Genome-wide characterization of the routes to pluripotency

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 Munoz, Robert Middleton, Othmar Korn, Hardip R. Patel, Carl A. White, Jong-Yeon Shin, Maely E. Gauthier, Kim-Anh Lê Cao, Jong-Il Kim, Jessica C. Mar, Nika Shakiba, William Ritchie, John E. J. Rasko, Sean M. Grimmond, Peter W. Zandstra, Christine A. Wells, Thomas Preiss, Jeong-Sun Seo, Albert J. R. Heck, Ian M. Rogers and Andras Nagy ()
Additional contact information
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
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
Andrew J. Corso: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, 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
Nicole Cloonan: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
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
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
Carl A. White: Institute of Biomaterials and Biomedical Engineering (IBBME), University of Toronto, Toronto M5S-3G9, Canada
Jong-Yeon Shin: Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul 110-799, 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
Jong-Il Kim: Genomic Medicine Institute, Medical Research Center, Seoul National University, 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
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
Christine A. Wells: Australian Institute for Bioengineering and Nanotechnology, The University of Queensland
Thomas Preiss: The John Curtin School of Medical Research, The Australian National University, Acton (Canberra), ACT 2601, Australia
Jeong-Sun Seo: Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul 110-799, 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
Ian M. Rogers: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada
Andras Nagy: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada

Nature, 2014, vol. 516, issue 7530, 198-206

Abstract: 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.

Date: 2014
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DOI: 10.1038/nature14046

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