Publication Date:
2010-11-19
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3059197/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3059197/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Muotri, Alysson R -- Marchetto, Maria C N -- Coufal, Nicole G -- Oefner, Ruth -- Yeo, Gene -- Nakashima, Kinichi -- Gage, Fred H -- 1-DP2-OD006495-01/OD/NIH HHS/ -- DP2 OD006495/OD/NIH HHS/ -- DP2 OD006495-01/OD/NIH HHS/ -- R01 MH088485/MH/NIMH NIH HHS/ -- R01 MH088485-03/MH/NIMH NIH HHS/ -- R01MH088485/MH/NIMH NIH HHS/ -- England -- Nature. 2010 Nov 18;468(7322):443-6. doi: 10.1038/nature09544.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉University of California San Diego, School of Medicine, Department of Pediatrics/Rady Children's Hospital San Diego, La Jolla, California 92093-0695, USA. muotri@ucsd.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21085180" target="_blank"〉PubMed〈/a〉
Keywords:
5' Untranslated Regions/genetics
;
Animals
;
Brain/cytology/metabolism
;
DNA Methylation
;
Gene Silencing
;
Humans
;
Induced Pluripotent Stem Cells/metabolism
;
Long Interspersed Nucleotide Elements/*genetics
;
Male
;
Methyl-CpG-Binding Protein 2/deficiency/genetics/*metabolism
;
Methylation
;
Mice
;
Neuroepithelial Cells/metabolism
;
Neurons/*metabolism
;
Organ Specificity
;
Promoter Regions, Genetic/genetics
;
Rats
;
Recombination, Genetic/*genetics
;
Rett Syndrome/genetics/pathology
;
Transcription, Genetic/genetics
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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