FOXO regulates RNA interference in Drosophila and protects from RNA virus infection
Ontology highlight
ABSTRACT:
ORGANISM(S): Drosophila melanogaster
PROVIDER: GSE73827 | GEO | 2015/10/08
SECONDARY ACCESSION(S): PRJNA298077
REPOSITORIES: GEO
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Project description:Small RNA pathways are important players in posttranscriptional regulation of gene expression. These pathways play important roles in all aspects of cellular physiology from development to fertility to innate immunity. However, almost nothing is known about the regulation of the central genes in these pathways. The forkhead box O (FOXO) family of transcription factors is a conserved family of DNA-binding proteins that responds to a diverse set of cellular signals. FOXOs are crucial regulators of cellular homeostasis that have a conserved role in modulating organismal aging and fitness. Here, we show that Drosophila FOXO (dFOXO) regulates the expression of core small RNA pathway genes. In addition, we find increased dFOXO activity results in an increase in RNA interference (RNAi) efficacy, establishing a direct link between cellular physiology and RNAi. Consistent with these findings, dFOXO activity is stimulated by viral infection and is required for effective innate immune response to RNA virus infection. Our study reveals an unanticipated connection among dFOXO, stress responses, and the efficacy of small RNA-mediated gene silencing and suggests that organisms can tune their gene silencing in response to environmental and metabolic conditions.
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Project description:Heart performance declines with age. Reduced protein quality control (PQC) due to decreased function of the ubiquitin/proteasome system (UPS), autophagy, and/or chaperone-mediated protein refolding is a likely contributor to age-associated cardiac performance decline. The transcription factor FOXO participates in the regulation of genes involved PQC and a host of other processes. Here, the effect of cardiac-restricted dFOXO overexpression was investigated in Drosophila, a genetically pliable and rapidly aging model. Modest dFOXO overexpression in the heart was protective, ameliorating functional decline with age. Increased expression of genes associated predominantly with UPS relative to other PQC components accompanied dFOXO-mediated cardioprotection, which was corroborated by a significant decrease in ubiquitinated myocardial proteins. In agreement, knockdown of upregulated UPS components seemingly induced premature aging. Despite these findings, excessive dFOXO overexpression or knockdown proved detrimental to heart function and overall organismal development. This study highlights Drosophila as a model of cardiac aging and FOXO as a tightly-regulated mediator of proteostasis and heart performance over time.
2016-07-01 | GSE73205 | GEO
Project description:FOXO transcription factors control numerous pathways involving metabolism, stress response, and longevity. Although direct targets of FOXO have been reported in various long-lived mutants and under stress conditions, no studies have investigated how normal aging impacts the cellular activity of FOXO. In this study, we compared genome wide dFOXO-bound sites in young and aged wild-type flies kept under normal feeding conditions to evaluate the dynamics of FOXO gene targeting during aging. Our results provide a new insight into FOXO chromatin targeting under a normal aging model and highlight the diverse regulatory mechanisms for FOXO transcriptional activity that are currently less understood.
2019-04-25 | GSE121102 | GEO
Project description:Mosquito-borne dengue virus (DENV, genus Flavivirus) has emerged as a major threat to global human health in recent decades, and novel strategies to contain the escalating dengue fever pandemic are urgently needed. RNA interference (RNAi) induced by exogenous small interfering RNAs (siRNAs) has shown promise for treatment of flavivirus infections in hosts and prevention of transmission by vectors. However, the impact of RNAi triggered by authentic virus infection on replication of DENV, or any flavivirus, has received little study. The objectives of the current study were threefold: first, to assess the utility of Drosophila melanogaster S2 cells for the study of DENV, second to investigate the impact of multiple enzymes in the RNAi pathway on DENV replication; and third to test for variation in the response of the four serotypes of DENV to modulation of RNAi.Three strains from each of the four DENV serotypes showed replication in S2 cells following infection at multiplicity of infection (MOI) 0.1 and MOI 10; each strain achieved titers > 4.0 log10pfu/ml five days after infection at MOI 10. The four serotypes did not differ in mean titer. S2 cells infected with DENV-1, 2, 3 or 4 produced siRNAs, indicating that infection triggered an RNAi response. Knockdown of one of the major enzymes in the RNAi pathway, Dicer-2 (Dcr-2), resulted in a 10 to 100-fold enhancement of replication of all twelve strains of DENV in S2 cells. While serotypes did not differ in their average response to Dcr-2 knockdown, strains within serotypes showed significant differences in their sensitivity to Dcr-2 knockdown. Moreover, knockdown of three additional components of the RNAi pathway, Argonaute 2 (Ago-2), Dcr-1 and Ago-1, also resulted in a significant increase in replication of the two DENV strains tested, and the magnitude of this increase was similar to that resulting from Dcr-2 knockdown.These findings indicate that DENV can replicate in Drosophila S2 cells and that the RNAi pathway plays a role in modulating DENV replication in these cells. S2 cells offer a useful cell culture model for evaluation of the interaction between DENV and the RNAi response.
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Project description:Heart performance declines with age. Reduced protein quality control (PQC) due to decreased function of the ubiquitin/proteasome system (UPS), autophagy, and/or chaperone-mediated protein refolding is a likely contributor to age-associated cardiac performance decline. The transcription factor FOXO participates in the regulation of genes involved PQC and a host of other processes. Here, the effect of cardiac-restricted dFOXO overexpression was investigated in Drosophila, a genetically pliable and rapidly aging model. Modest dFOXO overexpression in the heart was protective, ameliorating functional decline with age. Increased expression of genes associated predominantly with UPS relative to other PQC components accompanied dFOXO-mediated cardioprotection, which was corroborated by a significant decrease in ubiquitinated myocardial proteins. In agreement, knockdown of upregulated UPS components seemingly induced premature aging. Despite these findings, excessive dFOXO overexpression or knockdown proved detrimental to heart function and overall organismal development. This study highlights Drosophila as a model of cardiac aging and FOXO as a tightly-regulated mediator of proteostasis and heart performance over time. Two replicates of 4 different samples were analyzed. Two of these samples were controls (GMH5 x yw 1 week and GMH5 x yw 5 week).
2016-07-01 | E-GEOD-73205 | biostudies-arrayexpress
Project description:The fruit fly Drosophila melanogaster is a good model to unravel the molecular mechanisms of innate immunity and has led to some important discoveries about the sensing and signaling of microbial infections. The response of Drosophila to virus infections remains poorly characterized and appears to involve two facets. On the one hand, RNA interference involves the recognition and processing of dsRNA into small interfering RNAs by the host RNase Dicer-2 (Dcr-2), whereas, on the other hand, an inducible response controlled by the evolutionarily conserved JAK-STAT pathway contributes to the antiviral host defense. To clarify the contribution of the small interfering RNA and JAK-STAT pathways to the control of viral infections, we have compared the resistance of flies wild-type and mutant for Dcr-2 or the JAK kinase Hopscotch to infections by seven RNA or DNA viruses belonging to different families. Our results reveal a unique susceptibility of hop mutant flies to infection by Drosophila C virus and cricket paralysis virus, two members of the Dicistroviridae family, which contrasts with the susceptibility of Dcr-2 mutant flies to many viruses, including the DNA virus invertebrate iridescent virus 6. Genome-wide microarray analysis confirmed that different sets of genes were induced following infection by Drosophila C virus or by two unrelated RNA viruses, Flock House virus and Sindbis virus. Overall, our data reveal that RNA interference is an efficient antiviral mechanism, operating against a large range of viruses, including a DNA virus. By contrast, the antiviral contribution of the JAK-STAT pathway appears to be virus specific.
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Project description:To understand how reduced insulin/IGF-1 signaling extends Drosophila lifespan through its downstream transcription factor dFOXO. We conducted ChIP analysis with a dFOXO antibody followed by Illumina high-throughput sequencing from chico heterozygous mutants, which are long-lived and normal sized, and from adult flies with ablated insulin producing cells (IPCs), which are also long-lived. dFOXO bound at promoters of 273 genes common among these genotypes, thus potentially enriching for shared factors in control of aging.
2013-09-20 | GSE44686 | GEO
Project description:During prolonged nutrient restriction, developing animals redistribute vital nutrients to favor brain growth at the expense of other organs. In Drosophila, such brain sparing relies on a glia-derived growth factor to sustain proliferation of neural stem cells. However, whether other aspects of neural development are also spared under nutrient restriction is unknown. Here we show that dynamically growing somatosensory neurons in the Drosophila peripheral nervous system exhibit organ sparing at the level of arbor growth: Under nutrient stress, sensory dendrites preferentially grow as compared to neighboring non-neural tissues, resulting in dendrite overgrowth. These neurons express lower levels of the stress sensor FoxO than neighboring epidermal cells, and hence exhibit no marked induction of autophagy and a milder suppression of Tor signaling under nutrient stress. Preferential dendrite growth allows for heightened animal responses to sensory stimuli, indicative of a potential survival advantage under environmental challenges.
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Project description:Transcriptional analysis of dInR and dfoxo epistasis in Drosophila melanogaster. The experiment was performed to examine which parts of the transcriptional response to a reduction in insulin signalling in an adult female fly depend on the presence of the dfoxo transcription factor. Whole fly transcriptome was determined with flies over-expressing a dominant negative form of the insulin receptor, or the wild-type fly, in presence or absence of dfoxo.
2011-06-18 | E-TABM-757 | biostudies-arrayexpress
Project description:To understand how reduced insulin/IGF-1 signaling extends Drosophila lifespan through its downstream transcription factor dFOXO. We conducted ChIP analysis with a dFOXO antibody followed by Illumina high-throughput sequencing from chico heterozygous mutants, which are long-lived and normal sized, and from adult flies with ablated insulin producing cells (IPCs), which are also long-lived. dFOXO bound at promoters of 273 genes common among these genotypes, thus potentially enriching for shared factors in control of aging. Two replicates were sequenced from chico heterozygous mutants and IPC ablated flies.
2013-09-20 | E-GEOD-44686 | biostudies-arrayexpress