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Gene expression profiling in cells with Ago1 knockdown (Affymetrix)

ABSTRACT: Argonautes, a family of highly evolutionarily conserved proteins, are the central platform for small RNA-mediated gene regulatory mechanisms which occur mainly in the cytoplasm. To understand a potential role of Argonaute 1 (Ago1) protein in the nucleus of mammalian cells in regulating gene transcription and epigenetics, we performed integrated analyses of Ago1 ChIP-sequencing (GSE40536) and gene expression profiling in cells depleted of Ago1. For gene expression profiling, we knocked down the expression of Ago1 by siRNA in PC-3 cells and compared gene expression profiles in the cells depleted of Ago1 and cells receiving control treatments. We found that Ago1 depletion resulted in more downregulated genes which were enriched in gene responsible for promoting cell cycle progression, DNA replication and repair, and response to endogenous stimuli. Integrated analyses of Ago1-chromosomal interactions and gene expression changes in response to Ago1 depletion reveal a significant correlation between Ago1-bound genes and genes altered by Ago1 depletion. These genes are significantly enriched in cancer-related pathways. Our data suggests a nuclear function of Ago1 in regulating gene transcription.

ORGANISM(S): Homo sapiens

PROVIDER: GSE42600 | GEO | 2013/09/27

SECONDARY ACCESSION(S): PRJNA182335

REPOSITORIES: GEO

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Gene expression profiling in cells with Ago1 knockdown (Affymetrix)

Project description:Argonautes, a family of highly evolutionarily conserved proteins, are the central platform for small RNA-mediated gene regulatory mechanisms which occur mainly in the cytoplasm. To understand a potential role of Argonaute 1 (Ago1) protein in the nucleus of mammalian cells in regulating gene transcription and epigenetics, we performed integrated analyses of Ago1 ChIP-sequencing (GSE40536) and gene expression profiling in cells depleted of Ago1. For gene expression profiling, we knocked down the expression of Ago1 by siRNA in PC-3 cells and compared gene expression profiles in the cells depleted of Ago1 and cells receiving control treatments. We found that Ago1 depletion resulted in more downregulated genes which were enriched in gene responsible for promoting cell cycle progression, DNA replication and repair, and response to endogenous stimuli. Integrated analyses of Ago1-chromosomal interactions and gene expression changes in response to Ago1 depletion reveal a significant correlation between Ago1-bound genes and genes altered by Ago1 depletion. These genes are significantly enriched in cancer-related pathways. Our data suggests a nuclear function of Ago1 in regulating gene transcription. PC-3 cells were mock transfected or transfected with an Ago1 specific siRNA or a control siRNA. Each treatment was done in duplicates.

2013-09-27 | E-GEOD-42600 | biostudies-arrayexpress

Modeling neurodevelopmental disorder-associated human AGO1 mutations in C. elegans Argonaute alg-1. [ribosome profiling]

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

Modeling neurodevelopmental disorder-associated human AGO1 mutations in C. elegans Argonaute alg-1. [RNA-Seq]

2023-12-30 | GSE252065 | GEO

Modeling neurodevelopmental disorder-associated human AGO1 mutations in C. elegans Argonaute alg-1. [smallRNA-Seq]

2023-12-30 | GSE252064 | GEO

RNAi knock-down of CAF1-CCR4-NOT1 deadenylase complex or AGO1 in D. melanogaster S2 cells

Project description:miRNAs silence gene expression by repressing translation and/or by promoting mRNA decay. AGO1 is a key protein required for miRNA-mediated gene silencing. In animal cells, mRNA degradation of partially complementary miRNA targets occurs via deadenylation by the CAF1-CCR4-NOT1 deadenylase complex, followed by decapping and subsequent exonucleolytic digestion. To determine how generally miRNAs trigger deadenylation, we compared mRNA expression profiles in D. melanogaster cells depleted of AGO1, CAF1 or NOT1. We show that approximately 45% of AGO1-targets are regulated by both CAF1 and NOT1, indicating deadenylation is a widespread effect of miRNA regulation.<br><br>We employed RNA interference using long double-stranded RNAs to deplete cultured S2 cells of AGO1 (CG6671, 2 independent samples), CAF1 (CG5684, 2 independent samples), or NOT1 (CG1884, 3 independent samples). Further, we used Affymetrix oligonucleotide microarrays to analyze expression profiles in these samples. We included the following controls: mock RNAi treatment and GFP dsRNA treatment (3 and 2 independent samples, respectively).<br>

2008-12-03 | E-MEXP-1713 | biostudies-arrayexpress

Arabidopsis AGO1 N-terminal extension acts as an essential hub for PRMT5 interaction and post-translational modifications

Project description:Plant ARGONAUTE (AGO) proteins play pivotal roles in gene expression regulation through small (s)RNA-guided mechanisms. Among the ten AGO proteins in Arabidopsis thaliana, AGO1 stands out as the main effector of post-transcriptional gene silencing. Intriguingly, a specific region of AGO1, its N-terminal extension (NTE), has gained prominence in recent studies linked to diverse regulatory functions, including subcellular localization, sRNA loading, and interactions with regulatory factors. In the realm of post-translational modifications (PTMs), little is known about arginine methylation in Arabidopsis AGOs. This study reveals a novel and intricate landscape of AGO1 methylation. Here, we have elucidated that NTEAGO1 undergoes symmetric arginine dimethylation on specific residues, and interacts with the methyltransferase PRMT5, which catalyzes its methylation. Notably, we observed that the lack of symmetric dimethylarginine has no discernible impact on AGO1's subcellular localization or miRNA loading capabilities. However, the absence of PRMT5 significantly alters the loading of a subgroup of sRNAs into AGO1 and reshapes the NTEAGO1 interactome. Importantly, our research extends beyond AGO1, illustrating that symmetric arginine dimethylation of NTEs is a common process across Arabidopsis AGOs, taking place in AGO1, AGO2, AGO3, and AGO5, deepening our understanding of PTMs in the intricate landscape of RNA-associated gene regulation.

2024-05-22 | PXD049971 | Pride

The Arabidopsis F-box protein FBW2 degrades AGO1 to avoid spurious loading of illegitimate small RNA

Project description:RNA silencing is a conserved mechanism in eukaryotes and is involved in development, heterochromatin maintenance and defense against viruses. In plants, ARGONAUTE1 (AGO1) protein plays a central role in both microRNA (miRNA) and small interfering RNA (siRNA)-directed silencing and its expression is regulated at multiple levels. Here, we report that the F-box protein FBW2 targets proteolysis of AGO1 by a CDC48-mediated mechanism. We found that FBW2 assembles an SCF complex that recognizes the MID-PIWI domain of AGO1 and requires its C-terminal domain containing a GW motif for AGO1 turnover. We showed that FBW2 has a preference for the unloaded and for some mutated forms of AGO1 protein. While FBW2 loss of function does not lead to strong growth or developmental defects, it significantly increases RNA silencing activity. Interestingly, under conditions in which small RNA production or accumulation is affected, the failure to degrade AGO1 in fbw2 mutants becomes more deleterious for the plant. Hence, we showed that the non-degradable AGO1 protein assembles high molecular complexes and binds illegitimate small RNA leading to the cleavage of new target genes that belong to stress responses and cellular metabolic processes. Therefore, the control of AGO1 homeostasis by ubiquitin ligases, plays an important quality control to avoid off-target cleavage.

2022-04-01 | PXD024840 | Pride

Effect of submergence on wild-type (Col-0) and ago1-27 mutant

Project description:Hypoxia exerts major effects on gene expression, which is reconfigured to meet the needs of the stressed plant. In the recent years the mechanisms of oxygen sensing and transcriptional regulation of a cluster of anaerobic genes was described. We utilized a hypomorphic, post-transcriptional gene silencing defective ARGONAUTE1 (AGO1) mutant, ago1-27, to evaluate the contribution of AGO1 to plant tolerance to submergence and its effects on gene expression.

2019-12-01 | GSE116996 | GEO

RNAi knock down of four Argonaute paralogs (AGO1, AGO2, PIWI and Aubergine) and the microRNA-processing enzyme Drosha in Drosophila

Project description:RNA silencing pathways are conserved gene regulation mechanisms that lead to degradation, translational repression or transcriptional silencing of target-transcripts selected based on complementarity with small RNA molecules. The fraction of the genome regulated by these pathways has not been established. Argonaute proteins play fundamental roles in RNA silencing. To identify their physiological targets at the genomic level, we examined expression profiles in Drosophila cells depleted of 4 Argonaute paralogs (i.e. AGO1, AGO2, PIWI or Aubergine). We also profiled cells depleted of the microRNA (miRNA)-processing enzyme Drosha.

2006-11-20 | E-MEXP-295 | biostudies-arrayexpress

Total and AGO1 immunoprecipitated small RNA from Arabidopsis thaliana wild-type and ago1-57 mutant

Project description:In Arabidopsis thaliana, ARGONAUTE1 (AGO1) plays a central role[AQ1] in microRNA (miRNA) and small interfering RNA (siRNA)- mediated silencing and is a key component in antiviral responses. The polerovirus F-box P0 protein triggers AGO1 degradation as a viral counterdefense. Here, we identified a motif in AGO1 that is required for its interaction with the S phase kinase-associated protein1-cullin 1-F-box protein (SCF) P0 (SCFP0) complex and subsequent degradation. The AGO1 P0 degron is conserved and confers P0-mediated degradation to other AGO[AQ2] proteins. Interestingly, the degron motif is localized in the DUF1785 domain of AGO1, in which a single point mutation (ago1-57, obtained by forward genetic screening) compromises recognition by SCFP0. Recapitulating formation of the RNA-induced silencing complex in a cell-free system revealed that this mutation impairs RNA unwinding, leading to stalled forms of AGO1 still bound to double-stranded RNAs. In vivo, the DUF1785 is required for unwinding perfectly matched siRNA duplexes, but is mostly dispensable for unwinding imperfectly matched miRNA duplexes. Consequently, its mutation nearly abolishes phased siRNA production and sense transgene posttranscriptional gene silencing. Overall, our work sheds new light on the mode of AGO1 recognition by P0 and the in vivo function of DUF1785 in RNA silencing.

2018-06-22 | GSE104015 | GEO

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