GCNF-Dependent Activation of Cyclin D1 Expression via Repression of Mir302a During ESC Differentiation

Authors

  • Hongran Wang,

    1. Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, USA
    2. Department of Surgery, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, USA
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  • Xiaohong Wang,

    1. Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, USA
    2. Department of Surgery, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, USA
    3. Stem Cell Center, Texas Heart Institute, Houston, Texas, USA
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  • Trevor K. Archer,

    1. Chromatin and Gene Expression Section, Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, North Carolina, USA
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  • Thomas P. Zwaka,

    1. Department of Developmental & Regenerative Medicine, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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  • Austin J. Cooney

    Corresponding author
    1. Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, USA
    2. Department of Surgery, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, USA
    • Correspondence: Austin J. Cooney, Ph.D., Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA. Telephone: 1-713-798-6250; Fax: 1-713-790-1275; e-mail: acooney@bcm.edu

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Abstract

Cyclin D1 plays an important role in the regulation of cellular proliferation and its expression is activated during gastrulation in the mouse; however, it remains unknown how cyclin D1 expression is regulated during early embryonic development. Here, we define the role of germ cell nuclear factor (GCNF) in the activation of cyclin D1 expression during embryonic stem cell (ESC) differentiation as a model of early development. During our study of GCNF knockout (GCNF/) ESC, we discovered that loss of GCNF leads to the repression of cyclin D1 activation during ESC differentiation. This was determined to be an indirect effect of deregulation Mir302a, which is a cyclin D1 suppressor via binding to the 3′UTR of cyclin D1 mRNA. Moreover, we showed that Mir302 is a target gene of GCNF that inhibits Mir302 expression by binding to a DR0 element within its promoter. Inhibition of Mir302a using Mir302 inhibitor during differentiation of GCNF/ ESCs restored cyclin D1 expression. Similarly over-expression of GCNF during differentiation of GCNF/ ESCs rescued the inhibition of Mir302a expression and the activation of cyclin D1. These results reveal that GCNF plays a key role in regulating activation of cyclin D1 expression via inhibition of Mir302a. Stem Cells 2014;32:1527–1537

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