L1 retrotransposition in neurons is modulated by MeCP2

Alysson R. Muotri, Maria C.N. Marchetto, Nicole G. Coufal, Ruth Oefner, Gene Yeo, Kinichi Nakashima, Fred H. Gage

Research output: Contribution to journalArticle

376 Citations (Scopus)

Abstract

Long interspersed nuclear elements-1 (LINE-1 or L1s) are abundant retrotransposons that comprise approximately 20% of mammalian genomes. Active L1 retrotransposons can impact the genome in a variety of ways, creating insertions, deletions, new splice sites or gene expression fine-tuning. 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 tissues. In addition, L1 mobility in the adult hippocampus can be influenced by the environment. 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 activator. The transcriptional switch accompanies chromatin remodelling during neuronal differentiation, allowing a transient stimulation of L1 transcription. The activity of L1 retrotransposons during brain development can have an impact on gene expression and neuronal function, thereby increasing brain-specific genetic mosaicism. 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.

Original languageEnglish
Pages (from-to)443-446
Number of pages4
JournalNature
Volume468
Issue number7322
DOIs
Publication statusPublished - Nov 18 2010
Externally publishedYes

Fingerprint

Methyl-CpG-Binding Protein 2
Retroelements
TCF Transcription Factors
Neurons
Brain
Rodentia
Stem Cells
Long Interspersed Nucleotide Elements
Genome
Rett Syndrome
Gene Expression
Induced Pluripotent Stem Cells
Mutation
Inborn Genetic Diseases
Mosaicism
Chromatin Assembly and Disassembly
DNA Methylation
Nervous System Diseases
Hippocampus
Proteins

All Science Journal Classification (ASJC) codes

  • Medicine(all)
  • General

Cite this

Muotri, A. R., Marchetto, M. C. N., Coufal, N. G., Oefner, R., Yeo, G., Nakashima, K., & Gage, F. H. (2010). L1 retrotransposition in neurons is modulated by MeCP2. Nature, 468(7322), 443-446. https://doi.org/10.1038/nature09544

L1 retrotransposition in neurons is modulated by MeCP2. / Muotri, Alysson R.; Marchetto, Maria C.N.; Coufal, Nicole G.; Oefner, Ruth; Yeo, Gene; Nakashima, Kinichi; Gage, Fred H.

In: Nature, Vol. 468, No. 7322, 18.11.2010, p. 443-446.

Research output: Contribution to journalArticle

Muotri, AR, Marchetto, MCN, Coufal, NG, Oefner, R, Yeo, G, Nakashima, K & Gage, FH 2010, 'L1 retrotransposition in neurons is modulated by MeCP2', Nature, vol. 468, no. 7322, pp. 443-446. https://doi.org/10.1038/nature09544
Muotri AR, Marchetto MCN, Coufal NG, Oefner R, Yeo G, Nakashima K et al. L1 retrotransposition in neurons is modulated by MeCP2. Nature. 2010 Nov 18;468(7322):443-446. https://doi.org/10.1038/nature09544
Muotri, Alysson R. ; Marchetto, Maria C.N. ; Coufal, Nicole G. ; Oefner, Ruth ; Yeo, Gene ; Nakashima, Kinichi ; Gage, Fred H. / L1 retrotransposition in neurons is modulated by MeCP2. In: Nature. 2010 ; Vol. 468, No. 7322. pp. 443-446.
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