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

Author

Listed:
  • Dong-Sung Lee

    (Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University
    Seoul National University College of Medicine
    Seoul National University College of Medicine)

  • Jong-Yeon Shin

    (Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University
    Life Science Institute, Macrogen Inc.)

  • Peter D. Tonge

    (Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital)

  • Mira C. Puri

    (Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
    University of Toronto)

  • Seungbok Lee

    (Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University
    Seoul National University College of Medicine
    Seoul National University College of Medicine)

  • Hansoo Park

    (Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University
    Seoul National University College of Medicine
    Seoul National University College of Medicine)

  • Won-Chul Lee

    (Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University
    Life Science Institute, Macrogen Inc.)

  • 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
    Life Science Institute, Macrogen Inc.)

  • Jihye Kim

    (Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University
    Life Science Institute, Macrogen Inc.)

  • Mira Li

    (Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital)

  • Nicole Cloonan

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

  • 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
    College of Medical, Veterinary and Life Sciences, University of Glasgow)

  • Thomas Preiss

    (The John Curtin School of Medical Research, The Australian National University
    Molecular, Victor Chang Cardiac Research Institute, Sydney)

  • Sean M. Grimmond

    (Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland
    Wolfson Wohl Cancer Research Centre, Institute for Cancer Sciences, University of Glasgow)

  • Ian M. Rogers

    (Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
    University of Toronto
    University of Toronto)

  • Andras Nagy

    (Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital
    University of Toronto
    Institute of Medical Science, University of Toronto)

  • Jeong-Sun Seo

    (Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University
    Seoul National University College of Medicine
    Seoul National University College of Medicine
    Life Science Institute, Macrogen Inc.)

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.

Suggested Citation

  • 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, 2014. "An epigenomic roadmap to induced pluripotency reveals DNA methylation as a reprogramming modulator," Nature Communications, Nature, vol. 5(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6619
    DOI: 10.1038/ncomms6619
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    Cited by:

    1. Patricia Gerdes & Sue Mei Lim & Adam D. Ewing & Michael R. Larcombe & Dorothy Chan & Francisco J. Sanchez-Luque & Lucinda Walker & Alexander L. Carleton & Cini James & Anja S. Knaupp & Patricia E. Car, 2022. "Retrotransposon instability dominates the acquired mutation landscape of mouse induced pluripotent stem cells," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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