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Reprogramming triggers endogenous L1 and Alu retrotransposition in human induced pluripotent stem cells

Author

Listed:
  • Sabine Klawitter

    (Paul-Ehrlich-Institute
    Present address: Division of Inborn Metabolic Diseases, University Children’s Hospital, D-69120 Heidelberg, Germany.)

  • Nina V. Fuchs

    (Paul-Ehrlich-Institute
    Max-Delbrück-Center for Molecular Medicine)

  • Kyle R. Upton

    (Mater Research Institute, University of Queensland)

  • Martin Muñoz-Lopez

    (Pfizer/University of Granada and Andalusian Regional Government Center for Genomics and Oncology (GENYO), PTS Granada)

  • Ruchi Shukla

    (Mater Research Institute, University of Queensland)

  • Jichang Wang

    (Max-Delbrück-Center for Molecular Medicine)

  • Marta Garcia-Cañadas

    (Pfizer/University of Granada and Andalusian Regional Government Center for Genomics and Oncology (GENYO), PTS Granada)

  • Cesar Lopez-Ruiz

    (Pfizer/University of Granada and Andalusian Regional Government Center for Genomics and Oncology (GENYO), PTS Granada)

  • Daniel J. Gerhardt

    (Mater Research Institute, University of Queensland)

  • Attila Sebe

    (Paul-Ehrlich-Institute)

  • Ivana Grabundzija

    (Max-Delbrück-Center for Molecular Medicine)

  • Sylvia Merkert

    (Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Thoracic, Transplantation, and Vascular Surgery; REBIRTH, Cluster of Excellence, Hannover Medical School
    REBIRTH, Cluster of Excellence, Hannover Medical School)

  • Patricia Gerdes

    (Mater Research Institute, University of Queensland)

  • J. Andres Pulgarin

    (Pfizer/University of Granada and Andalusian Regional Government Center for Genomics and Oncology (GENYO), PTS Granada)

  • Anja Bock

    (Paul-Ehrlich-Institute)

  • Ulrike Held

    (Paul-Ehrlich-Institute)

  • Anett Witthuhn

    (Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Thoracic, Transplantation, and Vascular Surgery; REBIRTH, Cluster of Excellence, Hannover Medical School
    REBIRTH, Cluster of Excellence, Hannover Medical School)

  • Alexandra Haase

    (Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Thoracic, Transplantation, and Vascular Surgery; REBIRTH, Cluster of Excellence, Hannover Medical School
    REBIRTH, Cluster of Excellence, Hannover Medical School)

  • Balázs Sarkadi

    (Semmelweis University)

  • Johannes Löwer

    (Paul-Ehrlich-Institute)

  • Ernst J. Wolvetang

    (Australian Institute for Bioengineering and Nanotechnology, The University of Queensland)

  • Ulrich Martin

    (Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Thoracic, Transplantation, and Vascular Surgery; REBIRTH, Cluster of Excellence, Hannover Medical School
    REBIRTH, Cluster of Excellence, Hannover Medical School)

  • Zoltán Ivics

    (Paul-Ehrlich-Institute)

  • Zsuzsanna Izsvák

    (Max-Delbrück-Center for Molecular Medicine)

  • Jose L. Garcia-Perez

    (Pfizer/University of Granada and Andalusian Regional Government Center for Genomics and Oncology (GENYO), PTS Granada)

  • Geoffrey J. Faulkner

    (Mater Research Institute, University of Queensland
    Queensland Brain Institute, University of Queensland)

  • Gerald G. Schumann

    (Paul-Ehrlich-Institute)

Abstract

Human induced pluripotent stem cells (hiPSCs) are capable of unlimited proliferation and can differentiate in vitro to generate derivatives of the three primary germ layers. Genetic and epigenetic abnormalities have been reported by Wissing and colleagues to occur during hiPSC derivation, including mobilization of engineered LINE-1 (L1) retrotransposons. However, incidence and functional impact of endogenous retrotransposition in hiPSCs are yet to be established. Here we apply retrotransposon capture sequencing to eight hiPSC lines and three human embryonic stem cell (hESC) lines, revealing endogenous L1, Alu and SINE-VNTR-Alu (SVA) mobilization during reprogramming and pluripotent stem cell cultivation. Surprisingly, 4/7 de novo L1 insertions are full length and 6/11 retrotransposition events occurred in protein-coding genes expressed in pluripotent stem cells. We further demonstrate that an intronic L1 insertion in the CADPS2 gene is acquired during hiPSC cultivation and disrupts CADPS2 expression. These experiments elucidate endogenous retrotransposition, and its potential consequences, in hiPSCs and hESCs.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10286
    DOI: 10.1038/ncomms10286
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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.
    2. Jianli Tao & Qi Wang & Carlos Mendez-Dorantes & Kathleen H. Burns & Roberto Chiarle, 2022. "Frequency and mechanisms of LINE-1 retrotransposon insertions at CRISPR/Cas9 sites," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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