AMPK and calcineurin induced longevity is mediated by CRTC-1 and CREB
Ontology highlight
ABSTRACT:
ORGANISM(S): Caenorhabditis elegans
SUBMITTER: Ana Rodrigues
PROVIDER: E-GEOD-25513 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:AMPK (AAK-2) and calcineurin (TAX-6) mediate longevity exclusively through post-translational modification of CRTC-1, the sole C. elegans CRTC (CREB regulated transcriptional coactivator). We performed microarrays to examine the transcriptional responses elicited by the pro-longevity: activation of AMPK, deactivation of calcineurin, and decrease of CREB (CRH-1) activity.
2010-11-20 | GSE25513 | GEO
Project description:Low energy states delay aging in multiple species, yet mechanisms coordinating energetics and longevity across tissues remain poorly defined. The conserved energy sensor AMP-activated protein kinase (AMPK) and its corresponding phosphatase calcineurin modulate longevity via the ‘CREB regulated transcriptional coactivator (CRTC)-1 in C. elegans. We show that CRTC-1 specifically uncouples AMPK/calcineurin mediated effects on lifespan from pleiotropic side effects by reprogramming mitochondrial and metabolic function. Strikingly, this pro-longevity metabolic state is regulated cell-nonautonomously by CRTC-1 in the nervous system. CRTC-1/CREB act antagonistically with the functional PPARα ortholog, NHR-49 to promote distinct peripheral metabolic programs. Neuronal CRTC-1 drives mitochondrial fragmentation in distal tissues and suppresses the effect of AMPK on systemic mitochondrial metabolism and longevity via a cell-nonautonomous catecholamine signal. These results demonstrate that transcriptional control of neuronal signals can override enzymatic regulation of metabolism in peripheral tissues. Central perception of energetic state therefore represents a target to promote healthy aging. Experiment was performed with three biological replicates. Gravid adults grown at 20¡C on 100 mm NG plates seeded with OP50-1 E. coli were collected and treated with hypochlorite to release eggs. Eggs were incubated overnight in M9 media to obtain L1 synchronized populations. One thousand L1 larvae were grown on a 100 mm NG plate seeded with OP50-1 E. coli. Worms were harvested for RNA extraction when L4 larval stage was reached. Animals were collected and washed extensively with M9 media to remove bacteria. Worms were then snap frozen in liquid nitrogen. RNA was extracted by five freeze/thaw cycles in Qiazol then purified by RNeasy mini kit (Qiagen). RNA quality was checked using an Agilent Technologies 2100 Bioanalyzer. All samples had an RNA integrity number of 10. cDNA libraries were prepared from 4 ugs of total RNA using the TruSeq RNA Sample Preparation v2 kit (Illumina). 50-cycle paired-end sequencing was performed on an Illumina HiSeq 2000 by the Harvard Biopolymer Core. Read quality was evaluated with FASTQC. Adapter sequences and poor quality bases (<20) were trimmed and filtered with CUTADAPT, resulting in a median of 44 million reads per replicate. These were aligned to the C. elegans genome (ce6, WS238) using TopHat version 2.0.8 (Kim et al., 2013), with a median 35 million reads mapped in proper pairs. The number of reads mapping to each gene was counted with htseq-count. Genes with less than 1 Count Per Million Reads (CPM) were discarded from further analysis. Counts were normalized for sequencing depth and RNA composition across all samples with edgeR (Robinson et al., 2010). Genes were tested for differential expression between each mutant strain and wild-type using edgeR’s glm method. For each comparison, genes with less than 5 CPM were filtered and those with at least 50% change and False Discovery Rate (FDR) of 1% or less were considered differentially expressed.
2015-02-27 | E-GEOD-58931 | biostudies-arrayexpress
Project description:Low energy states delay aging in multiple species, yet mechanisms coordinating energetics and longevity across tissues remain poorly defined. The conserved energy sensor AMP-activated protein kinase (AMPK) and its corresponding phosphatase calcineurin modulate longevity via the ‘CREB regulated transcriptional coactivator (CRTC)-1 in C. elegans. We show that CRTC-1 specifically uncouples AMPK/calcineurin mediated effects on lifespan from pleiotropic side effects by reprogramming mitochondrial and metabolic function. Strikingly, this pro-longevity metabolic state is regulated cell-nonautonomously by CRTC-1 in the nervous system. CRTC-1/CREB act antagonistically with the functional PPARα ortholog, NHR-49 to promote distinct peripheral metabolic programs. Neuronal CRTC-1 drives mitochondrial fragmentation in distal tissues and suppresses the effect of AMPK on systemic mitochondrial metabolism and longevity via a cell-nonautonomous catecholamine signal. These results demonstrate that transcriptional control of neuronal signals can override enzymatic regulation of metabolism in peripheral tissues. Central perception of energetic state therefore represents a target to promote healthy aging.
2015-02-27 | GSE58931 | GEO
Project description:AMPK and calcineurin induced longevity is mediated by CRTC-1 and CREB
| PRJNA133763 | ENA
Project description:We applied a middle-down proteomics strategy for large scale protein analysis during in vivo development of Caenorhabditis elegans. We characterized post-translational modifications (PTMs) on histone H3 N-terminal tails at eight time points during the C. elegans lifecycle, including embryo, larval stages (L1 to L4), dauer and L1/L4 post dauer. Histones were analyzed by our optimized middle-down protein sequencing platform using high mass accuracy tandem mass spectrometry. This allows quantification of intact histone tails and detailed characterization of distinct histone tails carrying co-occurring PTMs. We measured temporally distinct combinatorial PTM profiles during C. elegans development. We show that the doubly modified form H3K23me3K27me3, which is rare or non-existent in mammals, is the most abundant PTM in all stages of C. elegans lifecycle. The abundance of H3K23me3 increased during development and it was mutually exclusive of the active marks H3K18ac, R26me1 and R40me1, suggesting a role for H3K23me3 in to silent chromatin. We observed distinct PTM profiles for normal L1 larvae and for L1-post dauer larvae, or L4 and L4 post-dauer, suggesting that histone PTMs mediate an epigenetic memory that is transmitted during dauer formation. Collectively, our data describe the dynamics of histone H3 combinatorial code during C. elegans lifecycle and demonstrate the feasibility of using middle-down proteomics to study in vivo development of multicellular organisms.
2015-11-02 | PXD002525 | Pride
Project description:We used gene expression profiling to address several specific questions that arose in a study of repair of ultraviolet C radiation in C elegans, as well as to generate hypotheses regarding the possible mechanism(s) of decreased DNA repair observed in old adults in that study. This analysis was performed in order to analyze gene expression in the strain (JK1107) and experimental conditions that we used for our DNA repair studies. The supplementary file GSE4766_Resolver_all_data.txt includes Resolver generated fold-changes and p values based on ratios built in Rosetta Resolver as described in the Rosetta Biosoftware Technical Note (Lee Weng, 2004), Data processing and analysis methods in the Rosetta Resolver system (http://www.rosettabio.com/tech/default.htm). Experiment Overall Design: Gene expression data for glp-1 (strain JK1107) nematodes were obtained by comparing mRNA expression level in replicate pools of 2000-3000 mixed-stage embryos, young (1-day) adults, and old (6-day) adults raised at 25ºC. Three replicate pools of embryo and young adult samples were analyzed, but only two replicate pools of 6-day adults were analyzed due to low RNA recovery.
2008-06-13 | E-GEOD-4766 | biostudies-arrayexpress
Project description:Mitochondrial activity is critical for cellular vitality and organismal longevity, yet underlying regulatory mechanisms spanning these different levels of organization remain elusive. From RNAi screens for mitochondrial biogenesis, we discovered NFYB-1, a subunit of the NF-Y transcriptional complex, as an ancestral regulator of mitochondrial function. NFYB-1 loss leads to reduced mitochondrial gene expression and oxygen consumption, mitochondrial fragmentation, disruption of mitochondrial stress pathways, and abolition of organismal longevity triggered by mitochondrial impairment. Multi-omics analysis reveals that NFYB-1 is a potent repressor of the ER stress response, as well as lysosomal prosaposin. Surprisingly, limiting prosaposin expression alters ceramide and cardiolipin pools, restores mitochondrial fusion, gene expression and longevity. Thus, the NFYB-1/prosaposin axis coordinates lysosomal to mitochondrial communication to enhance cellular mitochondrial function and organismal health.
2020-03-11 | PXD013233 | Pride
Project description:Probiotics play important role in maintaining the health and extend longevity in their host. Previous studies reported several live probiotic bacteria in enhancing longevity and improving diverse feature of the host’s health. In this study, we reported a new potential heat- killed probiotic bacterium Levilactobacillus brevis strain MRKAK9 improved longevity and different features of healthy aging, including age-associated physical activity, improved resistance to biotic and abiotic stress in C. elegans. The mechanistic investigations showed that heat-killed strain MRKAK9 promoted longevity and healthy aging by downregulating insulin-signaling pathway resulting in improved proteostasis, autophagy and preserving lysosomal functionality in C. elegans. Heat-killed strain MRKAK9-mediated downregulation of insulin signaling pathway was regulated by the miRNA mir-243, suggesting that mir-243 partially involved in enhancing longevity of C. elegans. Additionally, the structural component exopolysaccharide of the strain heat-killed MRKAK9 also downregulated insulin- signaling mechanisms, increased the expression of genes involved in proteostatsis, autophagy as well as improved expression of mir-243. This study indicates that heat-killed strain MRKAK9 improves longevity and healthy aging, suggesting its candidature as a novel postbiotic.
2024-08-10 | PXD041237 | Pride
Project description:Loss of function during ageing is accompanied by transcriptional drift, altering gene expression and contributing to a variety of age-related diseases. CREB-regulated transcriptional coactivators (CRTCs) have emerged as key regulators of gene expression that might be targeted to promote longevity. Here, we define the role of the Caenorhabditis elegans CRTC-1 in the epigenetic regulation of longevity. Endogenous CRTC-1 binds chromatin factors, including components of the COMPASS complex, which trimethylates lysine 4 on histone H3 (H3K4me3). CRISPR editing of endogenous CRTC-1 reveals that the CREB-binding domain in neurons is specifically required for H3K4me3-dependent longevity. However, this effect is independent of CREB but instead acts via the transcription factor AP-1. Strikingly, CRTC-1 also mediates global histone acetylation levels, and this acetylation is essential for H3K4me3-dependent longevity. Indeed, overexpression of an acetyltransferase enzyme is sufficient to promote longevity in wild-type worms. CRTCs, therefore, link energetics to longevity by critically fine-tuning histone acetylation and methylation to promote healthy ageing.
2023-08-02 | GSE239572 | GEO
Project description:Loss of function during ageing is accompanied by transcriptional drift, altering gene expression and contributing to a variety of age-related diseases. CREB-regulated transcriptional coactivators (CRTCs) have emerged as key regulators of gene expression that might be targeted to promote longevity. Here, we define the role of the Caenorhabditis elegans CRTC-1 in the epigenetic regulation of longevity. Endogenous CRTC-1 binds chromatin factors, including components of the COMPASS complex, which trimethylates lysine 4 on histone H3 (H3K4me3). CRISPR editing of endogenous CRTC-1 reveals that the CREB-binding domain in neurons is specifically required for H3K4me3-dependent longevity. However, this effect is independent of CREB but instead acts via the transcription factor AP-1. Strikingly, CRTC-1 also mediates global histone acetylation levels, and this acetylation is essential for H3K4me3-dependent longevity. Indeed, overexpression of an acetyltransferase enzyme is sufficient to promote longevity in wild-type worms. CRTCs, therefore, link energetics to longevity by critically fine-tuning histone acetylation and methylation to promote healthy ageing.
2023-09-28 | PXD045747 | JPOST Repository