L1 retrotransposition in neurons is modulated by MeCP2
By Alysson Renato Muotri, M. Marchetto, Nicole G. Coufal, Ruth Oefner, Gene W. Yeo, K. Nakashima, Fred H. Gage. Nature, 2010
637 citations recorded by the source corpus.
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.
Subfields: Genetics, Molecular Biology, Plant Science
View Paper: https://www.semanticscholar.org/paper/72345397b603ea76bb3885fcc473a01bb259142e
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Citations in the corpus
- Somatic retrotransposition alters the genetic landscape of the human brain (2011, background): “One explanation for the observed transpositional activity in the brain may be that the L1 promoter is transiently released from epigenetic suppression during neurogenesis 11-12 .”
- The role of adult hippocampal neurogenesis in brain health and disease (2018, neutral): “A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript Table 1 Signals regulating adult hippocampal neurogenesis Stages Regulators Secreted factors and downstream effectors (Morphogens, growth fa”
- Transposition Driven Genomic Heterogeneity in the Drosophila Brain: A Dissertation (2012, neutral): “24 Prior work in mammals suggests that L1 expression occurs in neurons because the L1-promoter is released during neurogenesis (Muotri et al, 2005; Muotri et al., 2010).”