A piRNA Pathway Primed by Individual Transposons Is Linked to De Novo DNA Methylation in Mice

Aravin, Alexei A.; Sachidanandam, Ravi; Bourc’his, Déborah; Schaefer, Christopher; Pezić, Dubravka; Tóth, Katalin; Bestor, Timothy H.; Hannon, Gregory J.

doi:10.1016/j.molcel.2008.09.003

Cited by 1,068 publications

(1,388 citation statements)

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“…Subsequently, the RNA products of this reaction may be loaded into the complementary Piwi-clade protein Ago3 for ping-pong amplification [107] (Box 1). Piwi also appears to initiate transcriptional gene silencing (TGS) by shuttling to the nucleus, recognizing transposon transcripts, and recruiting DNA [109,110] and/or chromatin modifiers, [111,112] which repress transcription of transposon loci (Box 2). This link between RNAi and heterochromatin formation is highly reminiscent of RNA induced transcriptional silencing (RITS) in budding yeast.…”

Section: Piwismentioning

confidence: 99%

From guide to target: molecular insights into eukaryotic RNA-interference machinery

Ipsaro

Joshua‐Tor

2015

Nat Struct Mol Biol

218

144

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Since its relatively recent discovery, RNA interference (RNAi) has emerged as a potent, specific, and ubiquitous means of gene regulation. Through a number of pathways that are conserved from yeast to humans, small non-coding RNAs direct molecular machinery to silence gene expression. In this review, we focus on mechanisms and structures that govern RNA silencing in higher organisms. In addition to highlighting recent advances, parallels and differences between RNAi pathways are discussed. Together, the studies reviewed herein reveal the versatility and programmability of RNA-induced Silencing Complexes (RISCs) and emphasize the importance of both upstream biogenesis and downstream silencing factors. Discovery and Biological Perspectives of RNA interferenceRNAi was first described by Fire and Mello in the 1990s when, in an attempt to use antisense RNA to down-regulate gene expression, they observed that double-stranded RNA (dsRNA) was more potent than sense or anti-sense RNA alone [1]. This seminal work boasted robust and specific gene knock down in addition to coining the term "RNA interference" (RNAi). Shortly beforehand, the discovery of individual regulatory RNAs in C. elegans hinted that small, non-coding RNAs might be a pervasive means of gene regulation in higher organisms [2,3]. In the following decade, with the mechanistic insight of Fire and Mello's work in hand, this idea was confirmed and it is now accepted that wellover 1,000 small RNAs are encoded in the human genome that may regulate over 60% of our genes [4,5]. It also became apparent that several seemingly disconnected phenomena are variations of RNAi-type pathways including co-suppression in plants, DNA elimination in Tetrahymena, and quelling in Neurospora [6]. The prevalence of RNAi is impressive and its importance is underscored by the fact that RNAi dysfunction is associated with numerous diseases and disorders including neurological maladies, cancers, and infertility.Shortly after the initial description of RNAi phenomenology, a burst of genetic, biochemical, biophysical, and bioinformatic efforts laid a strong foundation for identifying the molecular pathways, players, and parameters that govern silencing via RNAi. Work from Reprints and permissions information is available online at http://www.nature.com/reprints/index.html. HHMI Author ManuscriptHHMI Author Manuscript HHMI Author Manuscript numerous groups defined the molecular apparatus of RNAi as RISC (RNA-induced Silencing Complex), a ribonucleoprotein complex minimally comprised of a small singlestranded RNA (~20-31 nucleotides) and an Argonaute protein which serves as the effector molecule (reviewed in [7]). In this configuration, the loaded "guide" RNA acts as a specificity determinant that directs Argonaute and any other associated machinery to the target. The guide-loaded Argonaute platform underlies every example in the expansive array of known RNAi pathways in eukaryotes regardless of the source of the guide (structured loci, transposons, viral, etc.), the machinery ...

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Section: Piwismentioning

confidence: 99%

From guide to target: molecular insights into eukaryotic RNA-interference machinery

Ipsaro

Joshua‐Tor

2015

Nat Struct Mol Biol

218

144

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“…16 The activity of piRNAs in transposon silencing appears to be the most important event during embryonic development. 17 To facilitate silencing transposons in the testes of mammals or in the germ cells of invertebrates, the piwi proteins play essential roles in interacting with piRNAs.These piwi proteins are members of Argonautes, proteins that are needed for gene silencing in miRNA action, including MIWI, MIWI2 and MILI. The sequences of piRNAs guide the piwi proteins to their transposon targets.…”

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“…The sequences of piRNAs guide the piwi proteins to their transposon targets. 17 Decreased expression of these PIWI proteins is correlated with increased expression of transposons, leading to potential infertility. [17][18][19] We have previously observed that increased expression of miR-17 retards tissue growth.…”

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confidence: 99%

“…17 Decreased expression of these PIWI proteins is correlated with increased expression of transposons, leading to potential infertility. [17][18][19] We have previously observed that increased expression of miR-17 retards tissue growth. 11 Further examination showed that significantly higher incidences of infertility occurred in miR-17 transgenic mice.…”

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Reciprocal regulation of miRNAs and piRNAs in embryonic development

Yang

Xuan

et al. 2016

Cell Death Differ

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MicroRNAs (miRNAs) and piwi-interacting RNAs (piRNAs) are two classes of small noncoding RNAs, both of which play roles in regulating tissue development. It is unknown whether these distinct classes of noncoding RNAs can regulate one another. Here we show that ectopic expression of miR-17 inhibited mouse fertility and early embryonic development. Specifically, we found that the piRNA amplification loop was repressed by miR-17-5p, leading to increased levels of transposition mutagenesis. This occurred by suppressing the amplification loop of piRNAs with an identical 5′ sequence and by targeting Mili/Miwi2, an essential component of the piRNA amplification loop, and the DNA methyltransferase, Dnmt3a. We also found that increased levels of piRNAs could compete with miRNAs for target binding, resulting in increased expression of Dnmt3a and Mili. Increased Dnmt3a levels could in turn block miR-17-5p expression, while increased Mili expression could accelerate piRNA amplification and inhibit transposon generation, favoring embryonic development. We report for the first time the reciprocal regulation between miRNAs and piRNAs in mouse embryonic development. Cell Death and Differentiation (2016) 23, 1458-1470 doi:10.1038/cdd.2016; published online 18 March 2016A microRNA (miRNA) is a small non-coding RNA molecule of 18-24 nucleotides in length that are post-transcriptional regulators of gene expression. A miRNA has the capacity to affect the stability of hundreds of unique mRNAs 1 and may repress synthesis of hundreds of proteins by base-pairing with the targeting mRNAs. 2 The discovery of miRNAs in gene regulation has improved our understanding of posttranscriptional control of tissue development and aging. 3-5 A polycistronic miRNA cluster, miR-17~92, consisting of six mature miRNAs , and miR-92a-1), has been reported to play a fundamental role in development and remodeling. [6][7][8][9] Furthermore, members of miR-17-92 cluster are found to be commonly down-regulated in aging human cells. 10 We have found that ectopic expression of miR-17 retards tissue growth 11 and inhibits cell senescence. 12 Piwi-interacting RNA (piRNA) is the largest class of small non-coding RNAs expressed by animal cells. 13 piRNAs form complexes with piwi proteins, which function posttranscriptionally in silencing retrotransposons and other genetic elements in germ-line cells. 14 piRNA activity in gene regulation may lead to silencing of transposon expression, 15 as most piRNA sequences are antisense to transposon sequences. 16 The activity of piRNAs in transposon silencing appears to be the most important event during embryonic development. 17 To facilitate silencing transposons in the testes of mammals or in the germ cells of invertebrates, the piwi proteins play essential roles in interacting with piRNAs.These piwi proteins are members of Argonautes, proteins that are needed for gene silencing in miRNA action, including MIWI, MIWI2 and MILI. The sequences of piRNAs guide the piwi proteins to their transposon targets. 17 Decreased expressio...

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Small RNAs in epigenetic inheritance: from mechanisms to trait transmission

Cecere

2021

FEBS Letters

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Inherited information is transmitted to progeny primarily by the genome through the gametes. However, in recent years, epigenetic inheritance has been demonstrated in several organisms, including animals. Although it is clear that certain post-translational histone modifications, DNA methylation, and noncoding RNAs regulate epigenetic inheritance, the molecular mechanisms responsible for epigenetic inheritance are incompletely understood. This review focuses on the role of small RNAs in transmitting epigenetic information across generations in animals. Examples of documented cases of transgenerational epigenetic inheritance are discussed, from the silencing of transgenes to the inheritance of complex traits, such as fertility, stress responses, infections, and behavior. Experimental evidence supporting the idea that small RNAs are epigenetic molecules capable of transmitting traits across generations is highlighted, focusing on the mechanisms by which small RNAs achieve such a function. Just as the role of small RNAs in epigenetic processes is redefining the concept of inheritance, so too our understanding of the molecular pathways and mechanisms that govern epigenetic inheritance in animals is radically changing.

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A piRNA Pathway Primed by Individual Transposons Is Linked to De Novo DNA Methylation in Mice

Cited by 1,068 publications

References 34 publications

From guide to target: molecular insights into eukaryotic RNA-interference machinery

From guide to target: molecular insights into eukaryotic RNA-interference machinery

Reciprocal regulation of miRNAs and piRNAs in embryonic development

Small RNAs in epigenetic inheritance: from mechanisms to trait transmission

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