NuRD Blocks Reprogramming of Mouse Somatic Cells into Pluripotent Stem Cells§

Authors

  • Min Luo,

    1. Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen, China
    2. Shenzhen Center for Disease Control and Prevention, Shenzhen, China
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  • Te Ling,

    1. College of Life Sciences, Capital Normal University, Beijing, China
    2. Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, National Key Laboratory of Protein Engineering and Plant Gene Engineering, School of Life Science, Peking University, Beijing, China
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  • Wenbing Xie,

    1. Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, National Key Laboratory of Protein Engineering and Plant Gene Engineering, School of Life Science, Peking University, Beijing, China
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  • He Sun,

    1. Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen, China
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  • Yonggang Zhou,

    1. Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
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  • Qiaoyun Zhu,

    1. Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, National Key Laboratory of Protein Engineering and Plant Gene Engineering, School of Life Science, Peking University, Beijing, China
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  • Meili Shen,

    1. Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, National Key Laboratory of Protein Engineering and Plant Gene Engineering, School of Life Science, Peking University, Beijing, China
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  • Le Zong,

    1. Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, National Key Laboratory of Protein Engineering and Plant Gene Engineering, School of Life Science, Peking University, Beijing, China
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  • Guoliang Lyu,

    1. Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, National Key Laboratory of Protein Engineering and Plant Gene Engineering, School of Life Science, Peking University, Beijing, China
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  • Yun Zhao,

    1. Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
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  • Tao Ye,

    1. Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hong Kong
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  • Jun Gu,

    1. Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, National Key Laboratory of Protein Engineering and Plant Gene Engineering, School of Life Science, Peking University, Beijing, China
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  • Wei Tao,

    Corresponding author
    1. Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, National Key Laboratory of Protein Engineering and Plant Gene Engineering, School of Life Science, Peking University, Beijing, China
    • School of Life Science, Peking University, Beijing, 100871, China
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    • Telephone: 86-10-62767581; Fax: 86-10-62751526

  • Zhigang Lu,

    Corresponding author
    1. Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen, China
    • Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen, 518005, China
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    • Telephone: 86-755-26032949; Fax: 86-755-26035334

  • Ingrid Grummt

    Corresponding author
    1. Division of Molecular Biology of the Cell II, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany
    • German Cancer Research Center, DKFZ-ZMBH Alliance, INF 581, D-69120 Heidelberg, Germany
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  • Author contributions: Z.L., W.T., and I.G.: conception and design, data analysis and interpretation, writing and approval of manuscript; Z.L., M.L., T.L., H.S., and W.X.: collection and assembly of data, data analysis and interpretation; Y.G.Z.: data analysis and interpretation; Q.Z., M.S., L.Z., and G.L.: collection and assembly of data; Y.Z., T.Y., J.G.: other (support of manuscript); M.L., T.L. W.X., and H.S. contributed equally to this article.

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

  • §

    first published online in STEM CELLS EXPRESS March 26, 2013.

Abstract

Reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) by overexpression of a defined set of transcription factors requires epigenetic changes in pluripotency genes. Nuclear reprogramming is an inefficient process and the molecular mechanisms that reset the epigenetic state during iPSC generation are largely unknown. Here, we show that downregulation of the nucleosome remodeling and deacetylation (NuRD) complex is required for efficient reprogramming. Overexpression of Mbd3, a subunit of NuRD, inhibits induction of iPSCs by establishing heterochromatic features and silencing embryonic stem cell-specific marker genes, including Oct4 and Nanog. Depletion of Mbd3, on the other hand, improves reprogramming efficiency and facilitates the formation of pluripotent stem cells that are capable of generating viable chimeric mice, even in the absence of c-Myc or Sox2. The results establish Mbd3/NuRD as an important epigenetic regulator that restricts the expression of key pluripotency genes, suggesting that drug-induced downregulation of Mbd3/NuRD may be a powerful means to improve the efficiency and fidelity of reprogramming. STEM Cells2013;31:1278–1286

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