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Retrotransposon instability dominates the acquired mutation landscape of mouse induced pluripotent stem cells

Author

Listed:
  • Patricia Gerdes

    (Mater Research Institute - University of Queensland)

  • Sue Mei Lim

    (Monash University
    Monash Biomedicine Discovery Institute
    Monash University)

  • Adam D. Ewing

    (Mater Research Institute - University of Queensland)

  • Michael R. Larcombe

    (Monash University
    Monash Biomedicine Discovery Institute
    Monash University)

  • Dorothy Chan

    (Mater Research Institute - University of Queensland)

  • Francisco J. Sanchez-Luque

    (Mater Research Institute - University of Queensland
    GENYO. Pfizer-University of Granada-Andalusian Government Centre for Genomics and Oncological Research, PTS)

  • Lucinda Walker

    (Mater Research Institute - University of Queensland)

  • Alexander L. Carleton

    (Mater Research Institute - University of Queensland)

  • Cini James

    (Mater Research Institute - University of Queensland)

  • Anja S. Knaupp

    (Monash University
    Monash Biomedicine Discovery Institute
    Monash University)

  • Patricia E. Carreira

    (Mater Research Institute - University of Queensland)

  • Christian M. Nefzger

    (Monash University
    Monash Biomedicine Discovery Institute
    Monash University)

  • Ryan Lister

    (The University of Western Australia
    Harry Perkins Institute of Medical Research)

  • Sandra R. Richardson

    (Mater Research Institute - University of Queensland)

  • Jose M. Polo

    (Monash University
    Monash Biomedicine Discovery Institute
    Monash University
    The University of Adelaide)

  • Geoffrey J. Faulkner

    (Mater Research Institute - University of Queensland
    University of Queensland)

Abstract

Induced pluripotent stem cells (iPSCs) can in principle differentiate into any cell of the body, and have revolutionized biomedical research and regenerative medicine. Unlike their human counterparts, mouse iPSCs (miPSCs) are reported to silence transposable elements and prevent transposable element-mediated mutagenesis. Here we apply short-read or Oxford Nanopore Technologies long-read genome sequencing to 38 bulk miPSC lines reprogrammed from 10 parental cell types, and 18 single-cell miPSC clones. While single nucleotide variants and structural variants restricted to miPSCs are rare, we find 83 de novo transposable element insertions, including examples intronic to Brca1 and Dmd. LINE-1 retrotransposons are profoundly hypomethylated in miPSCs, beyond other transposable elements and the genome overall, and harbor alternative protein-coding gene promoters. We show that treatment with the LINE-1 inhibitor lamivudine does not hinder reprogramming and efficiently blocks endogenous retrotransposition, as detected by long-read genome sequencing. These experiments reveal the complete spectrum and potential significance of mutations acquired by miPSCs.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35180-x
    DOI: 10.1038/s41467-022-35180-x
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    as
    1. Sabine Klawitter & Nina V. Fuchs & Kyle R. Upton & Martin Muñoz-Lopez & Ruchi Shukla & Jichang Wang & Marta Garcia-Cañadas & Cesar Lopez-Ruiz & Daniel J. Gerhardt & Attila Sebe & Ivana Grabundzija & S, 2016. "Reprogramming triggers endogenous L1 and Alu retrotransposition in human induced pluripotent stem cells," Nature Communications, Nature, vol. 7(1), pages 1-14, April.
    2. Ewart Kuijk & Myrthe Jager & Bastiaan Roest & Mauro D. Locati & Arne Hoeck & Jerome Korzelius & Roel Janssen & Nicolle Besselink & Sander Boymans & Ruben Boxtel & Edwin Cuppen, 2020. "Publisher Correction: The mutational impact of culturing human pluripotent and adult stem cells," Nature Communications, Nature, vol. 11(1), pages 1-1, December.
    3. Jeffrey S. Han & Suzanne T. Szak & Jef D. Boeke, 2004. "Transcriptional disruption by the L1 retrotransposon and implications for mammalian transcriptomes," Nature, Nature, vol. 429(6989), pages 268-274, May.
    4. Jochen Utikal & Jose M. Polo & Matthias Stadtfeld & Nimet Maherali & Warakorn Kulalert & Ryan M. Walsh & Adam Khalil & James G. Rheinwald & Konrad Hochedlinger, 2009. "Immortalization eliminates a roadblock during cellular reprogramming into iPS cells," Nature, Nature, vol. 460(7259), pages 1145-1148, August.
    5. 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.
    6. Tomasz Chelmicki & Emeline Roger & Aurélie Teissandier & Mathilde Dura & Lorraine Bonneville & Sofia Rucli & François Dossin & Camille Fouassier & Sonia Lameiras & Deborah Bourc’his, 2021. "m6A RNA methylation regulates the fate of endogenous retroviruses," Nature, Nature, vol. 591(7849), pages 312-316, March.
    7. 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.
    8. Thomas M. Keane & Leo Goodstadt & Petr Danecek & Michael A. White & Kim Wong & Binnaz Yalcin & Andreas Heger & Avigail Agam & Guy Slater & Martin Goodson & Nicholas A. Furlotte & Eleazar Eskin & Chris, 2011. "Mouse genomic variation and its effect on phenotypes and gene regulation," Nature, Nature, vol. 477(7364), pages 289-294, September.
    9. Athurva Gore & Zhe Li & Ho-Lim Fung & Jessica E. Young & Suneet Agarwal & Jessica Antosiewicz-Bourget & Isabel Canto & Alessandra Giorgetti & Mason A. Israel & Evangelos Kiskinis & Je-Hyuk Lee & Yuin-, 2011. "Somatic coding mutations in human induced pluripotent stem cells," Nature, Nature, vol. 471(7336), pages 63-67, March.
    10. Ewart Kuijk & Myrthe Jager & Bastiaan Roest & Mauro D. Locati & Arne Hoeck & Jerome Korzelius & Roel Janssen & Nicolle Besselink & Sander Boymans & Ruben Boxtel & Edwin Cuppen, 2020. "The mutational impact of culturing human pluripotent and adult stem cells," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    11. Déborah Bourc'his & Timothy H. Bestor, 2004. "Meiotic catastrophe and retrotransposon reactivation in male germ cells lacking Dnmt3L," Nature, Nature, vol. 431(7004), pages 96-99, September.
    12. Jeffrey S. Han & Jef D. Boeke, 2004. "A highly active synthetic mammalian retrotransposon," Nature, Nature, vol. 429(6989), pages 314-318, May.
    13. Samer M. Hussein & Nizar N. Batada & Sanna Vuoristo & Reagan W. Ching & Reija Autio & Elisa Närvä & Siemon Ng & Michel Sourour & Riikka Hämäläinen & Cia Olsson & Karolina Lundin & Milla Mikkola & Ras , 2011. "Copy number variation and selection during reprogramming to pluripotency," Nature, Nature, vol. 471(7336), pages 58-62, March.
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