MIWI2 and MILI Have Differential Effects on piRNA Biogenesis and DNA Methylation

Manakov, Sergei A.; Pezić, Dubravka; Marinov, Georgi K.; Pastor, William A.; Sachidanandam, Ravi; Aravin, Alexei A.

doi:10.1016/j.celrep.2015.07.036

Cited by 101 publications

(98 citation statements)

References 30 publications

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“…Furthermore, strong hypomethylation was observed in two genomic locations [chromosome 9: 123924637-123925547; chromosome 17: 39011428-39011506; mm10/University of California, Santa Cruz (UCSC)], which accounted for 60% of all intergenic HMCs in the mutant hippocampi (highlighted in Dataset S4). Interestingly, consistent with Mili regulation of LINE1 promoter methylation in the germline (33,36), all LINE1-associated HMCs in the mutant hippocampi coincided with LINE1 promoters (50% of all LINE1 belonged to L1Md_F2, compared with a baseline representation of 26% in hippocampus) and that mutant hippocampi compared with mutant PFC exhibited a greater degree of LINE1 promoter hypomethylation (Fig. 3B and Dataset S5).…”

Section: Mili −/− Mice Exhibit Line1 Promoter Hypomethylation In Theimentioning

confidence: 53%

“…S7). In contrast, hippocampal LTR-associated HMCs were fewer and more evenly distributed throughout the length of the transposon as described for the germline (Dataset S5) (33,36), consistent with the paucity of LTR-derived sequences in neuronal piRNA fraction (Fig. 2 A and B and Dataset S3).…”

Section: Mili −/− Mice Exhibit Line1 Promoter Hypomethylation In Theimentioning

confidence: 73%

“…It is also possible that compared with Mili, Miwi2 was expressed in fewer cell types and also in a temporally restricted manner. Nevertheless, because Mili was shown to act upstream of Miwi2, and is also capable of functioning independently of Miwi2, our subsequent studies using Mili −/− mice should provide a comprehensive functional readout of the contributions of the piRNA pathway in mammalian brain (1,33).…”

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

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: Mili −/− Mice Exhibit Line1 Promoter Hypomethylation In Theimentioning

confidence: 53%

Section: Mili −/− Mice Exhibit Line1 Promoter Hypomethylation In Theimentioning

confidence: 73%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

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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“…Mice lacking the Piwi homologs showed substantial demethylation and repression of transposable elements targeted by piRNAs (Rajasethupathy et al 2012). Mili and Miwi2 regulate DNA methylation at the transposon loci too (Aravin et al 2008; Aravin et al 2007b; Kuramochi-Miyagawa et al 2008; Manakov et al 2015). Additionally, there are reports that piRNAs direct the DNA methylation on the non-transposon genomic loci (Watanabe et al 2011).…”

Section: Observations and Discussionmentioning

confidence: 99%

piRNAs and Their Functions in the Brain

Zuo

Wang

Tan

et al. 2016

International Journal of Human Genetics

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Piwi-interacting RNAs (piRNAs) are the non-coding RNAs with 24-32 nucleotides (nt). They exhibit stark differences in length, expression pattern, abundance, and genomic organization when compared to micro-RNAs (miRNAs). There are hundreds of thousands unique piRNA sequences in each species. Numerous piRNAs have been identified and deposited in public databases. Since the piRNAs were originally discovered and well-studied in the germline, a few other studies have reported the presence of piRNAs in somatic cells including neurons. This paper reviewed the common features, biogenesis, functions, and distributions of piRNAs and summarized their specific functions in the brain. This review may provide new insights and research direction for brain disorders.

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“…There are three stages of piRNA production during animal development: fetal/prenatal, prepachytene/postnatal, and pachytene/postnatal. At the fetal/prenatal stage, TE-derived piRNAs bound to PIWI proteins have been shown to participate in transcriptional silencing of these TEs through DNA methylation (Aravin et al , 2008Kuramochi-Miyagawa et al 2008;Manakov et al 2015;Nagamori et al 2015;Kojima-Kita et al 2016). Later in development, most postnatal piRNAs are produced from specific genomic regions termed piRNA clusters and divided into two types, depending on the stage of their expression: prepachytene clusters arising from genic sequences, and pachytene clusters of intergenic origin (Li et al 2013a).…”

Section: Introductionmentioning

confidence: 99%

Two modes of targeting transposable elements by piRNA pathway in human testis

Gainetdinov

Skvortsova

Kondratieva

et al. 2017

RNA

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PIWI proteins and their partner small RNAs, termed piRNAs, are known to control transposable elements (TEs) in the germline. Here, we provide evidence that in humans this control is exerted in two different modes. On the one hand, production of piRNAs specifically targeting evolutionarily youngest TEs (L1HS, L1PA2-L1PA6, LTR12C, SVA) is present both at prenatal and postnatal stages of spermatogenesis and is performed without involvement of piRNA clusters. On the other hand, at postnatal stages, piRNAs deriving from pachytene clusters target "older" TEs and thus complement cluster-independent piRNA production to achieve relevant targeting of virtually all TEs expressed in postnatal testis. We also find that converging transcription of antisense-oriented genes contributes to the origin of genic postnatal prepachytene clusters. Finally, while a fraction of pachytene piRNAs was previously shown to arise from long intergenic noncoding RNAs (lincRNAs, i.e., pachytene piRNA cluster primary transcripts), we ascertain that these are a specific set of lincRNAs that both possess distinguishing epigenetic features and are expressed exclusively in testis.

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MIWI2 and MILI Have Differential Effects on piRNA Biogenesis and DNA Methylation

Cited by 101 publications

References 30 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

piRNAs and Their Functions in the Brain

Two modes of targeting transposable elements by piRNA pathway in human testis

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