Endogenous siRNAs Promote Proteostasis and Longevity in Germline-less C. elegans
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PROVIDER: PRJNA505282 | ENA |
REPOSITORIES: ENA
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Project description:How lifespan and the rate of aging are set is a key problem in biology. Small RNAs are conserved molecules that impact diverse biological processes through the control of gene expression. However, in contrast to miRNAs, the role of endo-siRNAs in aging remains unexplored. Here, by combining deep sequencing and genomic and genetic approaches in C.CaenorhabditisC. elegans elegans, we reveal an unprecedented role for endo-siRNA molecules in the maintenance of proteostasis and lifespan extension in germline-less animals. Furthermore, we identify an endo-siRNA-regulated tyrosine phosphatase, which limits the longevity of germline-less animals by restricting the activity of the heat shock transcription factor HSF-1. Altogether, our findings point to endo-siRNAs as a link between germline removal and the HSF-1 proteostasis and longevity-promoting somatic pathway. This establishes a role for endo siRNAs in the aging process and identifies downstream genes and physiological processes that are regulated by the endo siRNAs to affect longevity.
2020-04-03 | GSE128935 | GEO
Project description:How lifespan and the rate of aging are set is a key problem in biology. Small RNAs are conserved molecules that impact diverse biological processes through the control of gene expression. However, in contrast to miRNAs, the role of endo-siRNAs in aging remains unexplored. Here, by combining deep sequencing and genomic and genetic approaches in C. elegans, we reveal an unprecedented role for endo-siRNA molecules in the maintenance of proteostasis and lifespan extension in germline-less animals. Furthermore, we identify an endo-siRNA-regulated tyrosine phosphatase, which limits the longevity of germline-less animals by restricting the activity of the heat shock transcription factor HSF-1. Altogether, our findings point to endo-siRNAs as a link between germline removal and the HSF-1 proteostasis and longevity-promoting somatic pathway. This establishes a role for endo siRNAs in the aging process and identifies downstream genes and physiological processes that are regulated by the endo siRNAs to affect longevity.
2020-04-03 | GSE122457 | GEO
Project description:Endogenous siRNAs promote proteostasis and longevity in germline-less Caenorhabditis elegans
| PRJNA529404 | ENA
Project description:How lifespan and the rate of aging are set is a key problem in biology. Small RNAs are conserved molecules that impact diverse biological processes through the control of gene expression. However, in contrast to miRNAs, the role of endo-siRNAs in aging remains unexplored. Here, by combining deep sequencing and genomic and genetic approaches in Caenorhabditis elegans, we reveal an unprecedented role for endo-siRNA molecules in the maintenance of proteostasis and lifespan extension in germline-less animals. Furthermore, we identify an endo-siRNA-regulated tyrosine phosphatase, which limits the longevity of germline-less animals by restricting the activity of the heat shock transcription factor HSF-1. Altogether, our findings point to endo-siRNAs as a link between germline removal and the HSF-1 proteostasis and longevity-promoting somatic pathway. This establishes a role for endo siRNAs in the aging process and identifies downstream genes and physiological processes that are regulated by the endo siRNAs to affect longevity.
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Project description:Transcriptome analysis in HEK293T transfected with plasmid carrying different isoforms of BPIFB4 gene. This gene was previously associated with exceptional longevity in a GWAS study performed on three different populations. Results indicate an up-regulation of stress response genes and proteostasis genes in HEK293T transfected with plasmid carrying the longevity-associated variant (LAV) of BPIFB4. Total RNA obtained from HEK293T over-expressing wild-type or mutated form of BPIFB4.
2015-06-12 | E-GEOD-63912 | biostudies-arrayexpress
Project description:Despite their prominent role in transposon silencing, expression of endo-siRNAs is not limited to the “non-self” DNA elements. Transcripts of protein-coding genes (“self” DNA) in some cases also produce endo-siRNAs in yeast, plants, and animals [1]. How cells distinguish these two populations of siRNAs to prevent unwanted silencing of self-genes in animals is not well understood. To address this question, we examined the expression of ectopic siRNAs from an LTR retrotransposon in C. elegans germline. We found that the abundance of ectopic siRNAs was dependent on their homologous target genes: ectopic siRNAs against genes expressed only in somatic cells can be abundantly expressed. In contrast, ectopic siRNAs against germline-expressed genes are often suppressed. This phenomenon, which we termed “target-directed siRNA suppression”, is dependent on the target mRNA and requires germline P-granule components. We found that siRNA suppression can also occur to naturally produced endo-siRNAs. We suggest that siRNA suppression plays an important role in regulating siRNA expression and preventing self-genes from aberrant epigenetic silencing.
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Project description:The balance between protein synthesis and protein breakdown is known as protein homeostasis (proteostasis) and loss of proteostasis is one of the Hallmarks of Aging. The latter is maybe best illustrated by the fact that many age-related diseases like Parkinson’s and Alzheimer’s are characterized by the appearance of protein aggregates. However, very few studies actually measure protein half-life, and hence the observed lowered protein translation rates in many longevity models do not necessarily mean that the combined rate of synthesis and degradation (i.e. proteostasis) is lost or changed. To get a better insight in the actual changes in proteostasis of each protein in the proteome we have developed a quantitative mass-spectrometry based method that allows for the estimation of the half-life of each individual protein in the proteome and that is suitable for use in C. elegans. We have used this method to determine protein half-lives in developing C. elegans models of longevity and age-related disease and found that proteostasis, as measured by proteome-wide protein half-life is indeed dramatically changed in these models. However, the observed changes are in some cases unexpected and suggest that the combined rate of protein synthesis and breakdown does not necessarily correlate with eventual lifespan or healthspan. Furthermore, we show that the proteostasis network has a remarkable plasticity; in the tested models large changes in protein half-life are observed in the entire proteome rather than in a subset of proteins, thereby largely balancing the relative rate at which various biological processes proceed. Lastly, our data indicate that proteostasis is regulated at the level of the whole organism rather than at the single cell level. The here described method and observations are a start to further unravel how proteostasis and healthy aging are intertwined.
2016-07-29 | PXD004561 | Pride
Project description:Gametogenesis involves active protein synthesis and heavily relies on proteostasis. How animals regulate germline proteostasis at the organismal level is poorly understood. Our recent work in C. elegans indicates that germline development requires coordinated activities between insulin/IGF-1 signaling and HSF-1, the transcriptional activator of many molecular chaperones in stress and physiological conditions. In this study, we show that HSF-1 is important for germline proteostasis at ambient temperature. Depletion of HSF-1 from germ cells impairs chaperone gene expression, causing protein degradation and aggregation and, consequently, declines in fecundity and gamete quality. Reduced insulin/IGF-1 signaling confers germ cells' tolerance to limited protein folding capacity and proteotoxic stress by lowering ribosome biogenesis and translation. Interestingly, regulation of germline proteostasis by insulin/IGF-1 signaling occurs non-cell-autonomously. Our data suggest that insulin/IGF-1 signaling controls the expression of the evolutionarily conserved intestinal peptide transporter PEPT-1 via its downstream transcription factor FOXO/DAF-16, therefore allowing dietary proteins to be incorporated into an amino acid pool that fuels ribosomal biogenesis and translation in the germline. We propose that this pathway plays a critical role in regulating germline protein synthesis, which must be at balance with HSF-1-dependent protein folding to achieve proteostasis in gametogenesis.
2024-05-20 | GSE256186 | GEO
Project description:Transcriptome analysis in HEK293T transfected with plasmid carrying different isoforms of BPIFB4 gene. This gene was previously associated with exceptional longevity in a GWAS study performed on three different populations. Results indicate an up-regulation of stress response genes and proteostasis genes in HEK293T transfected with plasmid carrying the longevity-associated variant (LAV) of BPIFB4.
2015-06-12 | GSE63912 | GEO