L1 retrotransposition in neurons is modulated by MeCP2

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

doi:10.1038/nature09544

Cited by 564 publications

(550 citation statements)

References 30 publications

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“…Alternatively, as nonintact retroviral sequences may retain their ability to be retrotransposed by active transposons nearby during embryogenesis 32 , retrotransposon activity could have introduced the observed mosaicism. Moreover, as L1-activity has been implicated in neurological diseases 37 and retroviral RNAs have been linked to schizophrenia 38 , this SNV may confirm a potentially relevant disease mechanism contributing to schizophrenia.…”

Section: Discussionmentioning

confidence: 74%

Optimized filtering reduces the error rate in detecting genomic variants by short-read sequencing

et al. 2011

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Section: Discussionmentioning

confidence: 74%

Optimized filtering reduces the error rate in detecting genomic variants by short-read sequencing

et al. 2011

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“…Finally, transposition has both beneficial and deleterious effects on human health (47). As opposed to its proposed role in homeostatic mechanism to environmental stress and adaptive behavior (48), increased LINE1 copy number has been found to be associated with Rett syndrome and schizophrenia (5,49). Furthermore, depletion of the stress-granule component, transposon-binding protein, TAR DNA-binding protein 43, leads to neurodegeneration in the familial form of amyotrophic lateral sclerosis and frontotemporal dementia (7).…”

Section: Discussionmentioning

confidence: 99%

Roles for small noncoding RNAs in silencing of retrotransposons in the mammalian brain

Nandi

Chandramohan

Fioriti

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Piwi-interacting RNAs (piRNAs), long thought to be restricted to germline, have recently been discovered in neurons of Aplysia, with a role in the epigenetic regulation of gene expression underlying long-term memory. We here ask whether piwi/piRNAs are also expressed and have functional roles in the mammalian brain. Large-scale RNA sequencing and subsequent analysis of protein expression revealed the presence in brain of several piRNA biogenesis factors including a mouse piwi (Mili), as well as small RNAs, albeit at low levels, resembling conserved piRNAs in mouse testes [primarily LINE1 (long interspersed nuclear element1) retrotransposon-derived]. Despite the seeming low expression of these putative piRNAs, single-base pair CpG methylation analyses across the genome of Mili/piRNA-deficient (Mili −/− ) mice demonstrate that brain genomic DNA is preferentially hypomethylated within intergenic areas and LINE1 promoter areas of the genome. Furthermore, Mili mutant mice exhibit behavioral deficits such as hyperactivity and reduced anxiety. These results suggest that putative piRNAs exist in mammalian brain, and similar to the role of piRNAs in testes, they may be involved in the silencing of retrotransposons, which in brain have critical roles in contributing to genomic heterogeneity underlying adaptation, stress response, and brain pathology. We also describe the presence of another class of small RNAs in the brain, with features of endogenous siRNAs, which may have taken over the role of invertebrate piRNAs in their capacity to target both transposons, as well as protein-coding genes. Thus, RNA interference through gene and retrotransposon silencing previously encountered in Aplysia may also have potential roles in the mammalian brain.piwi-interacting RNA | transposon | DNA methylation | behavior | endogenous siRNA P iwi-interacting RNAs (piRNAs) are 26-to 32-nt small noncoding RNAs that associate with the piwi clade of the Argonaute family of proteins and whose primary functions in mammals are associated with the silencing of transposons in the germline through de novo DNA methylation (1-4). Transposons constitute 44% of the human genome and could when active contribute to genetic heterogeneity, to alteration of behavior during adaptation, and to responses to stress. Somatic retrotransposition and its associated insertional mutagenesis have particularly important implications for brain disorders and are often associated with schizophrenia, Rett syndrome, and neurodegenerative disorders (5-7). The LINE1 (long interspersed nuclear element1) family of retrotransposons in particular is active in human and mouse hippocampus (8, 9).Although it has long been thought that piRNA expression and function are restricted to the germline, our laboratory and others have previously found that the piRNA pathway is functional in invertebrate neurons as well (10, 11). Aplysia neurons, in particular, have a strikingly abundant expression of piRNAs (contributing to at least 5% of the total noncoding RNA population); they in turn hav...

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“…During the last 6 years following the initial report of successful generation of pluripotent stem cells by reprogramming somatic cells via retroviral transduction of four transcription factors (ie, Oct4, Sox2, Klf4, and c-Myc) (Takahashi and Yamanaka, 2006), the technique has been further advanced (Kim, 2010) and applied by multiple groups to generate iPS-derived neuronal and glial cultures from patients (and animal models) to study brain disease in the culture dish. Examples include amyotrophic lateral sclerosis (motor neuron disease) (Dimos et al, 2008), Parkinson's disease (Wernig et al, 2008), Rett syndrome (Farra et al, 2012;Muotri et al, 2010), and schizophrenia (Brennand et al, 2011). These pioneering studies have paved the way for future iPS-based approaches that most certainly will become a mainstay in the field of biological psychiatry.…”

Section: Psychiatric Epigenetics In the Culture Dish?mentioning

confidence: 99%

Epigenetics in the Human Brain

Houston

Peter

Mitchell

et al. 2012

Neuropsychopharmacol

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Many cellular constituents in the human brain permanently exit from the cell cycle during pre-or early postnatal development, but little is known about epigenetic regulation of neuronal and glial epigenomes during maturation and aging, including changes in mood and psychosis spectrum disorders and other cognitive or emotional disease. Here, we summarize the current knowledge base as it pertains to genome organization in the human brain, including the regulation of DNA cytosine methylation and hydroxymethylation, and a subset of (altogether 4100) residue-specific histone modifications associated with gene expression, and silencing and various other functional chromatin states. We propose that high-resolution mapping of epigenetic markings in postmortem brain tissue or neural cultures derived from induced pluripotent cells (iPS), in conjunction with transcriptome profiling and whole-genome sequencing, will increasingly be used to define the molecular pathology of specific cases diagnosed with depression, schizophrenia, autism, or other major psychiatric disease. We predict that these highly integrative explorations of genome organization and function will provide an important alternative to conventional approaches in human brain studies, which mainly are aimed at uncovering group effects by diagnosis but generally face limitations because of cohort size.

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L1 retrotransposition in neurons is modulated by MeCP2

Cited by 564 publications

References 30 publications

Optimized filtering reduces the error rate in detecting genomic variants by short-read sequencing

Optimized filtering reduces the error rate in detecting genomic variants by short-read sequencing

Roles for small noncoding RNAs in silencing of retrotransposons in the mammalian brain

Epigenetics in the Human Brain

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