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L1 retrotransposition in human neural progenitor cells

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Abstract

Long interspersed element 1 (LINE-1 or L1) retrotransposons have markedly affected the human genome. L1s must retrotranspose in the germ line or during early development to ensure their evolutionary success, yet the extent to which this process affects somatic cells is poorly understood. We previously demonstrated that engineered human L1s can retrotranspose in adult rat hippocampus progenitor cells in vitro and in the mouse brain in vivo1. Here we demonstrate that neural progenitor cells isolated from human fetal brain and derived from human embryonic stem cells support the retrotransposition of engineered human L1s in vitro. Furthermore, we developed a quantitative multiplex polymerase chain reaction that detected an increase in the copy number of endogenous L1s in the hippocampus, and in several regions of adult human brains, when compared to the copy number of endogenous L1s in heart or liver genomic DNAs from the same donor. These data suggest that de novo L1 retrotransposition events may occur in the human brain and, in principle, have the potential to contribute to individual somatic mosaicism.

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Figure 1: L1 retrotransposition in hCNS-SCns.
Figure 2: L1 retrotransposition in hESC-derived NPCs.
Figure 3: Methylation analysis and ChIP for the endogenous human L1 5′ UTR.
Figure 4: Multiplex quantitative PCR analyses of L1 copy number in human tissues.

Change history

  • 27 August 2009

    The position of the 'DAPI' label on Fig. 1f was altered on 27 August 2009.

References

  1. Muotri, A. R. et al. Somatic mosaicism in neuronal precursor cells mediated by L1 retrotransposition. Nature 435, 903–910 (2005)

    Article  ADS  CAS  Google Scholar 

  2. Tang, Y., Nyengaard, J. R., De Groot, D. M. & Gundersen, H. J. Total regional and global number of synapses in the human brain neocortex. Synapse 41, 258–273 (2001)

    Article  CAS  Google Scholar 

  3. Uchida, N. et al. Direct isolation of human central nervous system stem cells. Proc. Natl Acad. Sci. USA 97, 14720–14725 (2000)

    Article  ADS  CAS  Google Scholar 

  4. Brouha, B. et al. Hot L1s account for the bulk of retrotransposition in the human population. Proc. Natl Acad. Sci. USA 100, 5280–5285 (2003)

    Article  ADS  CAS  Google Scholar 

  5. Moran, J. V. et al. High frequency retrotransposition in cultured mammalian cells. Cell 87, 917–927 (1996)

    Article  CAS  Google Scholar 

  6. Ostertag, E. M. et al. A mouse model of human L1 retrotransposition. Nature Genet. 32, 655–660 (2002)

    Article  CAS  Google Scholar 

  7. Ostertag, E. M., Prak, E. T., DeBerardinis, R. J., Moran, J. V. & Kazazian, H. H. Determination of L1 retrotransposition kinetics in cultured cells. Nucleic Acids Res. 28, 1418–1423 (2000)

    Article  CAS  Google Scholar 

  8. Kulpa, D. A. & Moran, J. V. Ribonucleoprotein particle formation is necessary but not sufficient for LINE-1 retrotransposition. Hum. Mol. Genet. 14, 3237–3248 (2005)

    Article  CAS  Google Scholar 

  9. Moran, J. & Gilbert, N. Mammalian LINE-1 Retrotransposons and Related Elements (ASM Press, 2002)

    Book  Google Scholar 

  10. Myers, J. S. et al. A comprehensive analysis of recently integrated human Ta L1 elements. Am. J. Hum. Genet. 71, 312–326 (2002)

    Article  CAS  Google Scholar 

  11. Morrish, T. A. et al. DNA repair mediated by endonuclease-independent LINE-1 retrotransposition. Nature Genet. 31, 159–165 (2002)

    Article  CAS  Google Scholar 

  12. Gilbert, N., Lutz, S., Morrish, T. A. & Moran, J. V. Multiple fates of L1 retrotransposition intermediates in cultured human cells. Mol. Cell. Biol. 25, 7780–7795 (2005)

    Article  CAS  Google Scholar 

  13. Symer, D. E. et al. Human L1 retrotransposition is associated with genetic instability in vivo . Cell 110, 327–338 (2002)

    Article  CAS  Google Scholar 

  14. Yeo, G. W. et al. Alternative splicing events identified in human embryonic stem cells and neural progenitors. PLoS Comput. Biol. 3, e196 (2007)

    Article  ADS  Google Scholar 

  15. Bourc'his, D. & Bestor, T. H. Meiotic catastrophe and retrotransposon reactivation in male germ cells lacking Dnmt3L. Nature 431, 96–99 (2004)

    Article  ADS  CAS  Google Scholar 

  16. Takai, D. & Jones, P. A. The CpG island searcher: a new WWW resource. In Silico Biol. 3, 235–240 (2003)

    CAS  PubMed  Google Scholar 

  17. Yu, F., Zingler, N., Schumann, G. & Stratling, W. H. Methyl-CpG-binding protein 2 represses LINE-1 expression and retrotransposition but not Alu transcription. Nucleic Acids Res. 29, 4493–4501 (2001)

    Article  CAS  Google Scholar 

  18. Tchenio, T., Casella, J. F. & Heidmann, T. Members of the SRY family regulate the human LINE retrotransposons. Nucleic Acids Res. 28, 411–415 (2000)

    Article  CAS  Google Scholar 

  19. Lee, C., Wevrick, R., Fisher, R. B., Ferguson-Smith, M. A. & Lin, C. C. Human centromeric DNAs. Hum. Genet. 100, 291–304 (1997)

    Article  CAS  Google Scholar 

  20. Pavlicek, A., Paces, J., Zika, R. & Hejnar, J. Length distribution of long interspersed nucleotide elements (LINEs) and processed pseudogenes of human endogenous retroviruses: implications for retrotransposition and pseudogene detection. Gene 300, 189–194 (2002)

    Article  CAS  Google Scholar 

  21. Grimaldi, G., Skowronski, J. & Singer, M. F. Defining the beginning and end of KpnI family segments. EMBO J. 3, 1753–1759 (1984)

    Article  CAS  Google Scholar 

  22. Gage, F. H. Mammalian neural stem cells. Science 287, 1433–1438 (2000)

    Article  ADS  CAS  Google Scholar 

  23. Prak, E. T., Dodson, A. W., Farkash, E. A. & Kazazian, H. H. Tracking an embryonic L1 retrotransposition event. Proc. Natl Acad. Sci. USA 100, 1832–1837 (2003)

    Article  ADS  CAS  Google Scholar 

  24. Garcia-Perez, J. L. et al. LINE-1 retrotransposition in human embryonic stem cells. Hum. Mol. Genet. 16, 1569–1577 (2007)

    Article  CAS  Google Scholar 

  25. van den Hurk, J. A. et al. L1 retrotransposition can occur early in human embryonic development. Hum. Mol. Genet. 16, 1587–1592 (2007)

    Article  CAS  Google Scholar 

  26. Thomson, J. A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998)

    Article  ADS  CAS  Google Scholar 

  27. Zhang, S. C., Wernig, M., Duncan, I. D., Brustle, O. & Thomson, J. A. In vitro differentiation of transplantable neural precursors from human embryonic stem cells. Nature Biotechnol. 19, 1129–1133 (2001)

    Article  CAS  Google Scholar 

  28. Forslund, O. et al. Nucleotide sequence and phylogenetic classification of candidate human papilloma virus type 92. Virology 312, 255–260 (2003)

    Article  CAS  Google Scholar 

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Acknowledgements

We thank J. Simon for excellent schematic drawings, M. L. Gage, J. Kim and H. Kopera for editorial comments, B. Miller and R. Keithley for cell culture assistance, C. T. Carson for hESC advice, D. Chambers and J. Barrie for flow cytometry assistance, L. Randolph-Moore for molecular advice, B. Aimone for statistics advice, T. Liang for microarray assistance, and Y. Lineu and J. Mosher for helpful comments. We also thank T. Fanning and M. Klymkowsky for the ORF1 protein and SOX3 antibodies, respectively. F.H.G. and N.G.C. are supported by the Picower Foundation, G. Harold and Leila Y. Mathers Charitable Foundation, Lookout Fund (MH082070), and the California Institute for Regenerative Medicine (CIRM). J.L.G.-P. is supported by Plan Estabilizacion Grupos SNS ENCYT 2015 (EMER07/56, Instituto de Salud Carlos III, Spain) and through the IRG-FP7-PEOPLE-2007 Marie Curie program. K.S.O. was supported by grants GM069985 and NS048187 from the National Institutes of Health (NIH). J.V.M. was supported by grants GM082970 and GM069985 from the NIH and by the Howard Hughes Medical Institute. Work in the laboratories of K.S.O. and J.V.M. only used NIH-approved stem cell lines.

Author Contributions N.G.C. and F.H.G. directed the project. J.V.M. and J.L.G.-P. directed aspects of the project conducted at Michigan. N.G.C., J.L.G.-P., J.V.M. and F.H.G. designed experiments and drafted the manuscript. N.G.C., F.H.G., J.L.G-P. and G.E.P. performed the experiments. G.W.Y. and M.T.L. carried out bioinformatics data analysis. Y.M. performed electrophysiology experiments. M.M. and K.S.O. provided hESC culture and NPC differentiation assistance. All authors commented on or contributed to the current manuscript.

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Correspondence to Fred H. Gage.

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Coufal, N., Garcia-Perez, J., Peng, G. et al. L1 retrotransposition in human neural progenitor cells. Nature 460, 1127–1131 (2009). https://doi.org/10.1038/nature08248

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