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Genome-wide characterization of the routes to pluripotency

Author

Listed:
  • Samer M. I. Hussein

    (Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada)

  • Mira C. Puri

    (Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada
    University of Toronto, Toronto, Ontario M5T 3H7, Canada)

  • Peter D. Tonge

    (Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada)

  • Marco Benevento

    (Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands
    Netherlands Proteomics Centre, Padualaan 8, 3584CH Utrecht, The Netherlands)

  • Andrew J. Corso

    (Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada
    Institute of Medical Science, University of Toronto, Toronto, Ontario M5T 3H7, Canada)

  • Jennifer L. Clancy

    (The John Curtin School of Medical Research, The Australian National University, Acton (Canberra), ACT 2601, Australia)

  • Rowland Mosbergen

    (Australian Institute for Bioengineering and Nanotechnology, The University of Queensland)

  • Mira Li

    (Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada)

  • Dong-Sung Lee

    (Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul 110-799, South Korea
    Seoul National University College of Medicine, Seoul 110-799, South Korea)

  • Nicole Cloonan

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
    QIMR Berghofer Medical Research Institute, Genomic Biology Lab)

  • David L. A. Wood

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland)

  • Javier Munoz

    (Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands
    Netherlands Proteomics Centre, Padualaan 8, 3584CH Utrecht, The Netherlands
    †Present addresses: Proteomics Unit, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain (J.M.); The University of Queensland Diamantina Institute, Translational Research Institute, 37 Kent Street, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia (K.-A.L.C.).)

  • Robert Middleton

    (Gene and Stem Cell Therapy Program and Bioinformatics Lab, Centenary Institute, Camperdown 2050, NSW, Australia & Sydney Medical School, 31 University of Sydney 2006)

  • Othmar Korn

    (Australian Institute for Bioengineering and Nanotechnology, The University of Queensland)

  • Hardip R. Patel

    (The John Curtin School of Medical Research, The Australian National University, Acton (Canberra), ACT 2601, Australia
    Genome Discovery Unit, The John Curtin School of Medical Research, The Australian National University, Acton (Canberra) 2601, ACT, Australia)

  • Carl A. White

    (Institute of Biomaterials and Biomedical Engineering (IBBME), University of Toronto, Toronto M5S-3G9, Canada
    The Donnelly Centre for Cellular and Biomolecular Research (CCBR), University of Toronto, Toronto M5S 3E1, Canada)

  • Jong-Yeon Shin

    (Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul 110-799, South Korea
    Life Science Institute, Macrogen Inc., Seoul 153-781, South Korea)

  • Maely E. Gauthier

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland)

  • Kim-Anh Lê Cao

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
    †Present addresses: Proteomics Unit, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain (J.M.); The University of Queensland Diamantina Institute, Translational Research Institute, 37 Kent Street, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia (K.-A.L.C.).)

  • Jong-Il Kim

    (Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul 110-799, South Korea
    Seoul National University College of Medicine, Seoul 110-799, South Korea)

  • Jessica C. Mar

    (Albert Einstein College of Medicine of Yeshiva University)

  • Nika Shakiba

    (Institute of Biomaterials and Biomedical Engineering (IBBME), University of Toronto, Toronto M5S-3G9, Canada)

  • William Ritchie

    (Gene and Stem Cell Therapy Program and Bioinformatics Lab, Centenary Institute, Camperdown 2050, NSW, Australia & Sydney Medical School, 31 University of Sydney 2006)

  • John E. J. Rasko

    (Gene and Stem Cell Therapy Program and Bioinformatics Lab, Centenary Institute, Camperdown 2050, NSW, Australia & Sydney Medical School, 31 University of Sydney 2006
    Cell and Molecular Therapies, Royal Prince Alfred Hospital, Camperdown 2050, New South Wales, Australia)

  • Sean M. Grimmond

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland)

  • Peter W. Zandstra

    (Institute of Biomaterials and Biomedical Engineering (IBBME), University of Toronto, Toronto M5S-3G9, Canada
    The Donnelly Centre for Cellular and Biomolecular Research (CCBR), University of Toronto, Toronto M5S 3E1, Canada)

  • Christine A. Wells

    (Australian Institute for Bioengineering and Nanotechnology, The University of Queensland
    College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK)

  • Thomas Preiss

    (The John Curtin School of Medical Research, The Australian National University, Acton (Canberra), ACT 2601, Australia
    Victor Chang Cardiac Research Institute, Darlinghurst (Sydney), New South Wales 2010, Australia)

  • Jeong-Sun Seo

    (Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul 110-799, South Korea
    Seoul National University College of Medicine, Seoul 110-799, South Korea
    Life Science Institute, Macrogen Inc., Seoul 153-781, South Korea)

  • Albert J. R. Heck

    (Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands
    Netherlands Proteomics Centre, Padualaan 8, 3584CH Utrecht, The Netherlands)

  • Ian M. Rogers

    (Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada
    University of Toronto, Toronto, Ontario M5S 1A8, Canada
    University of Toronto, Toronto, Ontario M5S 1E2, Canada)

  • Andras Nagy

    (Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada
    Institute of Medical Science, University of Toronto, Toronto, Ontario M5T 3H7, Canada
    University of Toronto, Toronto, Ontario M5S 1E2, Canada)

Abstract

Somatic cell reprogramming to a pluripotent state continues to challenge many of our assumptions about cellular specification, and despite major efforts, we lack a complete molecular characterization of the reprograming process. To address this gap in knowledge, we generated extensive transcriptomic, epigenomic and proteomic data sets describing the reprogramming routes leading from mouse embryonic fibroblasts to induced pluripotency. Through integrative analysis, we reveal that cells transition through distinct gene expression and epigenetic signatures and bifurcate towards reprogramming transgene-dependent and -independent stable pluripotent states. Early transcriptional events, driven by high levels of reprogramming transcription factor expression, are associated with widespread loss of histone H3 lysine 27 (H3K27me3) trimethylation, representing a general opening of the chromatin state. Maintenance of high transgene levels leads to re-acquisition of H3K27me3 and a stable pluripotent state that is alternative to the embryonic stem cell (ESC)-like fate. Lowering transgene levels at an intermediate phase, however, guides the process to the acquisition of ESC-like chromatin and DNA methylation signature. Our data provide a comprehensive molecular description of the reprogramming routes and is accessible through the Project Grandiose portal at http://www.stemformatics.org.

Suggested Citation

  • Samer M. I. Hussein & Mira C. Puri & Peter D. Tonge & Marco Benevento & Andrew J. Corso & Jennifer L. Clancy & Rowland Mosbergen & Mira Li & Dong-Sung Lee & Nicole Cloonan & David L. A. Wood & Javier , 2014. "Genome-wide characterization of the routes to pluripotency," Nature, Nature, vol. 516(7530), pages 198-206, December.
    • Handle: RePEc:nat:nature:v:516:y:2014:i:7530:d:10.1038_nature14046
    DOI: 10.1038/nature14046
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