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Journal ArticleDOI

PQM-1 Complements DAF-16 as a Key Transcriptional Regulator of DAF-2-Mediated Development and Longevity

TL;DR: It is discovered that PQM-1 is the elusive transcriptional activator that directly controls development genes by binding to the DAF-16-associated element (DAE), suggesting an elegant mechanism for balancing stress response and development.
About: This article is published in Cell.The article was published on 2013-08-01 and is currently open access. It has received 278 citations till now. The article focuses on the topics: Daf-16 & Transcription factor.
Citations
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Journal ArticleDOI
26 Dec 2013-Wormbook
TL;DR: Originally identified based on its role in the regulation of larval development and aging, IIS also controls a host of other biological processes and is likely to shed light on its functions and regulation in higher organisms, including humans.
Abstract: The C. elegans insulin/IGF-1 signaling (IIS) pathway connects nutrient levels to metabolism, growth, development, longevity, and behavior. This fundamental pathway is regulated by insulin-like peptide ligands that bind to the insulin/IGF-1 transmembrane receptor (IGFR) ortholog DAF-2. DAF-2/IGFR controls the activity of a conserved phosphoinositide 3-kinase (PI3K)/Akt kinase cascade, culminating in the regulation of a FoxO transcription factor, DAF-16, that governs most of the functions of this pathway. In light of the evolutionary conservation of the IIS pathway, its study in C. elegans is likely to shed light on its functions and regulation in higher organisms, including humans. Originally identified based on its role in the regulation of larval development and aging, IIS also controls a host of other biological processes. Here we review what is currently known about the biological functions and the molecular components of C. elegans IIS.

407 citations


Cites background from "PQM-1 Complements DAF-16 as a Key T..."

  • ...Most of the Class 2 genes, and some of the Class 1 genes, are regulated by the zinc finger transcription factor PQM-1, which acts in opposition to DAF-16/FoxO (Tepper et al., 2013) (Section 6....

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  • ..., 2010), and ChIP-Seq (Niu et al., 2011; Tepper et al., 2013), have revealed a large complement of DAF-16/FoxO targets (discussed in greater detail in Murphy, 2006)....

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  • ...The functions of most of these genes and their roles in normal development and life span control are not yet understood, but recent GO analysis suggests that many of these genes regulate growth and development (Tepper et al., 2013), and reducing expression of some of these genes by RNAi extends life span (Murphy et al....

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  • ...While PQM-1 is regulated by IIS, DAF-16 and PQM-1 also have an influence on the nuclear localization of one another, as the loss of each increases the nuclear occupancy of the other (Tepper et al., 2013)....

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  • ...In fact, ChIP-Seq data implicates the zinc finger transcription factor PQM-1 as the DAE-binding factor, acting antagonistically with DAF-16/FoxO (Tepper et al., 2013) (Section 6....

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Journal ArticleDOI
TL;DR: These results illustrate the highly dynamic pattern of CGV across three different environmental conditions that can be evoked by a stress response over a relatively short time-span (2 h) and that CGV is mainly determined by response related trans regulatory eQTL.
Abstract: Cryptic genetic variation (CGV) is the hidden genetic variation that can be unlocked by perturbing normal conditions. CGV can drive the emergence of novel complex phenotypes through changes in gene expression. Although our theoretical understanding of CGV has thoroughly increased over the past decade, insight into polymorphic gene expression regulation underlying CGV is scarce. Here we investigated the transcriptional architecture of CGV in response to rapid temperature changes in the nematode Caenorhabditis elegans. We analyzed regulatory variation in gene expression (and mapped eQTL) across the course of a heat stress and recovery response in a recombinant inbred population. We measured gene expression over three temperature treatments: i) control, ii) heat stress, and iii) recovery from heat stress. Compared to control, exposure to heat stress affected the transcription of 3305 genes, whereas 942 were affected in recovering animals. These affected genes were mainly involved in metabolism and reproduction. The gene expression pattern in recovering animals resembled both the control and the heat-stress treatment. We mapped eQTL using the genetic variation of the recombinant inbred population and detected 2626 genes with an eQTL in the heat-stress treatment, 1797 in the control, and 1880 in the recovery. The cis-eQTL were highly shared across treatments. A considerable fraction of the trans-eQTL (40–57%) mapped to 19 treatment specific trans-bands. In contrast to cis-eQTL, trans-eQTL were highly environment specific and thus cryptic. Approximately 67% of the trans-eQTL were only induced in a single treatment, with heat-stress showing the most unique trans-eQTL. These results illustrate the highly dynamic pattern of CGV across three different environmental conditions that can be evoked by a stress response over a relatively short time-span (2 h) and that CGV is mainly determined by response related trans regulatory eQTL.

290 citations


Additional excerpts

  • ...org) [30, 31], which were mapped to transcription start sites (according to [32]); and the KEGG pathway release 65....

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Journal ArticleDOI
07 Jan 2016-Nature
TL;DR: Together, neuron-specific and canonical IIS/FOXO-regulated targets enable the coordinated extension of neuronal activities, metabolism, and longevity under low-insulin signalling conditions.
Abstract: Insulin/insulin-like growth factor signalling (IIS) is a critical regulator of an organism's most important biological decisions from growth, development, and metabolism to reproduction and longevity. It primarily does so through the activity of the DAF-16 transcription factor (forkhead box O (FOXO) homologue), whose global targets were identified in Caenorhabditis elegans using whole-worm transcriptional analyses more than a decade ago. IIS and FOXO also regulate important neuronal and adult behavioural phenotypes, such as the maintenance of memory and axon regeneration with age, in both mammals and C. elegans, but the neuron-specific IIS/FOXO targets that regulate these functions are still unknown. By isolating adult C. elegans neurons for transcriptional profiling, we identified both the wild-type and IIS/FOXO mutant adult neuronal transcriptomes for the first time. IIS/FOXO neuron-specific targets are distinct from canonical IIS/FOXO-regulated longevity and metabolism targets, and are required for extended memory in IIS daf-2 mutants. The activity of the forkhead transcription factor FKH-9 in neurons is required for the ability of daf-2 mutants to regenerate axons with age, and its activity in non-neuronal tissues is required for the long lifespan of daf-2 mutants. Together, neuron-specific and canonical IIS/FOXO-regulated targets enable the coordinated extension of neuronal activities, metabolism, and longevity under low-insulin signalling conditions.

191 citations

Journal ArticleDOI
26 Feb 2015-Cell
TL;DR: It is demonstrated that while both local and distal mechanisms combine to modulate aging, distal regulation overrides local contribution and Targeting central perception of energetic state is therefore a potential strategy to promote healthy aging.

165 citations


Cites background from "PQM-1 Complements DAF-16 as a Key T..."

  • ...Understanding how neuronal CRTC-1 interacts with DAF-16 and/or PQM-1 and if they function intra- or intercellularly to modulate AMPK/ calcineurin-mediated longevity will be informative....

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  • ...The motif strongly resembles the GATA-like DAE (DAF-16 Associated Element), recently identified as the binding site for PQM-1 (Tepper et al., 2013). modENCODE ChIP-seq data also suggests that both DAF-16 and PQM-1 bind the acs2 promoter directly....

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  • ...We saw enrichment of the DAE element in genes downregulated when both AMPK and CRTC-1 were active, suggesting CRTC-1 might Cell 160, 842–855, February 26, 2015 ª2015 Elsevier Inc. 853 remotely regulate DAF-16/FOXO activity and/or activate its transacting antagonist PQM-1 (Tepper et al., 2013)....

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  • ...These data therefore suggest that DAF16 and/or PQM-1 might be acting downstream of the neuronal CRTC-1 signal to modulate metabolic gene expression....

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Journal ArticleDOI
TL;DR: A meta‐analysis of direct FOXO targets across tissues and organisms provides insight into the evolution of the FOXO network and highlights downstream genes and cofactors that may be particularly important for FOXO's conserved function in adult homeostasis and longevity.
Abstract: FOXO transcription factors (FOXOs) are central regulators of lifespan across species, yet they also have cell-specific functions, including adult stem cell homeostasis and immune function. Direct targets of FOXOs have been identified genome-wide in several species and cell types. However, whether FOXO targets are specific to cell types and species or conserved across cell types and throughout evolution remains uncharacterized. Here, we perform a meta-analysis of direct FOXO targets across tissues and organisms, using data from mammals as well as Caenorhabditis elegans and Drosophila. We show that FOXOs bind cell type-specific targets, which have functions related to that particular cell. Interestingly, FOXOs also share targets across different tissues in mammals, and the function and even the identity of these shared mammalian targets are conserved in invertebrates. Evolutionarily conserved targets show enrichment for growth factor signaling, metabolism, stress resistance, and proteostasis, suggesting an ancestral, conserved role in the regulation of these processes. We also identify candidate cofactors at conserved FOXO targets that change in expression with age, including CREB and ETS family factors. This meta-analysis provides insight into the evolution of the FOXO network and highlights downstream genes and cofactors that may be particularly important for FOXO's conserved function in adult homeostasis and longevity.

159 citations


Cites background or methods or result from "PQM-1 Complements DAF-16 as a Key T..."

  • ...For overlaps between FOXO binding and differential expression, genes were ranked by fold change (Foxo1+/+ vs Foxo1 / for mouse data) or FOXO/DAF-16 responsiveness in C. elegans (Tepper et al., 2013)....

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  • ...Only a subset of the FOXO/DAF-16 targets change in expression with age, consistent with previous studies (Tepper et al., 2013)....

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  • ...We used a meta-analysis of FOXO/DAF-16 gene expression datasets (Tepper et al., 2013) as well as microarray expression datasets from mouse cell types where ChIP-seq has been performed....

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  • ...The enrichment for GATA family factors is notable as this family includes ELT factors and PQM-1, and these factors have been previously implicated in aging in C. elegans (Budovskaya et al., 2008; Tepper et al., 2013; Zhang et al., 2013)....

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  • ...By interrogating the existing meta-analysis of DAF-16-transcribed genes in C. elegans (Tepper et al., 2013) (comparing daf-2 mutants vs. daf-2; daf16 mutants), we observed that DAF-16 binding is enriched at the genes most upregulated in conditions that activate DAF-16 (Fig....

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References
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Journal ArticleDOI
01 May 1974-Genetics
TL;DR: In this paper, the authors describe methods for the isolation, complementation and mapping of mutants of Caenorhabditis elegans, a small free-living nematode worm.
Abstract: Methods are described for the isolation, complementation and mapping of mutants of Caenorhabditis elegans, a small free-living nematode worm. About 300 EMS-induced mutants affecting behavior and morphology have been characterized and about one hundred genes have been defined. Mutations in 77 of these alter the movement of the animal. Estimates of the induced mutation frequency of both the visible mutants and X chromosome lethals suggests that, just as in Drosophila, the genetic units in C. elegans are large.

13,247 citations

Journal Article

8,375 citations


"PQM-1 Complements DAF-16 as a Key T..." refers methods in this paper

  • ...elegans Genetics All strains were cultured using standard methods (Brenner, 1974)....

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  • ...C. elegans Genetics All strains were cultured using standard methods (Brenner, 1974)....

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Journal ArticleDOI
18 Jul 2011-PLOS ONE
TL;DR: REVIGO is a Web server that summarizes long, unintelligible lists of GO terms by finding a representative subset of the terms using a simple clustering algorithm that relies on semantic similarity measures.
Abstract: Outcomes of high-throughput biological experiments are typically interpreted by statistical testing for enriched gene functional categories defined by the Gene Ontology (GO). The resulting lists of GO terms may be large and highly redundant, and thus difficult to interpret. REVIGO is a Web server that summarizes long, unintelligible lists of GO terms by finding a representative subset of the terms using a simple clustering algorithm that relies on semantic similarity measures. Furthermore, REVIGO visualizes this non-redundant GO term set in multiple ways to assist in interpretation: multidimensional scaling and graph-based visualizations accurately render the subdivisions and the semantic relationships in the data, while treemaps and tag clouds are also offered as alternative views. REVIGO is freely available at http://revigo.irb.hr/.

4,919 citations

Journal ArticleDOI
02 Dec 1993-Nature
TL;DR: Finding that mutations in the gene daf-2 can cause fertile, active, adult Caenorhabditis elegans hermaphrodites to live more than twice as long as wild type raises the possibility that the longevity of the dauer is not simply a consequence of its arrested growth, but instead results from a regulated lifespan extension mechanism that can be uncoupled from other aspects of dauer formation.
Abstract: We have found that mutations in the gene daf-2 can cause fertile, active, adult Caenorhabditis elegans hermaphrodites to live more than twice as long as wild type. This lifespan extension, the largest yet reported in any organism, requires the activity of a second gene, daf-16. Both genes also regulate formation of the dauer larva, a developmentally arrested larval form that is induced by crowding and starvation and is very long-lived. Our findings raise the possibility that the longevity of the dauer is not simply a consequence of its arrested growth, but instead results from a regulated lifespan extension mechanism that can be uncoupled from other aspects of dauer formation. daf-2 and daf-16 provide entry points into understanding how lifespan can be extended.

3,146 citations


"PQM-1 Complements DAF-16 as a Key T..." refers background in this paper

  • ...This effect is almost entirely dependent on activation of the FOXO transcription factor DAF-16 (Kenyon et al., 1993; Lin et al., 1997; Ogg et al., 1997)....

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Journal ArticleDOI
TL;DR: This book describes and illustrates how to compute a simple “naive” variance estimate and conŽ dence intervals that would be correct under the assumption of an underlying nonhomogeneous Poisson process model.
Abstract: (2003). Statistical Models and Methods for Lifetime Data. Technometrics: Vol. 45, No. 3, pp. 264-265.

2,583 citations


"PQM-1 Complements DAF-16 as a Key T..." refers methods in this paper

  • ...Survival Analysis Day 1 of adulthoodwas defined as t = 0, and the log-rank (Mantel-Cox)method was used to test the null hypothesis in Kaplan-Meier survival analysis (Lawless, 1982) and evaluated using OASIS survival analysis software (Yang et al., 2011)....

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