Project description:To identify DAF-16-dependent transcriptional alterations that occur in a long-lived C. elegans strain, we used cDNA microarrays and genomic analysis to identify putative direct and indirect DAF-16 transcriptional target genes. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Keywords: Logical Set
Project description:Insulin/IGF-1 Signaling (IIS) is known to constrain longevity by inhibiting the transcription factor FOXO. How phosphorylation mediated by IIS kinases regulates lifespan beyond FOXO remains unclear. Here, we profile IIS-dependent phosphorylation changes in a large-scale quantitative phosphoproteomic analysis of wild-type and three IIS mutant Caenorhabditis elegans strains. We quantify more than 15,000 phosphosites and find that 476 of these are differentially phosphorylated in the long-lived daf-2/insulin receptor mutant. We develop a machine learning-based method to prioritize 25 potential lifespan-related phosphosites. We perform validations to show that AKT-1 pT492 inhibits DAF-16/FOXO and compensates the loss of daf-2 function, that EIF-2α pS49 potently inhibits protein synthesis and daf-2 longevity, and that reduced phosphorylation of multiple germline proteins apparently transmits reduced DAF-2 signaling to the soma. In addition, an analysis of kinases with enriched substrates detects that casein kinase 2 (CK2) subunits negatively regulate lifespan. Our study reveals detailed functional insights into longevity.
Project description:Investigation of whole genome gene expression level changes in early generation Caenorhabditis elegans Bristol N2 prg-1 and Bristol N2 prg-1; daf-2 double mutant, compared to late-generation strains. A seven chip study using total RNA recovered from three separate alleles of Caenorhabditis elegans Bristol N2 prg-1 and four separate allelic combinations of a double mutant strain, Bristol N2 prg-1; daf-2 , in which prg-1 (pk2298) and prg-1 (tm872) are combined with one of three daf-2 alleles (e1368, 1370, m41).
Project description:DAF-12 is involved in development, dauer formation, and aging in Caenorhabditis elegans. To understand how DAF-12 is involved in these biologic processes, we performed chIP-chip using a DAF-12:TAP transgene and an anti-DAF-12 antibody. We identified 1175 genomic binding sites which were located within 5 kb of 3179 genes. These genes include known DAF-12 target genes as well as new genes involved in developmental timing, microRNA function, and stress resistance. The supplemental BED file contains all 1175 genomic binding sites described in our work.
Project description:Dietary restriction (DR) is the most effective and reproducible intervention to extend lifespan in divergent species1. In mammals, two regimens of DR, intermittent fasting (IF) and caloric restriction (CR), have proven to extend lifespan and reduce the incidence of age-related disorders2. An important characteristic of IF is that it can increase lifespan, even when there is little or no overall decrease in calorie intake2. The molecular mechanisms underlying IF-induced longevity, however, remain largely unknown. Here we establish an IF regimen that effectively extends the lifespan of Caenorhabditis elegans, and show that a nutrient-related signalling molecule, the low molecular weight GTPase Cel-Rheb, has a dual role in lifespan regulation; Cel-Rheb is required for the IF-induced longevity, whereas inhibition of Cel-Rheb mimics the CR effects. We also show that Cel-Rheb exerts its effects in part via the insulin/IGF-like signalling effector DAF-16 in IF, and that Cel-Rheb is required for fasting-induced nuclear translocation of DAF-16. We find that HSP-12.6, a DAF-16 target, functions to mediate the IF-induced longevity. Furthermore, our analyses demonstrate that most of fasting-induced upregulated genes require Cel-Rheb function for their induction, and that Cel-Rheb/Cel-TOR signalling is required for the fasting-induced downregulation of an insulin-like peptide, INS-7. These findings identify the essential role of signalling via Cel-Rheb in IF-induced longevity and gene expression changes, and suggest a molecular link between the IF-induced longevity and the insulin/IGF-like signalling pathway.
Project description:DAF-16/FoxO and EGL-27/GATA promote developmental growth in response to persistent somatic DNA damage [N2, daf-2, daf-16, daf-2 daf-16]