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Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells

Author

Listed:
  • Ryan Lister

    (Genomic Analysis Laboratory, The Salk Institute for Biological Studies)

  • Mattia Pelizzola

    (Genomic Analysis Laboratory, The Salk Institute for Biological Studies)

  • Yasuyuki S. Kida

    (Howard Hughes Medical Institute, Gene Expression laboratory, The Salk Institute for Biological Studies)

  • R. David Hawkins

    (Ludwig Institute for Cancer Research, 9500 Gilman Drive)

  • Joseph R. Nery

    (Genomic Analysis Laboratory, The Salk Institute for Biological Studies)

  • Gary Hon

    (Ludwig Institute for Cancer Research, 9500 Gilman Drive)

  • Jessica Antosiewicz-Bourget

    (Morgridge Institute for Research
    Genome Center of Wisconsin)

  • Ronan O’Malley

    (Genomic Analysis Laboratory, The Salk Institute for Biological Studies)

  • Rosa Castanon

    (Genomic Analysis Laboratory, The Salk Institute for Biological Studies)

  • Sarit Klugman

    (Ludwig Institute for Cancer Research, 9500 Gilman Drive)

  • Michael Downes

    (Howard Hughes Medical Institute, Gene Expression laboratory, The Salk Institute for Biological Studies)

  • Ruth Yu

    (Howard Hughes Medical Institute, Gene Expression laboratory, The Salk Institute for Biological Studies)

  • Ron Stewart

    (Morgridge Institute for Research
    Genome Center of Wisconsin)

  • Bing Ren

    (Ludwig Institute for Cancer Research, 9500 Gilman Drive
    University of California San Diego)

  • James A. Thomson

    (Morgridge Institute for Research
    Genome Center of Wisconsin
    Wisconsin National Primate Research Center, University of Wisconsin—Madison
    University of Wisconsin—Madison)

  • Ronald M. Evans

    (Howard Hughes Medical Institute, Gene Expression laboratory, The Salk Institute for Biological Studies)

  • Joseph R. Ecker

    (Genomic Analysis Laboratory, The Salk Institute for Biological Studies)

Abstract

Induced pluripotent stem cells (iPSCs) offer immense potential for regenerative medicine and studies of disease and development. Somatic cell reprogramming involves epigenomic reconfiguration, conferring iPSCs with characteristics similar to embryonic stem (ES) cells. However, it remains unknown how complete the reestablishment of ES-cell-like DNA methylation patterns is throughout the genome. Here we report the first whole-genome profiles of DNA methylation at single-base resolution in five human iPSC lines, along with methylomes of ES cells, somatic cells, and differentiated iPSCs and ES cells. iPSCs show significant reprogramming variability, including somatic memory and aberrant reprogramming of DNA methylation. iPSCs share megabase-scale differentially methylated regions proximal to centromeres and telomeres that display incomplete reprogramming of non-CG methylation, and differences in CG methylation and histone modifications. Lastly, differentiation of iPSCs into trophoblast cells revealed that errors in reprogramming CG methylation are transmitted at a high frequency, providing an iPSC reprogramming signature that is maintained after differentiation.

Suggested Citation

  • Ryan Lister & Mattia Pelizzola & Yasuyuki S. Kida & R. David Hawkins & Joseph R. Nery & Gary Hon & Jessica Antosiewicz-Bourget & Ronan O’Malley & Rosa Castanon & Sarit Klugman & Michael Downes & Ruth , 2011. "Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells," Nature, Nature, vol. 471(7336), pages 68-73, March.
    • Handle: RePEc:nat:nature:v:471:y:2011:i:7336:d:10.1038_nature09798
    DOI: 10.1038/nature09798
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    Cited by:

    1. Anne Senabouth & Maciej Daniszewski & Grace E. Lidgerwood & Helena H. Liang & Damián Hernández & Mehdi Mirzaei & Stacey N. Keenan & Ran Zhang & Xikun Han & Drew Neavin & Louise Rooney & Maria Isabel G, 2022. "Transcriptomic and proteomic retinal pigment epithelium signatures of age-related macular degeneration," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    2. Lakhal-Chaieb Lajmi & Greenwood Celia M.T. & Ouhourane Mohamed & Zhao Kaiqiong & Abdous Belkacem & Oualkacha Karim, 2017. "A smoothed EM-algorithm for DNA methylation profiles from sequencing-based methods in cell lines or for a single cell type," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 16(5-6), pages 313-331, December.
    3. Claire Vinel & Gabriel Rosser & Loredana Guglielmi & Myrianni Constantinou & Nicola Pomella & Xinyu Zhang & James R. Boot & Tania A. Jones & Thomas O. Millner & Anaelle A. Dumas & Vardhman Rakyan & Je, 2021. "Comparative epigenetic analysis of tumour initiating cells and syngeneic EPSC-derived neural stem cells in glioblastoma," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
    4. Maria Arez & Melanie Eckersley-Maslin & Tajda Klobučar & João Gilsa Lopes & Felix Krueger & Annalisa Mupo & Ana Cláudia Raposo & David Oxley & Samantha Mancino & Anne-Valerie Gendrel & Bruno Bernardes, 2022. "Imprinting fidelity in mouse iPSCs depends on sex of donor cell and medium formulation," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    5. Sun Shuying & Yu Xiaoqing, 2016. "HMM-Fisher: identifying differential methylation using a hidden Markov model and Fisher’s exact test," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 15(1), pages 55-67, March.
    6. Yu Xiaoqing & Sun Shuying, 2016. "HMM-DM: identifying differentially methylated regions using a hidden Markov model," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 15(1), pages 69-81, March.
    7. Nazifa Ahmed Moumi & Badhan Das & Zarin Tasnim Promi & Nishat Anjum Bristy & Md Shamsuzzoha Bayzid, 2019. "Quartet-based inference of cell differentiation trees from ChIP-Seq histone modification data," PLOS ONE, Public Library of Science, vol. 14(9), pages 1-25, September.
    8. 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.
    9. Tayma Handal & Sarah Juster & Manar Abu Diab & Shira Yanovsky-Dagan & Fouad Zahdeh & Uria Aviel & Roni Sarel-Gallily & Shir Michael & Ester Bnaya & Shulamit Sebban & Yosef Buganim & Yotam Drier & Vinc, 2024. "Differentiation shifts from a reversible to an irreversible heterochromatin state at the DM1 locus," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    10. Jingting Xu & Hong Hu & Yang Dai, 2016. "LMethyR-SVM: Predict Human Enhancers Using Low Methylated Regions based on Weighted Support Vector Machines," PLOS ONE, Public Library of Science, vol. 11(9), pages 1-18, September.
    11. Anyou Wang & Ying Du & Qianchuan He & Chunxiao Zhou, 2013. "A Quantitative System for Discriminating Induced Pluripotent Stem Cells, Embryonic Stem Cells and Somatic Cells," PLOS ONE, Public Library of Science, vol. 8(2), pages 1-10, February.

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