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The RNA phosphatase PIR-1 regulates endogenous small RNA pathways in C. elegans.

ABSTRACT: Eukaryotic cells regulate 5'-triphosphorylated RNAs (ppp-RNAs) to promote cellular functions and prevent recognition by antiviral RNA sensors. For example, RNA capping enzymes possess triphosphatase domains that remove the γ phosphates of ppp-RNAs during RNA capping. Members of the closely related PIR-1 (phosphatase that interacts with RNA and ribonucleoprotein particle 1) family of RNA polyphosphatases remove both the β and γ phosphates from ppp-RNAs. Here, we show that C. elegans PIR-1 dephosphorylates ppp-RNAs made by cellular RNA-dependent RNA polymerases (RdRPs) and is required for the maturation of 26G-RNAs, Dicer-dependent small RNAs that regulate thousands of genes during spermatogenesis and embryogenesis. PIR-1 also regulates the CSR-1 22G-RNA pathway and has critical functions in both somatic and germline development. Our findings suggest that PIR-1 modulates both Dicer-dependent and Dicer-independent Argonaute pathways and provide insight into how cells and viruses use a conserved RNA phosphatase to regulate and respond to ppp-RNA species.

SUBMITTER: Chaves DA

PROVIDER: S-EPMC7867642 | biostudies-literature |

REPOSITORIES: biostudies-literature

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The RNA phosphatase PIR-1 regulates endogenous small RNA pathways in C. elegans

Project description:Eukaryotic cells regulate 5’ triphosphorylated (ppp) RNAs to promote cellular functions and to prevent recognition by viral RNA sensors. For example, the triphosphatase domain of RNA capping enzymes removes the γ phosphate of ppp-RNAs in RNA capping reactions. Members of a related RNA polyphosphotase family including human PIR1 remove both the β and γ phosphates from ppp-RNAs. Here we demonstrate that C. elegans PIR-1, previously identified as a Dicer-interacting protein, dephosphorylates single and double-stranded ppp-RNAs, and is required for the maturation of 26G-RNAs, which regulate thousands of genes during spermatogenesis and embryogenesis. We find that 26G-RNAs are generated in a unique semi-phasing manner in which primary 26G-RNAs are required for generating secondary 26G-RNAs and PIR-1 is required for removing a diphosphate group from each triphosphorylated precursor, which only generates one 26G-RNA. Our findings also implicate PIR-1 in regulating ppp-RNAs in Dicer-independent pathways, supporting PIR-1 as a master phosphatase regulating ppp-RNAs.

2021-05-14 | GSE150690 | GEO

The RNA phosphatase PIR-1 regulates endogenous small RNA pathways in C. elegans

Project description:The RNA phosphatase PIR-1 regulates endogenous small RNA pathways in C. elegans

| PRJNA633158 | ENA

Guiding RNAi Design Through Characterization of Endogenous Small RNA Pathways.

Project description:RNA interference (RNAi) is a common eukaryotic gene regulation process driven by small RNA effectors. Mechanisms that govern regulatory small noncoding RNA behavior have been extensively described in only a handful of organisms, which suggests that the most effective RNAi approach in many organisms, such as insect pests, remains to be determined. Taking advantage of advances in high-throughput sequencing, characterization of small RNA molecules can be achieved through bioinformatic approaches without the need for genetic experiments. This chapter describes pipelines for characterizing three main classes of small RNAs (microRNAs, small-interfering RNAs, and piwi-associated RNAs) using computationally determined small RNA biogenesis signatures. Obtaining information regarding the abundance of different small RNA classes through these pipelines will lead to a better-informed RNAi strategy, thereby identifying the most efficacious approach for RNAi.

| S-EPMC8959004 | biostudies-literature

Effects of ADARs on small RNA processing pathways in C. elegans.

Project description:Adenosine deaminases that act on RNA (ADARs) are RNA editing enzymes that convert adenosine to inosine in double-stranded RNA (dsRNA). To evaluate effects of ADARs on small RNAs that derive from dsRNA precursors, we performed deep-sequencing, comparing small RNAs from wild-type and ADAR mutant Caenorhabditis elegans. While editing in small RNAs was rare, at least 40% of microRNAs had altered levels in at least one ADAR mutant strain, and miRNAs with significantly altered levels had mRNA targets with correspondingly affected levels. About 40% of siRNAs derived from endogenous genes (endo-siRNAs) also had altered levels in at least one mutant strain, including 63% of Dicer-dependent endo-siRNAs. The 26G class of endo-siRNAs was significantly affected by ADARs, and many altered 26G loci had intronic reads and histone modifications associated with transcriptional silencing. Our data indicate that ADARs, through both direct and indirect mechanisms, are important for maintaining wild-type levels of many small RNAs in C. elegans.

| S-EPMC3409262 | biostudies-other

Small RNA-mediated activation of sugar phosphatase mRNA regulates glucose homeostasis.

Project description:Glucose homeostasis is strictly controlled in all domains of life. Bacteria that are unable to balance intracellular sugar levels and deal with potentially toxic phosphosugars cease growth and risk being outcompeted. Here, we identify the conserved haloacid dehalogenase (HAD)-like enzyme YigL as the previously hypothesized phosphatase for detoxification of phosphosugars and reveal that its synthesis is activated by an Hfq-dependent small RNA in Salmonella typhimurium. We show that the glucose-6-P-responsive small RNA SgrS activates YigL synthesis in a translation-independent fashion by the selective stabilization of a decay intermediate of the dicistronic pldB-yigL messenger RNA (mRNA). Intriguingly, the major endoribonuclease RNase E, previously known to function together with small RNAs to degrade mRNA targets, is also essential for this process of mRNA activation. The exploitation of and targeted interference with regular RNA turnover described here may constitute a general route for small RNAs to rapidly activate both coding and noncoding genes.

| S-EPMC4151517 | biostudies-literature

Interplay between small RNA pathways shapes chromatin landscapes in C. elegans.

Project description:The nematode Caenorhabditis elegans contains several types of endogenous small interfering RNAs (endo-siRNAs) produced by RNA-dependent RNA polymerase (RdRP) complexes. Both 'silencing' siRNAs bound by Worm-specific Argonautes (WAGO) and 'activating' siRNAs bound by the CSR-1 Argonaute require the DRH-3 helicase, an RdRP component. Here, we show that, in the drh-3(ne4253) mutant deficient in RdRP-produced secondary endo-siRNAs, the silencing histone mark H3K9me3 is largely depleted, whereas in the csr-1 partially rescued null mutant strain (WM193), this mark is ectopically deposited on CSR-1 target genes. Moreover, we observe ectopic H3K9me3 at enhancer elements and an increased number of small RNAs that match enhancers in both drh-3 and csr-1 mutants. Finally, we detect accumulation of H3K27me3 at highly expressed genes in the drh-3(ne4253) mutant, which correlates with their reduced transcription. Our study shows that when abundant RdRP-produced siRNAs are depleted, there is ectopic elevation of noncoding RNAs linked to sites with increased silencing chromatin marks. Moreover, our results suggest that enhancer small RNAs may guide local H3K9 methylation.

| S-EPMC6582410 | biostudies-literature

Viral suppressors of RNA silencing hinder exogenous and endogenous small RNA pathways in Drosophila.

Project description:BackgroundIn plants and insects, RNA interference (RNAi) is the main responder against viruses and shapes the basis of antiviral immunity. Viruses counter this defense by expressing viral suppressors of RNAi (VSRs). While VSRs in Drosophila melanogaster were shown to inhibit RNAi through different modes of action, whether they act on other silencing pathways remained unexplored.Methodology/principal findingsHere we show that expression of various plant and insect VSRs in transgenic flies does not perturb the Drosophila microRNA (miRNA) pathway; but in contrast, inhibits antiviral RNAi and the RNA silencing response triggered by inverted repeat transcripts, and injection of dsRNA or siRNA. Strikingly, these VSRs also suppressed transposon silencing by endogenous siRNAs (endo-siRNAs).Conclusions/significanceOur findings identify VSRs as tools to unravel small RNA pathways in insects and suggest a cosuppression of antiviral RNAi and endo-siRNA silencing by viruses during fly infections.

| S-EPMC2689938 | biostudies-literature

Competition between virus-derived and endogenous small RNAs regulates gene expression in Caenorhabditis elegans.

Project description:Positive-strand RNA viruses encompass more than one-third of known virus genera and include many medically and agriculturally relevant human, animal, and plant pathogens. The nematode Caenorhabditis elegans and its natural pathogen, the positive-strand RNA virus Orsay, have recently emerged as a new animal model to understand the mechanisms and evolution of innate immune responses. In particular, the RNA interference (RNAi) pathway is required for C. elegans resistance to viral infection. Here we report the first genome-wide analyses of gene expression upon viral infection in C. elegans. Using the laboratory strain N2, we identify a novel C. elegans innate immune response specific to viral infection. A subset of these changes is driven by the RNAi response to the virus, which redirects the Argonaute protein RDE-1 from its endogenous small RNA cofactors, leading to loss of repression of endogenous RDE-1 targets. Additionally, we show that a C. elegans wild isolate, JU1580, has a distinct gene expression signature in response to viral infection. This is associated with a reduction in microRNA (miRNA) levels and an up-regulation of their target genes. Intriguingly, alterations in miRNA levels upon JU1580 infection are associated with a transformation of the antiviral transcriptional response into an antibacterial-like response. Together our data support a model whereby antiviral RNAi competes with endogenous small RNA pathways, causing widespread transcriptional changes. This provides an elegant mechanism for C. elegans to orchestrate its antiviral response, which may have significance for the relationship between small RNA pathways and immune regulation in other organisms.

| S-EPMC3730100 | biostudies-literature

Small RNA Sequencing Identifies PIWI-Interacting RNAs Deregulated in Glioblastoma-piR-9491 and piR-12488 Reduce Tumor Cell Colonies <i>In Vitro</i>.

Project description:Glioblastoma (GBM) is the most frequently occurring primary malignant brain tumor of astrocytic origin. To change poor prognosis, it is necessary to deeply understand the molecular mechanisms of gliomagenesis and identify new potential biomarkers and therapeutic targets. PIWI-interacting RNAs (piRNAs) help in maintaining genome stability, and their deregulation has already been observed in many tumors. Recent studies suggest that these molecules could also play an important role in the glioma biology. To determine GBM-associated piRNAs, we performed small RNA sequencing analysis in the discovery set of 19 GBM and 11 non-tumor brain samples followed by TaqMan qRT-PCR analyses in the independent set of 77 GBM and 23 non-tumor patients. Obtained data were subsequently bioinformatically analyzed. Small RNA sequencing revealed 58 significantly deregulated piRNA molecules in GBM samples in comparison with non-tumor brain tissues. Deregulation of piR-1849, piR-9491, piR-12487, and piR-12488 was successfully confirmed in the independent groups of patients and controls (all p < 0.0001), and piR-9491 and piR-12488 reduced GBM cells' ability to form colonies in vitro. In addition, piR-23231 was significantly associated with the overall survival of the GBM patients treated with Stupp regimen (p = 0.007). Our results suggest that piRNAs could be a novel promising diagnostic and prognostic biomarker in GBM potentially playing important roles in gliomagenesis.

| S-EPMC8415021 | biostudies-literature

AMPK regulates germline stem cell quiescence and integrity through an endogenous small RNA pathway.

Project description:During suboptimal growth conditions, Caenorhabditis elegans larvae undergo a global developmental arrest called "dauer." During this stage, the germline stem cells (GSCs) become quiescent in an AMP-activated Protein Kinase (AMPK)-dependent manner, and in the absence of AMPK, the GSCs overproliferate and lose their reproductive capacity, leading to sterility when mutant animals resume normal growth. These defects correlate with the altered abundance and distribution of a number of chromatin modifications, all of which can be corrected by disabling components of the endogenous small RNA pathway, suggesting that AMPK regulates germ cell integrity by targeting an RNA interference (RNAi)-like pathway during dauer. The expression of AMPK in somatic cells restores all the germline defects, potentially through the transmission of small RNAs. Our findings place AMPK at a pivotal position linking energy stress detected in the soma to a consequent endogenous small RNA-mediated adaptation in germline gene expression, thereby challenging the "permeability" of the Weismann barrier.

| S-EPMC6576793 | biostudies-literature

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