title: Reprogramming triggers endogenous L1 and Alu retrotransposition in human induced pluripotent stem cells.
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.
authors.affiliation: Division of Medical Biotechnology, Paul-Ehrlich-Institute, D-63225 Langen, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Klawitter
authors.affiliation: Division of Medical Biotechnology, Paul-Ehrlich-Institute, D-63225 Langen, Germany.|Max-Delbrück-Center for Molecular Medicine, D-13125 Berlin, Germany.
authors.forename: Nina V
authors.initials: NV
authors.lastname: Fuchs
authors.affiliation: Mater Research Institute, University of Queensland, TRI Building, Woolloongabba, Brisbane, Queensland 4102, Australia.
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Upton
authors.affiliation: Department of Human DNA Variability, Pfizer/University of Granada and Andalusian Regional Government Center for Genomics and Oncology (GENYO), PTS Granada, 18016 Granada, Spain.
authors.forename: Martin
authors.initials: M
authors.lastname: Muñoz-Lopez
authors.affiliation: Mater Research Institute, University of Queensland, TRI Building, Woolloongabba, Brisbane, Queensland 4102, Australia.
authors.forename: Ruchi
authors.initials: R
authors.lastname: Shukla
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, D-13125 Berlin, Germany.
authors.forename: Jichang
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Human DNA Variability, Pfizer/University of Granada and Andalusian Regional Government Center for Genomics and Oncology (GENYO), PTS Granada, 18016 Granada, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Garcia-Cañadas
authors.affiliation: Department of Human DNA Variability, Pfizer/University of Granada and Andalusian Regional Government Center for Genomics and Oncology (GENYO), PTS Granada, 18016 Granada, Spain.
authors.forename: Cesar
authors.initials: C
authors.lastname: Lopez-Ruiz
authors.affiliation: Mater Research Institute, University of Queensland, TRI Building, Woolloongabba, Brisbane, Queensland 4102, Australia.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Gerhardt
authors.affiliation: Division of Medical Biotechnology, Paul-Ehrlich-Institute, D-63225 Langen, Germany.
authors.forename: Attila
authors.initials: A
authors.lastname: Sebe
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, D-13125 Berlin, Germany.
authors.forename: Ivana
authors.initials: I
authors.lastname: Grabundzija
authors.affiliation: Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiac, Thoracic, Transplantation, and Vascular Surgery; REBIRTH, Cluster of Excellence, Hannover Medical School, D-30625 Hannover, Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Merkert
authors.affiliation: Mater Research Institute, University of Queensland, TRI Building, Woolloongabba, Brisbane, Queensland 4102, Australia.
authors.forename: Patricia
authors.initials: P
authors.lastname: Gerdes
authors.affiliation: Department of Human DNA Variability, Pfizer/University of Granada and Andalusian Regional Government Center for Genomics and Oncology (GENYO), PTS Granada, 18016 Granada, Spain.
authors.forename: J Andres
authors.initials: JA
authors.lastname: Pulgarin
authors.affiliation: Division of Medical Biotechnology, Paul-Ehrlich-Institute, D-63225 Langen, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Bock
authors.affiliation: Division of Medical Biotechnology, Paul-Ehrlich-Institute, D-63225 Langen, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Held
authors.affiliation: Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiac, Thoracic, Transplantation, and Vascular Surgery; REBIRTH, Cluster of Excellence, Hannover Medical School, D-30625 Hannover, Germany.
authors.forename: Anett
authors.initials: A
authors.lastname: Witthuhn
authors.affiliation: Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiac, Thoracic, Transplantation, and Vascular Surgery; REBIRTH, Cluster of Excellence, Hannover Medical School, D-30625 Hannover, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Haase
authors.affiliation: Department of Biophysics and Radiation Biology, Semmelweis University, H-1094 Budapest, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Sarkadi
authors.affiliation: Division of Medical Biotechnology, Paul-Ehrlich-Institute, D-63225 Langen, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Löwer
authors.affiliation: Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Queensland 4072, Australia.
authors.forename: Ernst J
authors.initials: EJ
authors.lastname: Wolvetang
authors.affiliation: Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department of Cardiac, Thoracic, Transplantation, and Vascular Surgery; REBIRTH, Cluster of Excellence, Hannover Medical School, D-30625 Hannover, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Martin
authors.affiliation: Division of Medical Biotechnology, Paul-Ehrlich-Institute, D-63225 Langen, Germany.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Ivics
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, D-13125 Berlin, Germany.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Izsvák
authors.affiliation: Department of Human DNA Variability, Pfizer/University of Granada and Andalusian Regional Government Center for Genomics and Oncology (GENYO), PTS Granada, 18016 Granada, Spain.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Garcia-Perez
authors.affiliation: Mater Research Institute, University of Queensland, TRI Building, Woolloongabba, Brisbane, Queensland 4102, Australia.|Queensland Brain Institute, University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Faulkner
authors.affiliation: Division of Medical Biotechnology, Paul-Ehrlich-Institute, D-63225 Langen, Germany.
authors.forename: Gerald G
authors.initials: GG
authors.lastname: Schumann
mesh_terms: D020087:Alu Elements / Q000235:genetics*; D002135:Calcium-Binding Proteins / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation / Q000235:genetics*; D065150:Cellular Reprogramming / Q000235:genetics*; D000067470:Cellular Reprogramming Techniques; D053595:Embryonic Stem Cells / Q000378:metabolism*; D044127:Epigenesis, Genetic; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics*; D018598:Minisatellite Repeats; D018626:Retroelements / Q000235:genetics; D033921:Vesicular Transport Proteins / Q000235:genetics
chemical_list: C479428:CADPS2 protein, human; D002135:Calcium-Binding Proteins; D018626:Retroelements; D033921:Vesicular Transport Proteins