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

  1. Hiroyuki Hirai1,2,
  2. Tetsuya Tani1,2,3,
  3. Nobuko Katoku-Kikyo1,4,
  4. Steven Kellner1,2,
  5. Peter Karian1,2,
  6. Meri Firpo1,4,
  7. Nobuaki Kikyo1,2,¶,*

Article first published online: 19 AUG 2011

DOI: 10.1002/stem.684

Issue

STEM CELLS

STEM CELLS

Volume 29, Issue 9, pages 1349–1361, September 2011

Additional Information

How to Cite

Hirai, H., Tani, T., Katoku-Kikyo, N., Kellner, S., Karian, P., Firpo, M. and Kikyo, N. (2011), Radical Acceleration of Nuclear Reprogramming by Chromatin Remodeling with the Transactivation Domain of MyoD. STEM CELLS, 29: 1349–1361. doi: 10.1002/stem.684

Author Information

  1. 1

    Stem Cell Institute, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA

  2. 2

    Division of Haematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA

  3. 3

    Laboratory of Animal Reproduction, Department of Agriculture, Kinki University, Nara, Japan

  4. 4

    Division of Endocrinology, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA

  1. Telephone: 612-624-0498; Fax: 612-624-2436

*Stem Cell Institute, University of Minnesota, MTRF, Room 2-216, 2001 6th St SE, Minneapolis, Minnesota 55455, USA

  1. †

    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.

  2. ‡

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

  3. §

    First published online in STEM CELLSEXPRESS July 5, 2011.

  4. Telephone: 612-624-0498; Fax: 612-624-2436

Publication History

  1. Issue published online: 19 AUG 2011
  2. Article first published online: 19 AUG 2011
  3. Accepted manuscript online: 5 JUL 2011 10:34AM EST
  4. Manuscript Accepted: 8 JUN 2011
  5. Manuscript Received: 3 APR 2011

Funded by

  • Richard M. Schulze Family Foundation
  • NIH. Grant Number: R01 DK082430
  • Leukemia Research Fund
  • Academic Health Center of the University of Minnesota

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Keywords:

  • Embryonic stem cells;
  • Induced pluripotent stem cells;
  • MyoD;
  • Oct4

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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