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

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, Sylvia Merkert, Patricia Gerdes, J. Andres Pulgarin, Anja Bock, Ulrike Held, Anett Witthuhn, Alexandra Haase, Balázs Sarkadi, Johannes Löwer, Ernst J. Wolvetang, Ulrich Martin, Zoltán Ivics, Zsuzsanna Izsvák, Jose L. Garcia-Perez (), Geoffrey J. Faulkner () and Gerald G. Schumann ()
Additional contact information
Sabine Klawitter: Paul-Ehrlich-Institute
Nina V. Fuchs: Paul-Ehrlich-Institute
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
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
Alexandra Haase: Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Thoracic, Transplantation, and Vascular Surgery; 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
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
Gerald G. Schumann: Paul-Ehrlich-Institute

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10286

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