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L1 retrotransposition in neurons is modulated by MeCP2

Nature volume 468, pages 443–446 (2010)Cite this article

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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.

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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.

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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.

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Author notes

  1. Alysson R. Muotri and Maria C. N. Marchetto: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatrics/Rady Children’s Hospital San Diego, Department of Cellular & Molecular Medicine, University of California San Diego, School of Medicine, Stem Cell Program, 9500 Gilman Drive, La Jolla, 92093-0695, California, USA

    Alysson R. Muotri

  2. Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, 92037, California, USA

    Maria C. N. Marchetto, Nicole G. Coufal, Ruth Oefner & Fred H. Gage

  3. Department of Cellular & Molecular Medicine, University of California San Diego, School of Medicine, Stem Cell Program, 9500 Gilman Dr, La Jolla, California 92093-0695, USA,

    Gene Yeo

  4. Laboratory of Molecular Neuroscience, Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma 630-0101, Japan,

    Kinichi Nakashima

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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.

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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)

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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

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