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Direct reprogramming of somatic cells is promoted by maternal transcription factor Glis1

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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Figure 1: Promotion of mouse iPSC generation by GLIS1.
Figure 2: Promotion of human iPSC generation by GLIS1.
Figure 3: Characterization of Glis1: expression and roles during iPSC generation.
Figure 4: Characterization of Glis1: target genes and protein–protein interactions.

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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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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 to Naoki Goshima or Shinya Yamanaka.

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The authors declare no competing financial interests.

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This file contains Supplementary Figures 1-10 with legends and Supplementary Tables 1-6. (PDF 2558 kb)

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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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