Epigenetic Reprogramming of the Germ Cell Nuclear Factor Gene Is Required for Proper Differentiation of Induced Pluripotent Cells

Authors

  • Hongran Wang,

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

    1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
    2. Stem cell center, Texas Heart Institute, Houston, Texas, USA
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    • Author contributions: H.W.: conception and design, collection and/or assembly of data, data analysis and interpretation, and manuscript writing; X.W.: collection and/or assembly of data and data analysis and interpretation; X.X..: collection and/or assembly of data; T.P.Z.: data analysis and interpretation; A.J.C.: conception and design, data analysis and interpretation, manuscript writing, financial support, and final approval of manuscript.

  • Xueping Xu,

    1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
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    • Author contributions: H.W.: conception and design, collection and/or assembly of data, data analysis and interpretation, and manuscript writing; X.W.: collection and/or assembly of data and data analysis and interpretation; X.X..: collection and/or assembly of data; T.P.Z.: data analysis and interpretation; A.J.C.: conception and design, data analysis and interpretation, manuscript writing, financial support, and final approval of manuscript.

  • Thomas P. Zwaka,

    1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
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    • Author contributions: H.W.: conception and design, collection and/or assembly of data, data analysis and interpretation, and manuscript writing; X.W.: collection and/or assembly of data and data analysis and interpretation; X.X..: collection and/or assembly of data; T.P.Z.: data analysis and interpretation; A.J.C.: conception and design, data analysis and interpretation, manuscript writing, financial support, and final approval of manuscript.

  • Austin J. Cooney

    Corresponding author
    1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
    • Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor plaza, Houston, Texas 77030, USA. E-mail: acooney@bcm.edu Telephone: +1-713-798-6250; Fax: +1-713-790-1275

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Abstract

Somatic cells have been reprogrammed into induced pluripotent stem (iPS) cells that recapitulate the pluripotent nature of embryonic stem (ES) cells. Reduced pluripotency and variable differentiation capacities have hampered progress with this technology for applications in regeneration medicine. We have previously shown that germ cell nuclear factor (Gcnf) is required for the repression of pluripotency genes during ES cell differentiation and embryonic development. Here we report that iPS cell lines, in which the Gcnf gene was properly reprogrammed, allowing expression of Gcnf, repress pluripotency genes during subsequent differentiation. In contrast, iPS clones in which the Gcnf gene was not reprogrammed maintained pluripotency gene expression during differentiation and did not differentiate properly either in vivo or in vitro. These mal-reprogrammed cells recapitulated the phenotype of Gcnf knockout (Gcnf−/−) ES cells. Reintroduction of Gcnf into either the Gcnf negative iPS cells or the Gcnf−/− ES cells rescued repression of Oct4 during differentiation. Our findings establish a key role for Gcnf as a regulator of iPS cell pluripotency gene expression. It also demonstrates that reactivation of the Gcnf gene may serve as a marker to distinguish completely reprogrammed iPS cells from incompletely pluripotent cells, which would make therapeutic use of iPS cells safer and more practical as it would reduce the oncogenic potential of iPS cells. STEM Cells 2013;31:2659–2666

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