An epigenomic roadmap to induced pluripotency reveals DNA methylation as a reprogramming modulator

Dong-Sung Lee, Jong-Yeon Shin, Peter D. Tonge, Mira C. Puri, Seungbok Lee, Hansoo Park, Won-Chul Lee, Samer M. I. Hussein, Thomas Bleazard, Ji-Young Yun, Jihye Kim, Mira Li, Nicole Cloonan, David Wood, Jennifer L. Clancy, Rowland Mosbergen, Jae-Hyuk Yi, Kap-Seok Yang, Hyungtae Kim, Hwanseok Rhee, Christine A. Wells, Thomas Preiss, Sean M. Grimmond, Ian M. Rogers, Andras Nagy and Jeong-Sun Seo ()
Additional contact information
Dong-Sung Lee: Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University
Jong-Yeon Shin: Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University
Peter D. Tonge: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
Mira C. Puri: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
Seungbok Lee: Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University
Hansoo Park: Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University
Won-Chul Lee: Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University
Samer M. I. Hussein: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
Thomas Bleazard: Faculty of Medical and Human Sciences, University of Manchester
Ji-Young Yun: Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University
Jihye Kim: Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University
Mira Li: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
Nicole Cloonan: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
David Wood: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Jennifer L. Clancy: The John Curtin School of Medical Research, The Australian National University
Rowland Mosbergen: Australian Institute for Bioengineering and Nanotechnology, The University of Queensland
Jae-Hyuk Yi: Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University
Kap-Seok Yang: Life Science Institute, Macrogen Inc.
Hyungtae Kim: Life Science Institute, Macrogen Inc.
Hwanseok Rhee: Macrogen Bioinformatics Center
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
Sean M. Grimmond: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
Ian M. Rogers: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
Andras Nagy: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
Jeong-Sun Seo: Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University

Nature Communications, 2014, vol. 5, issue 1, 1-10

Abstract: Abstract Reprogramming of somatic cells to induced pluripotent stem cells involves a dynamic rearrangement of the epigenetic landscape. To characterize this epigenomic roadmap, we have performed MethylC-seq, ChIP-seq (H3K4/K27/K36me3) and RNA-Seq on samples taken at several time points during murine secondary reprogramming as part of Project Grandiose. We find that DNA methylation gain during reprogramming occurs gradually, while loss is achieved only at the ESC-like state. Binding sites of activated factors exhibit focal demethylation during reprogramming, while ESC-like pluripotent cells are distinguished by extension of demethylation to the wider neighbourhood. We observed that genes with CpG-rich promoters demonstrate stable low methylation and strong engagement of histone marks, whereas genes with CpG-poor promoters are safeguarded by methylation. Such DNA methylation-driven control is the key to the regulation of ESC-pluripotency genes, including Dppa4, Dppa5a and Esrrb. These results reveal the crucial role that DNA methylation plays as an epigenetic switch driving somatic cells to pluripotency.

Date: 2014
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DOI: 10.1038/ncomms6619

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