stem Cells Via the Lefty1-Nodal-Smad2 Pathway§

Authors

  • Kyung-Soon Park,

    Corresponding author
    1. Department of Biomedical Science, College of Life Science andSeoul, Korea
    2. CHA Stem Cell Institute, CHA University, Seoul, Korea
    • Department of Biomedical Science, College of Life Science, CHA University, #606-16 Yeoksam-dong, Gangnam-gu, Seoul 135-081, Korea
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    • Tel.: 82-2-3468-3598; Fax: 82-2-538-4102

  • Young Cha,

    1. Department of Biomedical Science, College of Life Science andSeoul, Korea
    2. CHA Stem Cell Institute, CHA University, Seoul, Korea
    3. Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, Massachusetts, USA
    4. Harvard Stem Cell Institute, Boston, Massachusetts, USA
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  • Chun-Hyung Kim,

    1. Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, Massachusetts, USA
    2. Harvard Stem Cell Institute, Boston, Massachusetts, USA
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  • Hee-Jin Ahn,

    1. Department of Biomedical Science, College of Life Science andSeoul, Korea
    2. CHA Stem Cell Institute, CHA University, Seoul, Korea
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  • Dohoon Kim,

    1. Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, Massachusetts, USA
    2. Harvard Stem Cell Institute, Boston, Massachusetts, USA
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  • Sanghyeok Ko,

    1. Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, Massachusetts, USA
    2. Harvard Stem Cell Institute, Boston, Massachusetts, USA
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  • Kyeoung-Hwa Kim,

    1. Department of Biomedical Science, College of Life Science andSeoul, Korea
    2. CHA Stem Cell Institute, CHA University, Seoul, Korea
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  • Mi-Yoon Chang,

    1. Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, Massachusetts, USA
    2. Harvard Stem Cell Institute, Boston, Massachusetts, USA
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  • Jong-Hyun Ko,

    1. Department of Biological Sciences, Seoul National University, Seoul, Korea
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  • Yoo-Sun Noh,

    1. Department of Biological Sciences, Seoul National University, Seoul, Korea
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  • Yong-Mahn Han,

    1. Department of Biological Sciences and Center for Stem Cell Differentiation, KAIST, Daejeon, Korea
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  • Jonghwan Kim,

    1. Section of Molecular Cell and Developmental Biology and Institute for Cellular and Molecular Biology, The University of Texas at Austin, Texas, USA
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  • Jihwan Song,

    1. Department of Biomedical Science, College of Life Science andSeoul, Korea
    2. CHA Stem Cell Institute, CHA University, Seoul, Korea
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  • Jin Young Kim,

    1. Division of Mass Spectrometry, Korea Basic Science Institute, Chungbuk, Korea
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  • Paul J. Tesar,

    1. Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
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  • Robert Lanza,

    1. Advanced Cell Technology, Marlborough, Massachusetts, USA
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  • Kyung-Ah Lee,

    1. Department of Biomedical Science, College of Life Science andSeoul, Korea
    2. CHA Stem Cell Institute, CHA University, Seoul, Korea
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  • Kwang-Soo Kim

    Corresponding author
    1. CHA Stem Cell Institute, CHA University, Seoul, Korea
    2. Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, Belmont, Massachusetts, USA
    3. Harvard Stem Cell Institute, Boston, Massachusetts, USA
    • Molecular Neurobiology Laboratory, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, Massachusetts 02478, USA
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    • Telephone: 1-617-855-2024; Fax: 1-617-855-3479


  • Author contributions: K.-S.P. and K.-S.K.: concept and design, data analysis and interpretation, and writing; Y.C.: concept and design, collection and/or assembly of data, and data analysis and interpretation; C.-H.K., H.-J.A., D.K., S.K., K.-H.K., M.-Y.C., J.-H.K., J.Y.K., J.K., and J.S.: collection and/or assembly of data; Y.-S.N., Y.-M.H., P.J.T., R.L., and K.-A.L.: data analysis and interpretation. K.-S.P. and Y.C. contributed equally to this article.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLSEXPRESS November 25, 2012.

Abstract

Self-renewal and pluripotency are hallmark properties of pluripotent stem cells, including embryonic stem cells (ESCs) and iPS cells. Previous studies revealed the ESC-specific core transcription circuitry and showed that these core factors (e.g., Oct3/4, Sox2, and Nanog) regulate not only self-renewal but also pluripotent differentiation. However, it remains elusive how these two cell states are regulated and balanced during in vitro replication and differentiation. Here, we report that the transcription elongation factor Tcea3 is highly enriched in mouse ESCs (mESCs) and plays important roles in regulating the differentiation. Strikingly, altering Tcea3 expression in mESCs did not affect self-renewal under nondifferentiating condition; however, upon exposure to differentiating cues, its overexpression impaired in vitro differentiation capacity, and its knockdown biased differentiation toward mesodermal and endodermal fates. Furthermore, we identified Lefty1 as a downstream target of Tcea3 and showed that the Tcea3-Lefty1-Nodal-Smad2 pathway is an innate program critically regulating cell fate choices between self-replication and differentiation commitment. Together, we propose that Tcea3 critically regulates pluripotent differentiation of mESCs as a molecular rheostat of Nodal-Smad2/3 signaling. STEM CELLS2013;31:282–292

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