L1 retrotransposition in neurons is modulated by MeCP2
Open accessAbstract
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.
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Several neurological disorders, including Rhett Syndrome, Smith-Magenis syndrome and schizophrenia, are characterized by dysregulation of L1 activity.
“several neurological disorders, including Rhett Syndrome, Smith–Magenis syndrome and schizophrenia are characterized by dysregulation of L1 activity27,45,47.”
From SIRT6 represses LINE1 retrotransposons by ribosylating KAP1 but this repression fails with stress and age (2014) · cites this paper as [27]
The paper’s main text (page unavailable) reports increased L1 retrotransposition in Rett syndrome neuronal progenitor cells and brain tissue compared with controls. It does not address Smith–Magenis syndrome or schizophrenia, so it supports only the Rett syndrome part of the sentence. (LLM, conf=0.88)
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Self-citation
- Authors
- Muotri, A. R., Marchetto, M. C. N., Coufal, N. G., Oefner, R., Yeo, G., Nakashima, K., & Gage, F. H.
- Affiliations
- University of California San Diego (US)
- Salk Institute for Biological Studies (US)
- Nara Institute of Science and Technology (JP)
- Corresponding author
- Muotri, Alysson R.
- Gage, Fred H.
- ORCID
- Venue
- Nature
- Published
- 2010-11
- Volume
- 468
- Issue
- 7322
- Pages
- 443-446
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3059197
- OpenAlex
- W2015734897
- Cited by
- 626
- References
- 2
- Citations by year
- 2026: 20 · 2025: 29 · 2024: 28 · 2023: 7 · 2022: 30 · 2021: 28 · 2020: 36 · 2019: 31 · 2018: 45 · 2017: 47 · 2016: 52 · 2015: 44 · 2014: 51 · 2013: 67 · 2012: 56
- FWCI
- 29.23
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (1dp2od006495-01)
- National Institute of Mental Health (R01MH088485)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- LINE-1 retrotransposons, MeCP2, Rett syndrome, DNA methylation, neuronal differentiation, induced pluripotent stem cells, brain development, neurodevelopmental disorders, transposable elements, chromatin remodeling, TCF/LEF transcription
- MeSH terms
- Animals, Brain, Humans, Male, Methylation, Neurons, Organ Specificity, Promoter Regions, Genetic, Recombination, Genetic, Transcription, Genetic, Rett Syndrome, DNA Methylation, Long Interspersed Nucleotide Elements, 5' Untranslated Regions, Gene Silencing, Neuroepithelial Cells, Mice, Rats, Methyl-CpG-Binding Protein 2, Induced Pluripotent Stem Cells
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