L1 retrotransposon in neurons is modulated by MECP2

University of California San Diego, School of Medicine, Department of Pediatrics/Rady Children's Hospital San Diego, La Jolla, California 92093-0695, USA.
Nature (Impact Factor: 41.46). 11/2010; 468(7322):443-6. DOI: 10.1038/nature09544
Source: PubMed


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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    • "(C) Scatter plot analysis of BiPS cell clones vs. their parental BCD cell populations, ESCs, iPSCs, and PiPSCs. Bottom panel shows also scatter plot analysis of Fib-A, iPS-A, iPS-B and ES-C cell clones generated by a different laboratory (Muotri et al., 2010). "
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    • "In some organisms, epigenomic regulation modulates transposon activity (Creasey et al., 2014; Lorenz et al., 2012). Interestingly, MeCP2, which is mutated in patients with Rett syndrome (an autism spectrum disorder), can regulate L1 transposition (Amir et al., 1999; Muotri et al., 2010). MeCP2 is known for its role in regulating epigenetic processes; it binds 5mC residues, as well as the oxidized derivative, 5hmC. "
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    • "Studies of MECP2 knock-out and over-expressing mice show that MECP2 positively regulates the expression of a wide range of genes by associating with the transcriptional activator CREB1 and binding to cAMP response element-binding (CREB) sites (Chahrour et al., 2008). In the last several years, studies support a role for MECP2 in (1) modulating RNA splicing (Young et al., 2005), (2) global alterations of chromatin condensation (Skene et al., 2010), (3) activating retrotransposon transcription in neurons (Muotri et al., 2010), (4) promoting gene imprinting (Lasalle, 2007), and (5) regulating the expression of miRNAs important for brain development and plasticity (Klein et al., 2007; Urdinguio et al., 2010; Wu et al., 2010). Collectively, the evidence supports the concept that MeCP2 represents a complex and pleiotropic regulatory system that associates with 5-mC and 5-hmC and multiple ancillary proteins that serve to mediate downstream decisions regarding gene expression. "
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