Direct reprogramming of somatic cells is promoted by maternal transcription factor Glis1 (original) (raw)

Nature volume 474, pages 225–229 (2011)Cite this article

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Abstract

Induced pluripotent stem cells (iPSCs) are generated from somatic cells by the transgenic expression of three transcription factors collectively called OSK: Oct3/4 (also called Pou5f1), Sox2 and Klf41. However, the conversion to iPSCs is inefficient. The proto-oncogene Myc enhances the efficiency of iPSC generation by OSK but it also increases the tumorigenicity of the resulting iPSCs2. Here we show that the Gli-like transcription factor Glis1 (Glis family zinc finger 1) markedly enhances the generation of iPSCs from both mouse and human fibroblasts when it is expressed together with OSK. Mouse iPSCs generated using this combination of transcription factors can form germline-competent chimaeras. Glis1 is enriched in unfertilized oocytes and in embryos at the one-cell stage. DNA microarray analyses show that Glis1 promotes multiple pro-reprogramming pathways, including Myc, Nanog, Lin28, Wnt, Essrb and the mesenchymal–epithelial transition. These results therefore show that Glis1 effectively promotes the direct reprogramming of somatic cells during iPSC generation.

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Gene Expression Omnibus

Data deposits

The microarray data are available from the Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo/) with the accession number GSE26431.

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Acknowledgements

We thank T. Yamamoto, Y. Yamada and the members of our laboratory for valuable scientific discussions and administrative support. We thank M. Nakagawa, H. Seki, M. Murakami, A. Okada, M. Narita, M. Inoue, H. Shiga and T. Matsumoto for technical assistance and H. Suemori (Kyoto University) for human ES cells. This work was supported in part by grants from the New Energy and Industrial Technology Development Organization (NEDO), the Leading Project of the Ministry of Education, Culture, Sports, Science and Technology (MEXT), the Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program) of the Japanese Society for the Promotion of Science (JSPS), Grants-in-Aid for Scientific Research from JSPS and MEXT, and the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO). S.Y. is a member of scientific advisory boards of iPearian Inc. and iPS Academia Japan.

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Authors and Affiliations

  1. Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan ,
    Momoko Maekawa, Tomonori Nakamura, Ran Shibukawa, Ikumi Kodanaka, Tomoko Ichisaka & Shinya Yamanaka
  2. Yamanaka iPS Cell Special Project, JST, Kawaguchi 332-0012, Japan ,
    Momoko Maekawa, Ran Shibukawa, Ikumi Kodanaka & Shinya Yamanaka
  3. Japan Biological Informatics Consortium, Tokyo 135-0064, Japan ,
    Kei Yamaguchi, Yoshifumi Kawamura & Hiromi Mochizuki
  4. Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto 606-8507, Japan ,
    Tomonori Nakamura, Tomoko Ichisaka & Shinya Yamanaka
  5. Biomedicinal Information Research Center, National Institute of Advanced Industrial Science and Technology, Tokyo 135-0064, Japan ,
    Naoki Goshima
  6. Gladstone Institute of Cardiovascular Disease, San Francisco, 94158, California, USA
    Shinya Yamanaka

Authors

  1. Momoko Maekawa
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  2. Kei Yamaguchi
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  3. Tomonori Nakamura
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  4. Ran Shibukawa
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  5. Ikumi Kodanaka
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  6. Tomoko Ichisaka
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  7. Yoshifumi Kawamura
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  8. Hiromi Mochizuki
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  9. Naoki Goshima
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  10. Shinya Yamanaka
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Contributions

M.M. conducted most of the experiments in this study. K.Y. analysed the interactions of proteins. T.N. performed the computer analyses of the DNA microarray data, teratoma experiments, overexpression in ES cells and statistical analysis. R.S. generated mouse iPSCs and characterized mouse and human iPSCs. I.K. generated human iPSCs. T.I. performed the chimaera and teratoma experiments and maintained the mouse lines. Y.K. selected cDNA clones from HuPEX with bioinformatics. H.M. produced the retroviral expression clones. N.G. and S.Y. supervised the project. M.M. and S.Y. wrote the manuscript.

Corresponding authors

Correspondence toNaoki Goshima or Shinya Yamanaka.

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The authors declare no competing financial interests.

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Maekawa, M., Yamaguchi, K., Nakamura, T. et al. Direct reprogramming of somatic cells is promoted by maternal transcription factor Glis1.Nature 474, 225–229 (2011). https://doi.org/10.1038/nature10106

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Editorial Summary

Glis1 substitutes for c-Myc in stem-cell generation

Reprogramming of differentiated somatic cells to induced pluripotent stem (iPS) cells by exogenous expression of key transcription factors (Oct4, Sox2, Klf4 and c-Myc) has potential therapeutic applications. c-Myc enhances the efficiency of reprogramming, but the safety of using this oncogene has long been a concern. Now, Shinya Yamanaka and colleagues have found that the transcription factor Glis1 effectively and specifically promotes reprogramming of human and mouse somatic cells to iPS cells. Glis1 is highly enriched in unfertilized eggs and one-cell-stage embryos, and might be a link between reprogramming during iPS cell generation and after nuclear transfer into zygotes.