A Role for Neuronal piRNAs in the Epigenetic Control of Memory-Related Synaptic Plasticity

Rajasethupathy, Priyamvada; Antonov, Igor; Sheridan, Robert P.; Frey, Sebastian; Sander, Chris; Tuschl, Thomas; Kandel, Eric R.

doi:10.1016/j.cell.2012.02.057

Cited by 504 publications

(493 citation statements)

References 48 publications

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“…In view of our finding of piRNAs in the brain of Aplysia, we have begun to explore their possible presence and roles in the mammalian brain. Consistent with our previous report in Aplysia (10), we demonstrate in the mouse brain, albeit at a low level, the existence of many components of the piRNA pathway by RNA-Seq, immunoprecipitation, and Western blotting ( Fig. 1 and Figs.…”

Section: Discussionsupporting

confidence: 93%

“…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 have unique patterns of biogenesis (with most piRNA clusters containing one dominantly expressed piRNA) and predominant nuclear localization (10).…”

mentioning

confidence: 93%

“…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 have unique patterns of biogenesis (with most piRNA clusters containing one dominantly expressed piRNA) and predominant nuclear localization (10). Furthermore, Aplysia piRNAs have the function of guiding epigenetic modification to specified gene promoters based on sequence homology.…”

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confidence: 99%

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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: Discussionsupporting

confidence: 93%

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confidence: 93%

mentioning

confidence: 99%

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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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“…The negative correlation between promoter methylation and mRNA expression of galecin in P. fucata was the same with most similar researches in invertebrates. For example, methylation of a CpG island in CREB gene of Aplysia was corresponded to transcriptional repression [33]. The homeobox gene expressions in the Pacific oyster Crassostrea gigas were inversely correlated with their specific DNA methylation [21].…”

Section: Cpg1mentioning

confidence: 99%

DNA methylation is associated with expression level changes of galectin gene in mantle wound healing process of pearl oyster, Pinctada fucata

Huang

Guan

et al. 2015

Fish & Shellfish Immunology

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“…Initially identified as transcriptional suppressors of transposons in sperm cells, now they have been identified also in non-dividing neurons where they play an important role in the epigenetic control of memory-related synaptic plasticity [Rajasethupathy et al, 2012].…”

Section: American Journal Of Medical Genetics Part Amentioning

confidence: 99%

Epigenetics, fragile X syndrome and transcriptional therapy

Tabolacci

Chiurazzi

2013

American J of Med Genetics Pt A

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Epigenetics refers to the study of heritable changes in gene expression that occur without a change in DNA sequence. Epigenetic mechanisms therefore include all transcriptional controls that determine how genes are expressed during development and differentiation, but also in individual cells responding to environmental stimuli. The purpose of this review is to examine the basic principles of epigenetic mechanisms and their contribution to human disorders with a particular focus on fragile X syndrome (FXS), the most common monogenic form of developmental cognitive impairment. FXS represents a prototype of the so-called repeat expansion disorders due to "dynamic" mutations, namely the expansion (known as "full mutation") of a CGG repeat in the 5 0 UTR of the FMR1 gene. This genetic anomaly is accompanied by epigenetic modifications (mainly DNA methylation and histone deacetylation), resulting in the inactivation of the FMR1 gene. The presence of an intact FMR1 coding sequence allowed pharmacological reactivation of gene transcription, particularly through the use of the DNA demethylating agent 5 0 -aza-2 0 -deoxycytydine and/or inhibitors of histone deacetylases. These treatments suggested that DNA methylation is dominant over histone acetylation in silencing the FMR1 gene. The importance of DNA methylation in repressing FMR1 transcription is confirmed by the existence of rare unaffected males carrying unmethylated full mutations. Finally, we address the potential use of epigenetic approaches to targeted treatment of other genetic conditions. Ó 2013 Wiley Periodicals, Inc.Key words: fragile X syndrome; epigenetics; transcriptional therapy INTRODUCTION When in 1942 Conrad H. Waddington coined the term "epigenetics," the exact nature of genes and their role in heredity and in transcriptional regulation was not known; he used it as a conceptual model of how genes might interact with their surroundings to produce a phenotype [Waddington, 1942]. The term is a portmanteau of the words epigenesis (differentiation of cells from their initial totipotent state in embryonic development) and genetics. Only in 2008 at a Cold Spring harbor meeting, consensus was reached on the definition of epigenetic trait, as "stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence" [Berger et al., 2009]. The greek prefix epi-refers to features that are "on top of" genetics, that is, all those stable but reversible changes to DNA, RNA and proteins that regulate gene expression and allow cells with the same DNA to do different things at different times.Broadly speaking, epigenetic mechanisms include all transcriptional controls that regulate gene expression, whether during development and differentiation or in mature cells responding to the environment. Epigenetic changes can be inherited (e.g., imprinting) and be relatively stable (e.g., chromosome X inactivation), but are often rapidly imposed or removed on a given locus according to cell needs. Four major layers of epigenetic controls have ...

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A Role for Neuronal piRNAs in the Epigenetic Control of Memory-Related Synaptic Plasticity

Cited by 504 publications

References 48 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

DNA methylation is associated with expression level changes of galectin gene in mantle wound healing process of pearl oyster, Pinctada fucata

Epigenetics, fragile X syndrome and transcriptional therapy

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