Mobile DNA elements in the generation of diversity and complexity in the brain

Erwin, Jennifer A.; Marchetto, Maria C.; Gage, Fred H.

doi:10.1038/nrn3730

Cited by 231 publications

(228 citation statements)

References 79 publications

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“…AK027497) was indeed identified in human neuronal precursor cells, and both Mili and PL2L60 proteins were found to be expressed in the stem cell compartment of testes and in cancer stem cells (45,46). 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).…”

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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“…It is thus interesting to note that remarkably elevated levels of TE activity have been recorded in the brain (Erwin et al, 2014), that a higher range of KRAB-ZFPs is expressed in the brain than in most other adult human tissues , and that KRABZFPs disproportionately contribute to differences between the brain gene networks of chimpanzees and humans (Nowick et al, 2009). These observations suggest that the endovirome and its KRAB-ZFP controllers could have played an important role in the expansion of higher brain functions that were key to the emergence of modern humans.…”

Section: Discussionmentioning

confidence: 99%

KRAB zinc finger proteins

2017

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Krüppel-associated box domain zinc finger proteins (KRAB-ZFPs) are the largest family of transcriptional regulators in higher vertebrates. Characterized by an N-terminal KRAB domain and a C-terminal array of DNA-binding zinc fingers, they participate, together with their co-factor KAP1 (also known as TRIM28), in repression of sequences derived from transposable elements (TEs). Until recently, KRAB-ZFP/KAP1-mediated repression of TEs was thought to lead to irreversible silencing, and the evolutionary selection of KRAB-ZFPs was considered to be just the host component of an arms race against TEs. However, recent advances indicate that KRAB-ZFPs and their TE targets also partner up to establish speciesspecific regulatory networks. Here, we provide an overview of the KRAB-ZFP gene family, highlighting how its evolutionary history is linked to that of TEs, and how KRAB-ZFPs influence multiple aspects of development and physiology.

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“…30). In the genome of somatic cells, retrotranspositions are more frequent in neural precursors and neurons compared with other neural cell types (31)(32)(33).…”

Section: R E V I E W S E R I E S : E X T R a C E L L U L A R V E S I mentioning

confidence: 99%

Extracellular vesicles and intercellular communication within the nervous system

Zappulli¹,

Friis²,

Fitzpatrick³

et al. 2016

Journal of Clinical Investigation

200

162

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Mobile DNA elements in the generation of diversity and complexity in the brain

Cited by 231 publications

References 79 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

KRAB zinc finger proteins

Extracellular vesicles and intercellular communication within the nervous system

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