Piwi and piRNAs Act Upstream of an Endogenous siRNA Pathway to Suppress Tc3 Transposon Mobility in the Caenorhabditis elegans Germline

Das, Partha Pratim; Bagijn, Marloes P.; Goldstein, Leonard D.; Woolford, Julie R.; Lehrbach, Nicolas J; Sapetschnig, Alexandra; Buhecha, Heeran R.; Gilchrist, Michael J.; Howe, Kevin; Stark, Rory; Matthews, Nik; Berezikov, Eugène; Ketting, René F.; Tavaré, Simon; Miska, Eric A.

doi:10.1016/j.molcel.2008.06.003

Cited by 406 publications

(545 citation statements)

References 73 publications

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“…The diversity of Argonautes in C. elegans has proven advantageous for dissecting out the multiple roles of these proteins. C. elegans Argonautes ALG-1 and ALG-2 are essential for miRNA-mediated gene silencing, RDE-1 for exogenous RNAi, ERGO-1 for endogenous RNAi, and PRG-1 and PRG-2 for piRNA-mediated gene silencing, and a handful of other Argonautes are thought to bind secondary siRNAs but lack the ability to slice RNA targets (Grishok et al 2001;Yigit et al 2006;Batista et al 2008;Das et al 2008;Wang and Reinke 2008). csr-1 was first obtained in a germ-line cosuppression screen, which suggested that it may be involved in silencing repetitive transgene arrays in the germ line (Robert et al 2005).…”

Section: Discussionmentioning

confidence: 99%

A Genomewide RNAi Screen for Genes That Affect the Stability, Distribution and Function of P Granules in Caenorhabditis elegans

Updike

Strome

2009

Genetics

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P granules are non-membrane-bound organelles found in the germ-line cytoplasm throughout Caenorhabditis elegans development. Like their ''germ granule'' counterparts in other animals, P granules are thought to act as determinants of the identity and special properties of germ cells, properties that include the unique ability to give rise to all tissues of future generations of an organism. Therefore, understanding how P granules work is critical to understanding how cellular immortality and totipotency are retained, gained, and lost. Here we report on a genomewide RNAi screen in C. elegans, which identified 173 genes that affect the stability, localization, and function of P granules. Many of these genes fall into specific classes with shared P-granule phenotypes, allowing us to better understand how cellular processes such as protein degradation, translation, splicing, nuclear transport, and mRNA homeostasis converge on P-granule assembly and function. One of the more striking phenotypes is caused by the depletion of CSR-1, an Argonaute associated with an endogenous siRNA pathway that functions in the germ line. We show that CSR-1 and two other endo-siRNA pathway members, the RNA-dependent RNA polymerase EGO-1 and the helicase DRH-3, act to antagonize RNA and P-granule accumulation in the germ line. Our findings strengthen the emerging view that germ granules are involved in numerous aspects of RNA metabolism, including an endo-siRNA pathway in germ cells.

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Section: Discussionmentioning

confidence: 99%

A Genomewide RNAi Screen for Genes That Affect the Stability, Distribution and Function of P Granules in Caenorhabditis elegans

Updike

Strome

2009

Genetics

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“…Since only one family of retrotransposons on one chromosome was considered in our simulations, piRNAs can potentially improve the fitness of hosts by 0.99983 30 /0.99916 30 À 1 = 2.03% in each generation if the genome hosts 30 similarly active retrotransposon families and there are no synergistic effects between families. The effect of piRNAs on host fitness improvement might be conservative here because (1) in our simulation we only consider one chromosome which accounts for 25%-30% of the genome size of D. melanogaster, (2) the number of active retrotransposon families might be greater than 30 in the genome (Kaminker et al 2002;Quesneville et al 2005), and (3) piRNAs might reduce the retrotransposition rates by more than 10-fold (Das et al 2008). More pronounced effects of piRNAs were observed if we increase the effective population size by 10-fold and the retrotransposition rates by threefold.…”

Section: Forward Simulations Of the Population Genetics Of Pirts And mentioning

confidence: 99%

“…Recently, it was discovered that PIWI-interacting RNAs (piRNAs), a class of small (26-31 bp) RNA molecules, are crucial repressors of active TEs in the germlines of fruit flies and worms (Aravin et al 2001Nishida and Siomi 2006;Vagin et al 2006;Brennecke et al 2007Brennecke et al , 2008Nishida et al 2007;Yin and Lin 2007;Das et al 2008;Ghildiyal et al 2008;Girard and Hannon 2008;Siomi and Siomi 2008;Li et al 2009;). In Drosophila, three paralogs of the PIWI family-PIWI, AUB, and AGO3-are crucial components of the RNA-induced silencing complex (RISC).…”

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confidence: 99%

Population dynamics of PIWI-interacting RNAs (piRNAs) and their targets in Drosophila

Lü¹,

Clark²

2009

Genome Res.

101

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Transposable elements (TEs) are mobile DNA sequences that make up a large fraction of eukaryotic genomes. Recently it was discovered that PIWI-interacting RNAs (piRNAs), a class of small RNA molecules that are mainly generated from transposable elements, are crucial repressors of active TEs in the germline of fruit flies. By quantifying expression levels of 32 TE families in piRNA pathway mutants relative to wild-type fruit flies, we provide evidence that piRNAs can severely silence the activities of retrotransposons. We incorporate piRNAs into a population genetic framework for retrotransposons and perform forward simulations to model the population dynamics of piRNA loci and their targets. Using parameters optimized for Drosophila melanogaster, our simulation results indicate that (1) piRNAs can significantly reduce the fitness cost of retrotransposons; (2) retrotransposons that generate piRNAs (piRTs) are selectively more advantageous, and such retrotransposon insertions more easily attain high frequency or fixation; (3) retrotransposons that are repressed by piRNAs (targetRTs), however, also have an elevated probability of reaching high frequency or fixation in the population because their deleterious effects are attenuated. By surveying the polymorphisms of piRT and targetRT insertions across nine strains of D. melanogaster, we verified these theoretical predictions with population genomic data. Our theoretical and empirical analysis suggests that piRNAs can significantly increase the fitness of individuals that bear them; however, piRNAs may provide a shelter or Trojan horse for retrotransposons, allowing them to increase in frequency in a population by shielding the host from the deleterious consequences of retrotransposition.[Supplemental material is available online at http://www.genome.org.] Like other kinds of mutations, however, most mutations created by TE insertions are deleterious to the host and are thus selected against. Approximately 50%-80% of mutations arising in D. melanogaster can be attributed to TEs (Finnegan 1992;Ashburner et al. 2004). Based on the copy number of TEs in D. melanogaster, it was estimated that TEs can decrease the fitness of hosts by 0.4%-5% (Eanes et al. 1987;Charlesworth and Langley 1989;Mackay et al. 1992;Pasyukova et al. 2004). The fitness costs of TEs are generally mediated through the following mechanisms: (1) TE insertions disrupt genes (Charlesworth and Charlesworth 1983;Finnegan 1992;McDonald et al. 1997); (2) transcription and translation of TE-encoded genes are costly (Brookfield 1991; Nuzhdin 1999); and (3) ectopic recombination among dispersed and heterozygous TEs creates deleterious chromosomal rearrangements (Montgomery et al. 1987;Langley et al. 1988;Charlesworth and Langley 1989;Petrov et al. 2003). It has been demonstrated that different TE families are regulated by different mechanisms, although these mechanisms are not mutually exclusive (Biemont et al. 1994;Carr et al. 2002;Petrov et al. 2003). Despite their being under strong selective pressure, TEs ...

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“…In C. elegans, mutation of dcr-1 results in severe defects in germline development, malformed unfertilized oocytes, and sterility (14-16). Similarly, mutation of prg-1 (piwi-related gene) abrogates the expression of 21U RNAs (a piwi-interacting class of small RNAs) and results in impaired germline proliferation and sterility at elevated temperatures (17)(18)(19). Small RNAs also can serve as heritable parental silencing factors to regulate filial gene expression; in D. melanogaster, misregulation of maternally inherited piRNAs results in activation of transposons and hybrid dysgenesis (20).…”

mentioning

confidence: 99%

26G endo-siRNAs regulate spermatogenic and zygotic gene expression in Caenorhabditis elegans

Han

Manoharan

Harkins

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

166

294

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Endogenous small interfering RNAs (endo-siRNAs) regulate diverse gene expression programs in eukaryotes by either binding and cleaving mRNA targets or mediating heterochromatin formation; however, the mechanisms of endo-siRNA biogenesis, sorting, and target regulation remain poorly understood. Here we report the identification and function of a specific class of germline-generated endo-siRNAs in Caenorhabditis elegans that are 26 nt in length and contain a guanine at the first nucleotide position (i.e., 26G RNAs). 26G RNAs regulate gene expression during spermatogenesis and zygotic development, and their biogenesis requires the ERI-1 exonuclease and the RRF-3 RNA-dependent RNA polymerase (RdRP). Remarkably, we identified two nonoverlapping subclasses of 26G RNAs that sort into specific RNA-induced silencing complexes (RISCs) and differentially regulate distinct mRNA targets. Class I 26G RNAs target genes are expressed during spermatogenesis, whereas class II 26G RNAs are maternally inherited and silence gene expression during zygotic development. These findings implicate a class of endo-siRNAs in the global regulation of transcriptional programs required for fertility and development.endogenous siRNA ͉ germline ͉ RNA interference S mall RNAs bind Argonaute/Piwi proteins in the RNAinduced silencing complex (RISC) and, through base pairing, guide RISC to silence their cognate targets. While the taxonomy of small RNAs remains fluid, they can be defined in part by nucleotide length, 5Ј nucleotide composition, chemical modifications, genetic requirements for biogenesis, mode of silencing, and biological functions. For example, microRNAs are processed from double-stranded hairpin precursors by the RNase III-like enzyme Dicer to the Ϸ22-nt mature form containing a 5Ј-monophosphate nucleotide. The microRNAs associate with Argonaute (Ago) proteins in RISC and mediate translational repression and/or degradation of their target mRNAs (1). In contrast, Piwi-interacting RNAs (piRNAs) are typically longer than microRNAs, possess a uridine in the first nucleotide, and are generated by a Dicer-independent self-amplification pathway. The piRNAs bind to Piwi proteins in RISC and silence transposons (2).Endogenous small interfering RNAs (endo-siRNAs) represent an emerging class of small RNAs described and characterized in Caenorhabditis elegans by Ambros et al. (3). These endo-siRNAs are perfectly antisense to target transcripts and require the C. elegans Dicer, DCR-1, the RNA-dependent RNA polymerase (RdRP) RRF-3, and the exonuclease ERI-1 for expression (4,5). By large-scale pyrosequencing, Ruby et al. determined that other endo-siRNAs target transcripts associated with spermatogenesis and transposons (6). Therefore, C. elegans endo-siRNAs appear to be a diverse class of small RNAs, with distinct biological functions and genetic requirements for biogenesis. The recent discovery of endo-siRNAs derived from transposable elements, natural antisense transcripts, and hairpin RNAs in Drosophila melanogaster and Mus musculus (7-12) fur...

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Piwi and piRNAs Act Upstream of an Endogenous siRNA Pathway to Suppress Tc3 Transposon Mobility in the Caenorhabditis elegans Germline

Cited by 406 publications

References 73 publications

A Genomewide RNAi Screen for Genes That Affect the Stability, Distribution and Function of P Granules in Caenorhabditis elegans

A Genomewide RNAi Screen for Genes That Affect the Stability, Distribution and Function of P Granules in Caenorhabditis elegans

Population dynamics of PIWI-interacting RNAs (piRNAs) and their targets in Drosophila

26G endo-siRNAs regulate spermatogenic and zygotic gene expression in Caenorhabditis elegans

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