Opposing roles of microRNA Argonautes during Caenorhabditis elegans aging
| Autor: | Jerry S. Chen, William P. Schreiner, Laura B. Chipman, Ian Nicastro, James P. Broughton, Amy E. Pasquinelli, Antti P. Aalto |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Nematoda Molecular biology Biochemistry RNA interference Sequencing techniques Gene expression Medicine and Health Sciences Developmental Genetics (clinical) Caenorhabditis elegans Genes Helminth Regulation of gene expression Gene Expression Regulation Developmental Longevity/genetics Insulin/genetics Eukaryota Forkhead Transcription Factors/physiology RNA sequencing Animal Models Argonaute Cell biology Nucleic acids Phenotypes Insulin-Like Growth Factor I/metabolism Genetic interference Experimental Organism Systems Caenorhabditis Elegans Argonaute Proteins Argonaute Proteins/physiology Epigenetics Anatomy Receptor Research Article lcsh:QH426-470 Insulin/metabolism RNA Helminth/physiology Longevity Biology Research and Analysis Methods 03 medical and health sciences Caenorhabditis elegans Proteins/genetics Model Organisms Receptor Insulin/genetics Helminth Genetics Animals MicroRNAs/physiology Non-coding RNA Transcription factor Gene Ecology Evolution Behavior and Systematics Biology and life sciences Signal Transduction/physiology Organisms Helminth/physiology biology.organism_classification Invertebrates Gene regulation Gastrointestinal Tract Insulin receptor lcsh:Genetics MicroRNAs 030104 developmental biology Molecular biology techniques Gene Expression Regulation Genes Mutation biology.protein Caenorhabditis elegans/physiology Caenorhabditis RNA-Binding Proteins/physiology RNA Digestive System |
| Zdroj: | PLoS Genetics PLoS Genetics, Vol 14, Iss 6, p e1007379 (2018) Aalto, A P, Nicastro, I A, Broughton, J P, Chipman, L B, Schreiner, W P, Chen, J S & Pasquinelli, A E 2018, ' Opposing roles of microRNA Argonautes during Caenorhabditis elegans aging ', PLoS Genetics, vol. 14, no. 6, e1007379 . https://doi.org/10.1371/journal.pgen.1007379 |
| ISSN: | 1553-7404 1553-7390 |
| DOI: | 10.1371/journal.pgen.1007379 |
| Popis: | Argonaute (AGO) proteins partner with microRNAs (miRNAs) to target specific genes for post-transcriptional regulation. During larval development in Caenorhabditis elegans, Argonaute-Like Gene 1 (ALG-1) is the primary mediator of the miRNA pathway, while the related ALG-2 protein is largely dispensable. Here we show that in adult C. elegans these AGOs are differentially expressed and, surprisingly, work in opposition to each other; alg-1 promotes longevity, whereas alg-2 restricts lifespan. Transcriptional profiling of adult animals revealed that distinct miRNAs and largely non-overlapping sets of protein-coding genes are misregulated in alg-1 and alg-2 mutants. Interestingly, many of the differentially expressed genes are downstream targets of the Insulin/ IGF-1 Signaling (IIS) pathway, which controls lifespan by regulating the activity of the DAF-16/ FOXO transcription factor. Consistent with this observation, we show that daf-16 is required for the extended lifespan of alg-2 mutants. Furthermore, the long lifespan of daf-2 insulin receptor mutants, which depends on daf-16, is strongly reduced in animals lacking alg-1 activity. This work establishes an important role for AGO-mediated gene regulation in aging C. elegans and illustrates that the activity of homologous genes can switch from complementary to antagonistic, depending on the life stage. Author summary Tiny non-coding RNAs called microRNAs (miRNAs) are broadly conserved across animal species and have established roles in regulating development, metabolism and behavior. In humans, aberrant expression or function of specific miRNAs has been associated with a wide variety of diseases, underscoring the critical role of these molecules in organismal viability. Argonaute (AGO) proteins are essential co-factors for miRNAs to regulate the expression of target genes. In C. elegans nematodes, two highly related AGOs (ALG-1 and ALG-2; Argonaute-Like Genes) play largely overlapping roles in the miRNA pathway during development. Here we report that the activities of these two AGOs diverge in aging animals, as loss of ALG-1 shortens lifespan, while loss of ALG-2 extends it. These opposite longevity phenotypes are associated with differential regulation of specific miRNAs and protein-coding genes that act in the Insulin/ IGF-1 Signaling (IIS) pathway. Furthermore, we present genetic evidence that alg-1 and alg-2 operate within this pathway to impact aging. In sum, our findings reveal that two related AGOs function antagonistically within the conserved insulin signaling pathway that regulates longevity. |
| Databáze: | OpenAIRE |
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