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

• Published in: Nature communications Vol. 7; no. 1; pp. 10286 - 14
• Main Authors: Klawitter, Sabine, Fuchs, Nina V., Upton, Kyle R., Muñoz-Lopez, Martin, Shukla, Ruchi, Wang, Jichang, Garcia-Cañadas, Marta, Lopez-Ruiz, Cesar, Gerhardt, Daniel J., Sebe, Attila, Grabundzija, Ivana, Merkert, Sylvia, Gerdes, Patricia, Pulgarin, J. Andres, Bock, Anja, Held, Ulrike, Witthuhn, Anett, Haase, Alexandra, Sarkadi, Balázs, Löwer, Johannes, Wolvetang, Ernst J., Martin, Ulrich, Ivics, Zoltán, Izsvák, Zsuzsanna, Garcia-Perez, Jose L., Faulkner, Geoffrey J., Schumann, Gerald G.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.01.2016; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/100; 13/106; 13/109; 14; 14/32; 38; 38/1; 38/22; 38/23; 38/71; 42; 631/136/532/2064/2117; 631/136/532/2064/2158; 631/136/532/2435; 631/337; Alu Elements - genetics; Calcium-Binding Proteins - genetics; Cell Line; Cell Proliferation - genetics; Cellular Reprogramming - genetics; Cellular Reprogramming Techniques; Cultivation; Embryonic Stem Cells - metabolism; Epigenesis, Genetic; Epigenetics; Genomes; Humanities and Social Sciences; Humans; Induced Pluripotent Stem Cells - metabolism; Long Interspersed Nucleotide Elements - genetics; Minisatellite Repeats; multidisciplinary; Retroelements - genetics; Science; Stem cells; Transplants & implants; Variance analysis; Vesicular Transport Proteins - genetics; Queensland Australia; Australia; Germany
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms10286

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. Genetic and epigenetic abnormalities have been found to result from reprogramming of differentiated cells into human induced pluripotent stem cells (hiPSCs). Here, Klawitter et al. identify endogenous L1, Alu and SVA mobilization during reprogramming, highlighting the risk of insertional mutagens in hiPSCs.