Direct reprogramming of somatic cells is promoted by maternal transcription factor Glis1 (original) (raw)
- Letter
- Published: 08 June 2011
- Kei Yamaguchi3,
- Tomonori Nakamura1,4,
- Ran Shibukawa1,2,
- Ikumi Kodanaka1,2,
- Tomoko Ichisaka1,4,
- Yoshifumi Kawamura3,
- Hiromi Mochizuki3,
- Naoki Goshima5 &
- …
- Shinya Yamanaka1,2,4,6
Nature volume 474, pages 225–229 (2011)Cite this article
- 11k Accesses
- 299 Citations
- 40 Altmetric
- Metrics details
Subjects
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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Additional access options:
Similar content being viewed by others
Accession codes
Primary accessions
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.
References
- Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006)
Article CAS Google Scholar - Nakagawa, M. et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nature Biotechnol. 26, 101–106 (2008)
Article CAS Google Scholar - Yamanaka, S. A fresh look at iPS cells. Cell 137, 13–17 (2009)
Article CAS Google Scholar - Yamanaka, S. Strategies and new developments in the generation of patient-specific pluripotent stem cells. Cell Stem Cell 1, 39–49 (2007)
Article CAS Google Scholar - Yamanaka, S. Elite and stochastic models for induced pluripotent stem cell generation. Nature 460, 49–52 (2009)
Article ADS CAS Google Scholar - Yamanaka, S. & Blau, H. M. Nuclear reprogramming to a pluripotent state by three approaches. Nature 465, 704–712 (2010)
Article ADS CAS Google Scholar - Wilmut, I., Schnieke, A. E., McWhir, J., Kind, A. J. & Campbell, K. H. Viable offspring derived from fetal and adult mammalian cells. Nature 385, 810–813 (1997)
Article ADS CAS Google Scholar - Egli, D., Rosains, J., Birkhoff, G. & Eggan, K. Developmental reprogramming after chromosome transfer into mitotic mouse zygotes. Nature 447, 679–685 (2007)
Article ADS CAS Google Scholar - Okita, K., Ichisaka, T. & Yamanaka, S. Generation of germ-line competent induced pluripotent stem cells. Nature 448, 313–317 (2007)
Article ADS CAS Google Scholar - Kim, Y. S. et al. Identification of Glis1, a novel Gli-related, Kruppel-like zinc finger protein containing transactivation and repressor functions. J. Biol. Chem. 277, 30901–30913 (2002)
Article CAS Google Scholar - Guo, G. et al. Resolution of cell fate decisions revealed by single-cell gene expression analysis from zygote to blastocyst. Dev. Cell 18, 675–685 (2010)
Article CAS Google Scholar - Hong, H. et al. Suppression of induced pluripotent stem cell generation by the p53-p21 pathway. Nature 460, 1132–1135 (2009)
Article ADS CAS Google Scholar - Feng, B. et al. Reprogramming of fibroblasts into induced pluripotent stem cells with orphan nuclear receptor Esrrb. Nature Cell Biol. 11, 197–203 (2009)
Article CAS Google Scholar - Marson, A. et al. Wnt signaling promotes reprogramming of somatic cells to pluripotency. Cell Stem Cell 3, 132–135 (2008)
Article CAS Google Scholar - Yu, J. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917–1920 (2007)
Article ADS CAS Google Scholar - Silva, J. et al. Nanog is the gateway to the pluripotent ground state. Cell 138, 722–737 (2009)
Article CAS Google Scholar - Nakagawa, M., Takizawa, N., Narita, M., Ichisaka, T. & Yamanaka, S. Promotion of direct reprogramming by transformation-deficient Myc. Proc. Natl Acad. Sci. USA 107, 14152–14157 (2010)
Article ADS CAS Google Scholar - Samavarchi-Tehrani, P. et al. Functional genomics reveals a BMP-driven mesenchymal-to-epithelial transition in the initiation of somatic cell reprogramming. Cell Stem Cell 7, 64–77 (2010)
Article CAS Google Scholar - Li, R. et al. A mesenchymal-to-epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts. Cell Stem Cell 7, 51–63 (2010)
Article CAS Google Scholar - Niwa, H., Burdon, T., Chambers, I. & Smith, A. Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. Genes Dev. 12, 2048–2060 (1998)
Article CAS Google Scholar - Goshima, N. et al. Human protein factory for converting the transcriptome into an _in vitro_-expressed proteome. Nature Methods 5, 1011–1017 (2008)
Article CAS Google Scholar - Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007)
Article CAS Google Scholar - Morita, S., Kojima, T. & Kitamura, T. Plat-E: an efficient and stable system for transient packaging of retroviruses. Gene Ther. 7, 1063–1066 (2000)
Article CAS Google Scholar - McMahon, A. P. & Bradley, A. The _Wnt_-1 (_int_-1) proto-oncogene is required for development of a large region of the mouse brain. Cell 62, 1073–1085 (1990)
Article CAS Google Scholar - Hashimoto, J. et al. Novel in vitro protein fragment complementation assay applicable to high-throughput screening in a 1536-well format. J. Biomol. Screen. 14, 970–979 (2009)
Article CAS Google Scholar
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.
Author information
Authors and Affiliations
- 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 - Yamanaka iPS Cell Special Project, JST, Kawaguchi 332-0012, Japan ,
Momoko Maekawa, Ran Shibukawa, Ikumi Kodanaka & Shinya Yamanaka - Japan Biological Informatics Consortium, Tokyo 135-0064, Japan ,
Kei Yamaguchi, Yoshifumi Kawamura & Hiromi Mochizuki - Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto 606-8507, Japan ,
Tomonori Nakamura, Tomoko Ichisaka & Shinya Yamanaka - Biomedicinal Information Research Center, National Institute of Advanced Industrial Science and Technology, Tokyo 135-0064, Japan ,
Naoki Goshima - Gladstone Institute of Cardiovascular Disease, San Francisco, 94158, California, USA
Shinya Yamanaka
Authors
- Momoko Maekawa
You can also search for this author inPubMed Google Scholar - Kei Yamaguchi
You can also search for this author inPubMed Google Scholar - Tomonori Nakamura
You can also search for this author inPubMed Google Scholar - Ran Shibukawa
You can also search for this author inPubMed Google Scholar - Ikumi Kodanaka
You can also search for this author inPubMed Google Scholar - Tomoko Ichisaka
You can also search for this author inPubMed Google Scholar - Yoshifumi Kawamura
You can also search for this author inPubMed Google Scholar - Hiromi Mochizuki
You can also search for this author inPubMed Google Scholar - Naoki Goshima
You can also search for this author inPubMed Google Scholar - Shinya Yamanaka
You can also search for this author inPubMed Google Scholar
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.
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Information
This file contains Supplementary Figures 1-10 with legends and Supplementary Tables 1-6. (PDF 2558 kb)
PowerPoint slides
Rights and permissions
About this article
Cite this article
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
- Received: 25 May 2010
- Accepted: 11 April 2011
- Published: 08 June 2011
- Issue Date: 09 June 2011
- DOI: https://doi.org/10.1038/nature10106
This article is cited by
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.