@article{c1485a6a1d0e49b79689e50d10387bfc,
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.",
author = "Sabine Klawitter and Fuchs, {Nina V.} and Upton, {Kyle R.} and Martin Mu{\~n}oz-Lopez and Ruchi Shukla and Jichang Wang and Marta Garcia-Ca{\~n}adas and Cesar Lopez-Ruiz and Gerhardt, {Daniel J.} and Attila Sebe and Ivana Grabundzija and Sylvia Merkert and Patricia Gerdes and Pulgarin, {J. Andres} and Anja Bock and Ulrike Held and Anett Witthuhn and Alexandra Haase and Bal{\'a}zs Sarkadi and Johannes L{\"o}wer and Wolvetang, {Ernst J.} and Ulrich Martin and Zolt{\'a}n Ivics and Zsuzsanna Izsv{\'a}k and Garcia-Perez, {Jose L.} and Faulkner, {Geoffrey J.} and Schumann, {Gerald G.}",
note = "Funding Information: We thank O. Weichenrieder for the generous gift of an anti-ORF1p antibody, R. L{\"o}wer and Csaba Miskey for helpful discussions, K.-M. Hanschmann for statistical analyses, as well as S. Heras and F. Sanchez-Luque for technical suggestions on RNA extraction and manipulation. This work was supported by the LOEWE Center for Cell and Gene Therapy Frankfurt (funded by the Hessian Ministry of Higher Education, Research and the Arts; funding reference number: III L 4-518/17.004 [2010]) (to S.K. and G.G.S.), grants SCHU1014/8-1 (to G.G.S.) and MA2331/11-1 (to U.M.) from the Deutsche Forschungsgemeinschaft, and EU-FP6/CliniGene-NoE-Fexibility fund FLEXI7-m (to G.G.S. and Z.Iz.), EU-FP7 InduStem (grant number 230675 to Z.Iv.), Hungarian stem cell project T{\'A}MOP-4.2.2-08/1-2008-0015 (to A.S., B.S., Z.Iz. and Z.Iv.), OTKA 83533 (B.S.), the Bundesministerium f{\"u}r Bildung und Forschung (ReGene, grant number 01GN1003A, to Z.Iv.) and REBIRTH Cluster of Excellence, EXC 62/3 (to U.M.). G.J.F. acknowledges the support of an NHMRC Career Development Fellowship (GNT1045237) and NHMRC Project Grants GNT1042449, GNT1045991, GNT1067983 and GNT1068789. J.L.G.P{\textquoteright}s lab is supported by CICE-FEDER-P09-CTS-4980, CICE-FEDER-P12-CTS-2256, Plan Nacional de I + D + I 2008-2011 and 2013-2016 (FIS-FEDER-PI11/01489 and FIS-FEDER-PI14/02152), PCIN-2014-115-ERA-NET NEURON II, the European Research Council (ERC-Consolidator ERC-STG-2012-233764) and by an International Early Career Scientist grant from the Howard Hughes Medical Institute (IECS-55007420). M.M.-L. was supported by PeS-FEDER-PI-0224-2011.",
year = "2016",
month = jan,
day = "8",
doi = "10.1038/ncomms10286",
language = "English",
volume = "7",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
}