Increased L1 Retrotransposition in the Neuronal Genome in Schizophrenia

Bundo, Miki; Toyoshima, Manabu; Okada, Yohei; Akamatsu, Wado; Ueda, Junko; Nemoto-Miyauchi, Taeko; Sunaga, Fumiko; Toritsuka, Michihiro; Ikawa, Daisuke; Kakita, Akiyoshi; Kato, Masaaki; Kasai, Kiyoto; Kishimoto, Toshifumi; Nawa, Hiroyuki; Okano, Hideyuki; Yoshikawa, Takeo; Kato, Takeshi; Iwamoto, Kazuya

doi:10.1016/j.neuron.2013.10.053

Cited by 278 publications

(295 citation statements)

References 40 publications

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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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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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“…Numerous such events could be detected in tumor tissues and cells (Miki et al 1992;Lee et al 2012), some of which might be causal. Somatic integration even was proposed to contribute to neuropsychiatric disease, such as schizophrenia (Bundo et al 2014). Apart from being detrimental or neutral, a minority of events has the potential to turn out beneficial.…”

Section: Te Functions: To the Moon!mentioning

confidence: 99%

The Persistent Contributions of RNA to Eukaryotic Gen(om)e Architecture and Cellular Function

Brosius

2014

Cold Spring Harbor Perspectives in Biology

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“…To study chronological changes in the L1-ORF2 copy numbers, 6 groups of mice at various ages (3,8,15,18,20, and »55 weeks) were analyzed. Six mice from each group (3 males and 3 females) and 6 8-week-old mice used for validation (3 males and 3 females) were deeply anaesthetised and perfused transcardially with cold 4% paraformaldehyde in phosphate-buffered saline (PBS), and genomic DNA was extracted from the right and left hippocampi and the prefrontal cortex.…”

Section: Animalsmentioning

confidence: 99%

“…2 Notably, L1 is active in neuronal precursor cells, and L1-RTP insertions provoke the expression of neuron-specific genes when their gene structures are altered by de novo L1 insertion. [3][4][5] Recent studies have identified L1-mediated somatic mosaicism in normal adult brains, 6,7 and high copy numbers of L1 were detected in the brain of a schizophrenia patient, 8 Okudaira et al recently reported that stimulants such as methamphetamine and cocaine induced L1-RTP in neuronal cells, 9,10 and Moszczynska et al demonstrated that glutamate activated L1-RTP. 10 These observations imply that L1-RTP is physiologically regulated via the axis of glutamate and the glutamate receptor and that normal brain maturation is affected by the deregulation of L1-RTP, which functions as a molecular basis of psychiatric disorders.…”

Section: Introductionmentioning

confidence: 99%

Modulation of long interspersed nuclear element-1 in the mouse hippocampus during maturation

Ueno

Okamura²,

Mishina

et al. 2016

Mobile Genetic Elements

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Background: Retrotransposition of long interspersed nuclear element-1 (L1-RTP) is proposed to contribute to central nervous system (CNS) plasticity by inducing mosaicism of neuronal cells. Clinical studies have identified increased L1 copy numbers in the brains of patients with psychiatric disorders. These observations implicate that L1-RTP is important for neurogenesis and that its deregulation represents a risk factor for mental disorders. However, no supportive evidence is available for understanding the importance of L1-RTP in CNS function. Findings: To explore the physiological role of L1-RTP in CNS, we examined the L1 copy number during maturation. Interestingly, the L1 copy number increased after birth in the mouse hippocampus, but not the frontal lobe, with maximal copy numbers found in 8-week-old mice. This age-dependent L1 increase was abolished by administration of a reverse-transcriptase inhibitor, stavudine (d4T), which showed no toxic effects. Notably, the age-dependent L1 increase was attenuated by post-weaning social isolation (SI) stress, a well-known intervention for inducing psychiatric disorders in mice, or deletion of the NR2A gene that encodes a subunit of the glutamate receptor. Moreover, the negative effects of SI stress on L1-RTP were partially restored by environmental enrichment with voluntary running, but not by fluoxetine, a commonly used antipsychiatric drug. Finally, behavioral experiments revealed that learning memory was defective in d4T-treated mice, which was similarly observed in mice raised under SI stress. Conclusion: We detected the modulation of L1-RTP in the hippocampus during maturation of the CNS. In a recent study, we demonstrated that stimulants such as methamphetamine and cocaine were active in the induction of L1-RTP in neuronal cells, and previous studies have shown that NR2A-deficient mice are susceptible to mental abnormality. Herein, our data support the notion that the age-dependent modulation of L1-RTP is involved in genome differentiation in the hippocampus, and that modulation defects are linked to the development of psychiatric disorders.

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Increased L1 Retrotransposition in the Neuronal Genome in Schizophrenia

Cited by 278 publications

References 40 publications

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

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

The Persistent Contributions of RNA to Eukaryotic Gen(om)e Architecture and Cellular Function

Modulation of long interspersed nuclear element-1 in the mouse hippocampus during maturation

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