Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

L1 retrotransposition in neurons is modulated by MeCP2

Abstract

Long interspersed nuclear elements-1 (LINE-1 or L1s) are abundant retrotransposons that comprise approximately 20% of mammalian genomes1,2,3. Active L1 retrotransposons can impact the genome in a variety of ways, creating insertions, deletions, new splice sites or gene expression fine-tuning4,5,6. We have shown previously that L1 retrotransposons are capable of mobilization in neuronal progenitor cells from rodents and humans and evidence of massive L1 insertions was observed in adult brain tissues but not in other somatic tissues7,8. In addition, L1 mobility in the adult hippocampus can be influenced by the environment9. The neuronal specificity of somatic L1 retrotransposition in neural progenitors is partially due to the transition of a Sox2/HDAC1 repressor complex to a Wnt-mediated T-cell factor/lymphoid enhancer factor (TCF/LEF) transcriptional activator7,10. The transcriptional switch accompanies chromatin remodelling during neuronal differentiation, allowing a transient stimulation of L1 transcription7. The activity of L1 retrotransposons during brain development can have an impact on gene expression and neuronal function, thereby increasing brain-specific genetic mosaicism11,12. Further understanding of the molecular mechanisms that regulate L1 expression should provide new insights into the role of L1 retrotransposition during brain development. Here we show that L1 neuronal transcription and retrotransposition in rodents are increased in the absence of methyl-CpG-binding protein 2 (MeCP2), a protein involved in global DNA methylation and human neurodevelopmental diseases. Using neuronal progenitor cells derived from human induced pluripotent stem cells and human tissues, we revealed that patients with Rett syndrome (RTT), carrying MeCP2 mutations, have increased susceptibility for L1 retrotransposition. Our data demonstrate that L1 retrotransposition can be controlled in a tissue-specific manner and that disease-related genetic mutations can influence the frequency of neuronal L1 retrotransposition. Our findings add a new level of complexity to the molecular events that can lead to neurological disorders.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: MeCP2 silences L1 expression.
Figure 2: MeCP2 modulates neuronal L1 retrotransposition in vivo.
Figure 3: Endogenous L1 retrotransposition in mouse neuroepithelial cells.
Figure 4: L1 retrotransposition in RTT patients.

References

  1. Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001)

    Article  CAS  ADS  Google Scholar 

  2. Gibbs, R. A. et al. Genome sequence of the Brown Norway rat yields insights into mammalian evolution. Nature 428, 493–521 (2004)

    Article  CAS  ADS  Google Scholar 

  3. Mouse Genome Sequencing Consortium. Initial sequencing and comparative analysis of the mouse genome. Nature 420, 520–562 (2002)

  4. Kazazian, H. H., Jr Mobile elements and disease. Curr. Opin. Genet. Dev. 8, 343–350 (1998)

    Article  CAS  Google Scholar 

  5. Han, J. S., Szak, S. T. & Boeke, J. D. Transcriptional disruption by the L1 retrotransposon and implications for mammalian transcriptomes. Nature 429, 268–274 (2004)

    Article  CAS  ADS  Google Scholar 

  6. Perepelitsa-Belancio, V. & Deininger, P. RNA truncation by premature polyadenylation attenuates human mobile element activity. Nature Genet. 35, 363–366 (2003)

    Article  CAS  Google Scholar 

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

    Article  CAS  ADS  Google Scholar 

  8. Coufal, N. G. et al. L1 retrotransposition in human neural progenitor cells. Nature 460, 1127–1131 (2009)

    Article  CAS  ADS  Google Scholar 

  9. Muotri, A. R., Zhao, C., Marchetto, M. C. & Gage, F. H. Environmental influence on L1 retrotransposons in the adult hippocampus. Hippocampus 19, 1002–1007 (2009)

    Article  CAS  Google Scholar 

  10. Kuwabara, T. et al. Wnt-mediated activation of NeuroD1 and retro-elements during adult neurogenesis. Nature Neurosci. 12, 1097–1105 (2009)

    Article  CAS  Google Scholar 

  11. Muotri, A. R. & Gage, F. H. Generation of neuronal variability and complexity. Nature 441, 1087–1093 (2006)

    Article  CAS  ADS  Google Scholar 

  12. Singer, T., McConnell, M. J., Marchetto, M. C., Coufal, N. G. & Gage, F. H. LINE-1 retrotransposons: mediators of somatic variation in neuronal genomes? Trends Neurosci. 33, 345–354 (2010)

    Article  CAS  Google Scholar 

  13. Nan, X. et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393, 386–389 (1998)

    Article  CAS  ADS  Google Scholar 

  14. Jones, P. L. et al. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nature Genet. 19, 187–191 (1998)

    Article  CAS  Google Scholar 

  15. 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 

  16. Zhao, X. et al. Mice lacking methyl-CpG binding protein 1 have deficits in adult neurogenesis and hippocampal function. Proc. Natl Acad. Sci. USA 100, 6777–6782 (2003)

    Article  CAS  ADS  Google Scholar 

  17. Klose, R. J. et al. DNA binding selectivity of MeCP2 due to a requirement for A/T sequences adjacent to methyl-CpG. Mol. Cell 19, 667–678 (2005)

    Article  CAS  Google Scholar 

  18. Rowe, H. M. et al. KAP1 controls endogenous retroviruses in embryonic stem cells. Nature 463, 237–240 (2010)

    Article  CAS  ADS  Google Scholar 

  19. 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 

  20. Moran, J. V. & Gilbert, N. in Mobile DNA II, Vol. 2 (eds Craig, N. L., Craigie, R., Gellert, M. & Lambowitz, A. M.) Ch. 35, 836–869 (ASM Press, 2002)

    Book  Google Scholar 

  21. Amir, R. E. et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nature Genet. 23, 185–188 (1999)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  24. Esnault, C., Maestre, J. & Heidmann, T. Human LINE retrotransposons generate processed pseudogenes. Nature Genet. 24, 363–367 (2000)

    Article  CAS  Google Scholar 

  25. Dewannieux, M., Esnault, C. & Heidmann, T. LINE-mediated retrotransposition of marked Alu sequences. Nature Genet. 35, 41–48 (2003)

    Article  CAS  Google Scholar 

  26. Wei, W. et al. Human L1 retrotransposition: cis preference versus trans complementation. Mol. Cell. Biol. 21, 1429–1439 (2001)

    Article  CAS  Google Scholar 

  27. Guy, J., Gan, J., Selfridge, J., Cobb, S. & Bird, A. Reversal of neurological defects in a mouse model of Rett syndrome. Science 315, 1143–1147 (2007)

    Article  CAS  ADS  Google Scholar 

  28. Palmer, T. D., Takahashi, J. & Gage, F. H. The adult rat hippocampus contains primordial neural stem cells. Mol. Cell. Neurosci. 8, 389–404 (1997)

    Article  CAS  Google Scholar 

  29. Nakashima, K. et al. Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300. Science 284, 479–482 (1999)

    Article  CAS  ADS  Google Scholar 

  30. Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

A.R.M. is supported by the National Institutes of Health through the NIH Director’s New Innovator Award Program, 1-DP2-OD006495-01 and by the Emerald Foundation. F.H.G. is supported by the Mathers Foundation, Lookout Fund, and NIH/NINDS R01MH088485. The authors would like to thank A. Huynh, B. Aimone, K. Stecker, B. Berg and D. Sepp for help during the 3D brain model assembly, J. Moran and J. Garcia-Perez for discussion and critical review of the manuscript, M. Gage for editorial comments, and B. Moddy and G. Peng for experimental assistance.

Author information

Authors and Affiliations

Authors

Contributions

A.R.M. and M.C.N.M. are the leading authors. They contributed to the concept, designed and performed the experiments, analysed the data, and wrote the manuscript. N.G.C. performed and analysed qPCR experiments. R.O. performed tissue culture experiments and quantification. G.Y. helped with statistical analysis and data interpretation. K.N. contributed reagents, and performed data analyses and manuscript revision. F.H.G. contributed to the concept, analysed the data and revised the manuscript.

Corresponding authors

Correspondence to Alysson R. Muotri or Fred H. Gage.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

The file contains Supplementary Materials and Methods, Supplementary Figures 1-6 with legends and Supplementary References. (PDF 13171 kb)

Supplementary Movie 1

The movie shows an animated version from a 3-dimensional reconstruction of representative WT and MeCP2 KO mouse brains carrying the L1-EGFP transgene. (MOV 3183 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Muotri, A., Marchetto, M., Coufal, N. et al. L1 retrotransposition in neurons is modulated by MeCP2. Nature 468, 443–446 (2010). https://doi.org/10.1038/nature09544

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature09544

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing