The endogenous siRNA pathway in<i>Drosophila</i>impacts stress resistance and lifespan by regulating metabolic homeostasis

Lim, Do Hwan; Oh, Chun Taek; Lee, Langho; Hong, Jin Hwa; Noh, Su Hyun; Hwang, Seungwoo; Kim, Sung‐Chan; Han, Sung‐Jun; Lee, Young Sik

doi:10.1016/j.febslet.2011.08.034

Cited by 49 publications

(51 citation statements)

References 43 publications

(64 reference statements)

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“…These cellular defenses against TE activation include siRNA-directed induction and maintenance of repressive heterochromatin to prevent TE expression, and degradation of target transcripts. siRNA pathway mutants exhibit both an activation of TEs and a shortening of life span (15,24). Here we provide evidence that many heterochromatin genes and TEs do in fact increase expression with age in two different tissues.…”

Section: Discussionmentioning

confidence: 67%

“…In addition to their effects of delaying age-related heterochromatin gene and TE silencing loss, both increased Sir2 expression and decreased Adar expression have been shown to extend life span in flies (21,25), whereas Dicer-2 and Ago2 mutants are short-lived (15,24). Given our findings presented earlier, we examined whether increased expression of Su(var)3-9 or Dicer-2 also have a positive effect on life span.…”

Section: Genetic Interventions That Affect Heterochromatin Structure mentioning

confidence: 99%

“…In addition to their roles in heterochromatin formation and maintenance, these pathways have also been linked to aging. Decreasing activity of the siRNA pathway through Ago2 and Dicer-2 mutants leads to derepression of TE activity and shortened life span (15,24). Sir2 has a central role in aging, with increased gene dosage shown to extend life span in yeast (2) and in nine of 10 studies in nematodes and flies (25)(26)(27)(28).…”

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confidence: 99%

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Chromatin-modifying genetic interventions suppress age-associated transposable element activation and extend life span in Drosophila

Wood

Jones

Jiang

et al. 2016

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

176

201

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Transposable elements (TEs) are mobile genetic elements, highly enriched in heterochromatin, that constitute a large percentage of the DNA content of eukaryotic genomes. Aging in Drosophila melanogaster is characterized by loss of repressive heterochromatin structure and loss of silencing of reporter genes in constitutive heterochromatin regions. Using next-generation sequencing, we found that transcripts of many genes native to heterochromatic regions and TEs increased with age in fly heads and fat bodies. A dietary restriction regimen, known to extend life span, repressed the age-related increased expression of genes located in heterochromatin, as well as TEs. We also observed a corresponding age-associated increase in TE transposition in fly fat body cells that was delayed by dietary restriction. Furthermore, we found that manipulating genes known to affect heterochromatin structure, including overexpression of Sir2, Su(var)3-9, and Dicer-2, as well as decreased expression of Adar, mitigated age-related increases in expression of TEs. Increasing expression of either Su(var)3-9 or Dicer-2 also led to an increase in life span. Mutation of Dicer-2 led to an increase in DNA double-strand breaks. Treatment with the reverse transcriptase inhibitor 3TC resulted in decreased TE transposition as well as increased life span in TE-sensitized Dicer-2 mutants. Together, these data support the retrotransposon theory of aging, which hypothesizes that epigenetically silenced TEs become deleteriously activated as cellular defense and surveillance mechanisms break down with age. Furthermore, interventions that maintain repressive heterochromatin and preserve TE silencing may prove key to preventing damage caused by TE activation and extending healthy life span.aging | heterochromatin | transposable elements | dietary restriction | silencing

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Section: Discussionmentioning

confidence: 67%

Section: Genetic Interventions That Affect Heterochromatin Structure mentioning

confidence: 99%

mentioning

confidence: 99%

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Chromatin-modifying genetic interventions suppress age-associated transposable element activation and extend life span in Drosophila

Wood

Jones

Jiang

et al. 2016

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

176

201

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“…Chromatin immunoprecipitation and DNA fluorescence in situ hybridization experiments further demonstrate that both Ago-2 and Dcr-2 are integrated in the regulatory complex that causes RNA polymerase II pausing and play a role in the correct execution of the global transcriptional repression after heat-shock. Consistent with a role for the siRNA pathway in stress regulation, it was reported that dcr-2 mutants were more sensitive to different types of stresses such as toxic chemicals, starvation and cold shock, and had a reduced lifespan [196]. Furthermore, abnormal lipid and carbohydrate metabolism was associated with loss of Dcr-2 and comparative proteomics revealed changes in expression of proteins associated with cellular metabolism, stress resistance, cell cycle [196].…”

Section: Heat-shock Proteins and Stressmentioning

confidence: 68%

“…Consistent with a role for the siRNA pathway in stress regulation, it was reported that dcr-2 mutants were more sensitive to different types of stresses such as toxic chemicals, starvation and cold shock, and had a reduced lifespan [196]. Furthermore, abnormal lipid and carbohydrate metabolism was associated with loss of Dcr-2 and comparative proteomics revealed changes in expression of proteins associated with cellular metabolism, stress resistance, cell cycle [196]. During heat shock, Dcr-2 protein levels are reduced and dicing activity of long dsRNA substrates is diminished [197].…”

Section: Heat-shock Proteins and Stressmentioning

confidence: 82%

Defense Mechanisms against Viral Infection in <em>Drosophila</em>: RNAi versus Non-RNAi

Swevers¹,

Liu²,

Smagghe³

2018

Preprint

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RNAi is considered a major antiviral defense mechanism in insects but its relative importance compared to other antiviral pathways has not been evaluated comprehensively. Here, it is attempted to give an overview of the antiviral defense mechanisms in Drosophila that involve both RNAi and non-RNAi to acquire a sense of their relative importance. While RNAi is considered important in most viral infections, many other pathways can exist that confer antiviral resistance. It is noted that very few direct recognition mechanisms of virus infections have been identified in Drosophila and that the activation of immune pathways may be accomplished indirectly through cell damage incurred by viral replication. In several cases, protection against viral infection can be obtained in RNAi mutants by non-RNAi mechanisms, confirming the variability of the RNAi defense mechanism according to the type of infection and the physiological status of the host. This analysis invites to investigate more systematically the relative contribution of RNAi in the antiviral response and more specifically to ask whether RNAi efficiency is affected when other defense mechanisms predominate. While Drosophila can function as a useful model, this issue may be more critical for economically important insects that are either controlled (agricultural pests and vectors of diseases) or protected from parasite infection (beneficial insects as bees) by RNAi products.

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Microarray analysis of Drosophila dicer‐2 mutants reveals potential regulation of mitochondrial metabolism by endogenous siRNAs

Lim¹,

Lee²,

Oh³

et al. 2012

J of Cellular Biochemistry

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RNA interference is a eukaryotic regulatory mechanism by which small non-coding RNAs typically mediate specific silencing of their cognate genes. In Drosophila, the RNase III enzyme Dicer-2 (Dcr-2) is essential for biogenesis of endogenous small interfering RNAs (endo-siRNAs), which have been implicated in regulation of endogenous protein-coding genes. Although much is known about microRNA-based regulatory networks, the biological functions of endo-siRNAs in animals remain poorly understood. We performed gene expression profiling on Drosophila dcr-2 null mutant pupae to investigate transcriptional effects caused by a severe defect in endo-siRNA production, and found 306 up-regulated and 357 down-regulated genes with at least a twofold change in expression compared with the wild type. Most of these up-regulated and down-regulated genes were associated with energy metabolism and development, respectively. Importantly, mRNA sequences of 39% of the up-regulated genes were perfectly complementary to the sequences of previously reported endo-siRNAs, suggesting they may be direct targets of endo-siRNAs. We confirmed up-regulation of five selected genes matching endo-siRNAs and concomitant down-regulation of the corresponding endo-siRNAs in dcr-2 mutant pupae. Most of the potential endo-siRNA target genes were associated with energy metabolism, including the citric acid cycle and oxidative phosphorylation in mitochondria, implying that these are major metabolic processes directly affected by endo-siRNAs in Drosophila. Consistent with this finding, dcr-2 null mutant pupae had lower ATP content compared with controls, indicating that mitochondrial energy production is impaired in these mutants. Our data support a potential role for the endo-siRNA pathway in energy homeostasis through regulation of mitochondrial metabolism.

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The endogenous siRNA pathway inDrosophilaimpacts stress resistance and lifespan by regulating metabolic homeostasis

Cited by 49 publications

References 43 publications

Chromatin-modifying genetic interventions suppress age-associated transposable element activation and extend life span in Drosophila

Chromatin-modifying genetic interventions suppress age-associated transposable element activation and extend life span in Drosophila

Defense Mechanisms against Viral Infection in <em>Drosophila</em>: RNAi versus Non-RNAi

Microarray analysis of Drosophila dicer‐2 mutants reveals potential regulation of mitochondrial metabolism by endogenous siRNAs

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