Radical Acceleration of Nuclear Reprogramming by Chromatin Remodeling with the Transactivation Domain of MyoD§

Authors

  • Hiroyuki Hirai,

    1. Stem Cell Institute, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
    2. Division of Haematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
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  • Tetsuya Tani,

    1. Stem Cell Institute, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
    2. Division of Haematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
    3. Laboratory of Animal Reproduction, Department of Agriculture, Kinki University, Nara, Japan
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  • Nobuko Katoku-Kikyo,

    1. Stem Cell Institute, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
    2. Division of Endocrinology, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
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  • Steven Kellner,

    1. Stem Cell Institute, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
    2. Division of Haematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
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  • Peter Karian,

    1. Stem Cell Institute, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
    2. Division of Haematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
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  • Meri Firpo,

    1. Stem Cell Institute, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
    2. Division of Endocrinology, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
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  • Nobuaki Kikyo

    Corresponding author
    1. Stem Cell Institute, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
    2. Division of Haematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
    • Stem Cell Institute, University of Minnesota, MTRF, Room 2-216, 2001 6th St SE, Minneapolis, Minnesota 55455, USA
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    • Telephone: 612-624-0498; Fax: 612-624-2436


  • Author contributions: H.H. and N.K.: conception and design, collection and assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; T.T.: conception and design, collection and assembly of data, data analysis and, interpretation, final approval of manuscript; N.K.-K., S.K., and P.K.: collection and assembly of data, final approval of manuscript; M.F.: financial support, data analysis and interpretation, final approval of manuscript.

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

  • §

    First published online in STEM CELLSEXPRESS July 5, 2011.

Abstract

Induced pluripotent stem cells (iPSCs) can be created by reprogramming differentiated cells through introduction of defined genes, most commonly Oct4, Sox2, Klf4, and c-Myc (OSKM). However, this process is slow and extremely inefficient. Here, we demonstrate radical acceleration of iPSC creation with a fusion gene between Oct4 and the powerful transactivation domain (TAD) of MyoD (M3O). Transduction of M3O as well as Sox2, Klf4, and c-Myc into fibroblasts effectively remodeled patterns of DNA methylation, chromatin accessibility, histone modifications, and protein binding at pluripotency genes, raising the efficiency of making mouse and human iPSCs more than 50-fold in comparison to OSKM. These results identified that one of the most critical barriers to iPSC creation is poor chromatin accessibility and protein recruitment to pluripotency genes. The MyoD TAD has a capability of overcoming this problem. Our approach of fusing TADs to unrelated transcription factors has far-reaching implications as a powerful tool for transcriptional reprogramming beyond application to iPSC technology. STEM CELLS 2011; 29:1349–1361

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