title: An epigenomic roadmap to induced pluripotency reveals DNA methylation as a reprogramming modulator.
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.
authors.affiliation: 1] Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul 110-799, Korea [2] Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Korea [3] Department of Biochemistry, Seoul National University College of Medicine, Seoul 110-799, Korea.
authors.forename: Dong-Sung
authors.initials: DS
authors.lastname: Lee
authors.affiliation: 1] Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul 110-799, Korea [2] Life Science Institute, Macrogen Inc., Seoul 153-781, Korea.
authors.forename: Jong-Yeon
authors.initials: JY
authors.lastname: Shin
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Tonge
authors.affiliation: 1] Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5 [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5T 3H7.
authors.forename: Mira C
authors.initials: MC
authors.lastname: Puri
authors.affiliation: 1] Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul 110-799, Korea [2] Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Korea [3] Department of Biochemistry, Seoul National University College of Medicine, Seoul 110-799, Korea.
authors.forename: Seungbok
authors.initials: S
authors.lastname: Lee
authors.affiliation: 1] Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul 110-799, Korea [2] Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Korea [3] Department of Biochemistry, Seoul National University College of Medicine, Seoul 110-799, Korea.
authors.forename: Hansoo
authors.initials: H
authors.lastname: Park
authors.affiliation: 1] Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul 110-799, Korea [2] Life Science Institute, Macrogen Inc., Seoul 153-781, Korea.
authors.forename: Won-Chul
authors.initials: WC
authors.lastname: Lee
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5.
authors.forename: Samer M I
authors.initials: SM
authors.lastname: Hussein
authors.affiliation: Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bleazard
authors.affiliation: 1] Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul 110-799, Korea [2] Life Science Institute, Macrogen Inc., Seoul 153-781, Korea.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Yun
authors.affiliation: 1] Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul 110-799, Korea [2] Life Science Institute, Macrogen Inc., Seoul 153-781, Korea.
authors.forename: Jihye
authors.initials: J
authors.lastname: Kim
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5.
authors.forename: Mira
authors.initials: M
authors.lastname: Li
authors.affiliation: 1] Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia [2] QIMR Berghofer Medical Research Institute, Genomic Biology Lab, 300 Herston Road, Herston, Queensland 4006, Australia.
authors.forename: Nicole
authors.initials: N
authors.lastname: Cloonan
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Wood
authors.affiliation: Genome Biology Department, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory 2601, Australia.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Clancy
authors.affiliation: Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Rowland
authors.initials: R
authors.lastname: Mosbergen
authors.affiliation: Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul 110-799, Korea.
authors.forename: Jae-Hyuk
authors.initials: JH
authors.lastname: Yi
authors.affiliation: Life Science Institute, Macrogen Inc., Seoul 153-781, Korea.
authors.forename: Kap-Seok
authors.initials: KS
authors.lastname: Yang
authors.affiliation: Life Science Institute, Macrogen Inc., Seoul 153-781, Korea.
authors.forename: Hyungtae
authors.initials: H
authors.lastname: Kim
authors.affiliation: Macrogen Bioinformatics Center, Macrogen, Seoul 153-781, Republic of Korea.
authors.forename: Hwanseok
authors.initials: H
authors.lastname: Rhee
authors.affiliation: 1] Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Queensland 4072, Australia [2] College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland G12 8TA, UK.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Wells
authors.affiliation: 1] Genome Biology Department, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory 2601, Australia [2] Molecular, Structural &Computational Biology Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales 2010, Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Preiss
authors.affiliation: 1] Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia [2] Wolfson Wohl Cancer Research Centre, Institute for Cancer Sciences, University of Glasgow, Bearsden, Glasgow Scotland G61 1BD, UK.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Grimmond
authors.affiliation: 1] Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5 [2] Department of Physiology, University of Toronto, Toronto, Ontario, Canada M5T 3H7 [3] Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario, Canada M5T3H7.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Rogers
authors.affiliation: 1] Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5 [2] Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario, Canada M5T3H7 [3] Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada M5T 3H7.
authors.forename: Andras
authors.initials: A
authors.lastname: Nagy
authors.affiliation: 1] Genomic Medicine Institute (GMI), Medical Research Center, Seoul National University, Seoul 110-799, Korea [2] Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, Korea [3] Department of Biochemistry, Seoul National University College of Medicine, Seoul 110-799, Korea [4] Life Science Institute, Macrogen Inc., Seoul 153-781, Korea.
authors.forename: Jeong-Sun
authors.initials: JS
authors.lastname: Seo