Caenorhabditis elegans
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ABSTRACT:
PROVIDER: PRJNA152313 | ENA |
REPOSITORIES: ENA
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Project description:Caenorhabditis elegans contains twenty-five Argonautes, of which, only ALG-1 and ALG-2 are known to interact with miRNAs. ALG-5 belongs to the AGO subfamily of Argonautes that includes ALG-1 and ALG-2, but its role in small RNA pathways is unknown. We analyzed by high-throughput sequencing the small RNAs associated with ALG-5, ALG-1, and ALG-2, as well as changes in mRNA expression in alg-5, alg-1, and alg-2 mutants.
2017-06-09 | GSE98935 | GEO
Project description:MicroRNAs (miRNAs) are essential regulators involved in multiple biological processes. To achieve their gene repression function, they are loaded in miRNA-specific Argonautes to form the miRNA-induced silencing complex (miRISC). Mammals and C. elegans possess more than one paralog of miRNA-specific Argonautes but the dynamic between them remains unclear. Here, we report the conserved dipeptidyl peptidase DPF-3 as a new interactor of the miRNA-specific Argonautes ALG-1 and ALG-2 in C. elegans. Knockout of dpf-3 increases ALG-2 levels and miRISC formation in alg-1 null animals, thereby compensating for ALG-1 loss and rescuing miRNA-related defects observed. DPF-3 can cleave an ALG-2 N-terminal peptide in vitro but does not appear to rely on this catalytic activity to regulate ALG-2 in vivo. This study uncovers the importance of DPF-3 in the miRNA pathway and provides insights on how multiple miRNA Argonautes contribute to achieve proper miRNA-mediated gene regulation in animals.
2025-03-06 | PXD055867 | Pride
Project description:Argonaute proteins are at the core of the microRNA-mediated gene silencing pathway essential for animals. In C. elegans, the microRNA-specific Argonautes ALG-1 and ALG-2 regulate multiple processes required for proper animal developmental timing and viability. Here, we identified a new phosphorylation site, serine 642, on ALG-1 that modulates microRNA association. Mutating ALG-1 serine 642 into a phospho-mimicking residue impairs microRNA binding and causes embryonic lethality and post-embryonic phenotypes that are common with alteration of microRNA functions. Monitoring microRNA levels in alg-1 phosphorylation mutant animals reveal that miRNA passenger strands strongly increase but are not preferentially loaded into ALG-1, indicating that the miRNA binding defects could also lead to miRNA duplexes accumulation. Our genetic and biochemical experiments support the protein kinase A KIN-1 as the putative kinase that phosphorylates ALG-1 serine 642. Altogether, our data indicate that PKA triggers the ALG-1 phosphorylation to regulate its microRNAs association during C. elegans development.
2022-09-10 | GSE198352 | GEO
Project description:The Argonautes (AGOs) are widely expressed, evolutionarily conserved RNA binding proteins that play an important role in gene expression regulation. The AGOs bind to small regulatory noncoding RNAs such as micro RNAs (miRNAs), short interfering RNAs (siRNAs), Piwi-interacting RNAs (piRNAs) etc. The small regulatory noncoding RNAs serve the function of guiding the AGOs to the right target RNAs by complementary base pairing. Additionally, the AGOs interact with GW182 (TNRC6A/-B/-C) proteins and together with small RNAs, they form an effector ribonucleo protein complex named, RNA Induced Silencing Complex (RISC) that regulates several aspects of transcriptional and post-transcriptional gene expression. ALG-1 (Argonaute Like Gene) and ALG-2 are the AGO proteins in C. elegans that are required for miRNA mediated gene expression regulation. Our efforts towards the characterization of the protein complexes comprised of ALG-1 led to the identification of DPF-3, a conserved protease belonging to clinically relevant Di Peptidyl Peptidase IV family, as the novel interacting partner of ALG-1. We have further explored the role of DPF-3 in AGO regulation.
2025-03-06 | PXD060454 | Pride
Project description:MicroRNAs (miRNAs) are essential regulators involved in multiple biological processes. To achieve their gene repression function, they are loaded in miRNA-specific Argonautes to form the miRNA-induced silencing complex (miRISC). Mammalians and C. elegans intriguingly possess more than one paralog of miRNA-specific Argonautes and the dynamic between them remains unclear. Here, using C. elegans as a model system, we report dipeptidyl peptidase DPF-3 as a new interactor of miRNA-specific Argonautes ALG-1 and ALG-2. Knockout of dpf-3 rescues miRNA-related defects observed in alg-1 null animals and allows ALG-2 to better compensate for the lack of its paralog through higher expression and activity. While DPF-3 can cleave a N-terminal dipeptide of ALG-2 in vitro, we show that it is likely not the molecular mechanism used by DPF-3 to regulate ALG-2. This study uncovers the importance of a dipeptidyl peptidase in the miRNA pathway and provide insights in miRNA-specific Argonautes regulation dynamics in animals.
2025-03-06 | GSE276186 | GEO
Project description:MicroRNAs (miRNA) associate with Argonaute proteins and negatively regulate gene expression by base pairing with complementary sequences in the 3’ UTRs of target genes. De novo coding variants in the human Argonaute gene AGO1 were reported to cause neurodevelopmental disorder (NDD) with intellectual disability (ID). Most of the altered amino acids are conserved between the miRNA associated Argonautes in H. sapiens and C. elegans, suggesting that the human AGO1 mutations could disrupt evolutionarily conserved functions in miRNA biogenesis or target repression. We genetically modeled four human AGO1 mutations in C. elegans by introducing identical mutations into the C. elegans AGO1 homolog, ALG-1. These alg-1 NDD mutations caused phenotypes in C. elegans indicative of disrupted miRNA processing, miRISC formation, and/or target repression. We show that the alg-1 NDD mutations are antimorphic as they cause developmental and molecular phenotypes stronger than those exhibited by the alg-1 null mutants, likely by sequestrating functional miRNA silencing complex (miRISC) components into non-functional complexes that fail to confer robust gene repression. The alg-1 NDD mutations cause allele-specific disruptions in mature miRNA profiles, both in overall abundances and ALG-1 NDD association, accompanied by perturbation of downstream gene expression, including altered translational efficiency and/or mRNA abundance. The perturbed genes include those with human orthologs whose dysfunction is associated with NDD. These cross-clade genetic studies illuminate fundamental Argonaute functions and provide insights into the conservation of miRNA-mediated post-transcriptional regulatory mechanisms.
2023-12-30 | GSE252064 | GEO
Project description:MicroRNAs are regulators of gene expression whose functions are critical for normal development and physiology. We have previously characterized mutations in a Caenorhabditis elegans microRNA-specific Argonaute ALG-1 (Argonaute-like gene) that are antimorphic [alg-1(anti)]. alg-1(anti) mutants have dramatically stronger microRNA-related phenotypes than animals with a complete loss of ALG-1. ALG-1(anti) miRISC (microRNA induced silencing complex) fails to undergo a functional transition from microRNA processing to target repression. To better understand this transition, we characterized the small RNA population associated with ALG-1(anti) complexes in vivo. alg-1(anti) mutants dramatically overaccumulated microRNA* (passenger) strands, and immunoprecipitated ALG-1(anti) complexes contained nonstoichiometric yields of mature microRNA and microRNA* strands, with some microRNA* strands present in the ALG-1(anti) Argonaute far in excess of the corresponding mature microRNAs. We show complex and microRNA-specific defects in microRNA strand selection and microRNA* strand disposal. For certain microRNAs (for example mir-58), microRNA guide strand selection by ALG-1(anti) appeared normal, but microRNA* strand release was inefficient. For other microRNAs (such as mir-2), both the microRNA and microRNA* strands were selected as guide by ALG-1(anti), indicating a defect in normal specificity of the strand choice. Our results suggest that wild-type ALG-1 complexes recognize structural features of particular microRNAs in the context of conducting the strand selection and microRNA* ejection steps of miRISC maturation.
2015-09-07 | GSE72659 | GEO
Project description:microRNAs regulate gene expression through interaction with an Argonaute protein family member. While some members of this protein family retain an enzymatic activity capable of cleaving RNA molecules complementary to Argonaute-bound small RNAs, the role of the slicing activity in the canonical microRNA pathway is still unclear in animals. To address the importance of slicing Argonautes in animals, we created Caenorhabditis elegans mutant strains carrying catalytically dead endogenous ALG-1 and ALG-2, the only two slicing Argonautes essential for the miRNA pathway in this animal model. We observe that the loss of ALG-1 and ALG-2 slicing activity affects overall animal fitness and causes phenotypes reminiscent of miRNA defects only when grown and maintained at restrictive temperature. Furthermore, the analysis of global miRNA expression show that the catalytic activity of ALG-1 and ALG-2 differentially regulate the level of specific subsets of miRNAs in young adults. We also demonstrate that altering the slicing activity of those miRNA-specific Argonautes does not result in any defect in the production of canonical miRNAs. Together, these data support that the slicing activity of miRNA-specific Argonautes functions to maintain levels of a set of miRNAs for optimal viability and fitness in animals particularly exposed to specific growing conditions.
2024-03-15 | GSE222733 | GEO
Project description:MicroRNAs (miRNA) associate with Argonaute proteins and negatively regulate gene expression by base pairing with complementary sequences in the 3’ UTRs of target genes. De novo coding variants in the human Argonaute gene AGO1 were reported to cause neurodevelopmental disorder (NDD) with intellectual disability (ID). Most of the altered amino acids are conserved between the miRNA associated Argonautes in H. sapiens and C. elegans, suggesting that the human AGO1 mutations could disrupt evolutionarily conserved functions in miRNA biogenesis or target repression. We genetically modeled four human AGO1 mutations in C. elegans by introducing identical mutations into the C. elegans AGO1 homolog, ALG-1. These alg-1 NDD mutations caused phenotypes in C. elegans indicative of disrupted miRNA processing, miRISC formation, and/or target repression. We show that the alg-1 NDD mutations are antimorphic as they cause developmental and molecular phenotypes stronger than those exhibited by the alg-1 null mutants, likely by sequestrating functional miRNA silencing complex (miRISC) components into non-functional complexes that fail to confer robust gene repression. The alg-1 NDD mutations cause allele-specific disruptions in mature miRNA profiles, both in overall abundances and ALG-1 NDD association, accompanied by perturbation of downstream gene expression, including altered translational efficiency and/or mRNA abundance. The perturbed genes include those with human orthologs whose dysfunction is associated with NDD. These cross-clade genetic studies illuminate fundamental Argonaute functions and provide insights into the conservation of miRNA-mediated post-transcriptional regulatory mechanisms.
2023-12-30 | GSE252065 | GEO
Project description:MicroRNAs (miRNA) associate with Argonaute proteins and negatively regulate gene expression by base pairing with complementary sequences in the 3’ UTRs of target genes. De novo coding variants in the human Argonaute gene AGO1 were reported to cause neurodevelopmental disorder (NDD) with intellectual disability (ID). Most of the altered amino acids are conserved between the miRNA associated Argonautes in H. sapiens and C. elegans, suggesting that the human AGO1 mutations could disrupt evolutionarily conserved functions in miRNA biogenesis or target repression. We genetically modeled four human AGO1 mutations in C. elegans by introducing identical mutations into the C. elegans AGO1 homolog, ALG-1. These alg-1 NDD mutations caused phenotypes in C. elegans indicative of disrupted miRNA processing, miRISC formation, and/or target repression. We show that the alg-1 NDD mutations are antimorphic as they cause developmental and molecular phenotypes stronger than those exhibited by the alg-1 null mutants, likely by sequestrating functional miRNA silencing complex (miRISC) components into non-functional complexes that fail to confer robust gene repression. The alg-1 NDD mutations cause allele-specific disruptions in mature miRNA profiles, both in overall abundances and ALG-1 NDD association, accompanied by perturbation of downstream gene expression, including altered translational efficiency and/or mRNA abundance. The perturbed genes include those with human orthologs whose dysfunction is associated with NDD. These cross-clade genetic studies illuminate fundamental Argonaute functions and provide insights into the conservation of miRNA-mediated post-transcriptional regulatory mechanisms.
2023-12-30 | GSE252063 | GEO