skip to main content

Title: The GATA transcription factor/ MTA ‐1 homolog egr‐1 promotes longevity and stress resistance in Caenorhabditis elegans

Aging is associated with a large number of both phenotypic and molecular changes, but for most of these, it is not known whether these changes are detrimental, neutral, or protective. We have identified a conservedCaenorhabditis elegansGATA transcription factor/MTA‐1 homologegr‐1(lin‐40) that extends lifespan and promotes resistance to heat and UV stress when overexpressed. Expression ofegr‐1increases with age, suggesting that it may promote survival during normal aging. This increase in expression is dependent on the presence of the germline, raising the possibility thategr‐1expression is regulated by signals from the germline. In addition, loss ofegr‐1suppresses the long lifespan of insulin receptordaf‐2mutants. The DAF‐16 FOXO transcription factor is required for the increased stress resistance ofegr‐1overexpression mutants, andegr‐1is necessary for the proper regulation ofsod‐3(a reporter for DAF‐16 activity). These results indicate thategr‐1acts within the insulin signaling pathway.egr‐1can also activate the expression of its paralogegl‐27,another factor known to extend lifespan and increase stress resistance, suggesting that the two genes act in a common program to promote survival. These results identifyegr‐1as part of a longevity‐promoting circuit that changes with age in a manner that is beneficial for the lifespan of the organism.

more » « less
Author(s) / Creator(s):
Publisher / Repository:
Date Published:
Journal Name:
Aging Cell
Medium: X Size: p. 329-339
["p. 329-339"]
Sponsoring Org:
National Science Foundation
More Like this
  1. Abstract

    The interactions between a host and its resident microbes form complicated networks that can affect host physiology. Disentangling these host-microbe interactions can help us better understand mechanisms by which bacteria affect hosts, while also defining the integral commensal protection that host-associated microbiota offer to promote health. Here we utilize a tractable genetic model organism,Caenorhabditis elegans, to study the effects of host environments on bacterial gene expression and metabolic pathways. First, we compared the transcriptomic profiles ofE.coliOP50in vitro(on agar plates) versusin vivo(fed toC.eleganshost). Our data revealed that 110 biosynthetic genes were enriched in host-associatedE.coli. Several of these expressed genes code for the precursors and products needed for the synthesis of lipopolysaccharides (LPS), which are important for innate immune and stress responses, as well as pathogenicity. Secondly, we compared the transcriptomic profiles ofE.colifed to hosts with different genetic backgrounds, including the long-liveddaf-2/insulin like growth factor (IGF) receptor and short liveddaf-16/FOXO transcription factor mutants. We find that hosts genetics also alters bacterial metabolic pathways. Given that bacteria influence host health, this transcriptomics approach can elucidate genes mediating host aging.

    more » « less
  2. Abstract

    CCR4‐NOT is a versatile eukaryotic protein complex that controls multiple steps in gene expression regulation from synthesis to decay. In yeast, CCR4‐NOT has been implicated in stress response regulation, though this function in other organisms remains unclear. In a genome‐wide RNAi screen, we identified a subunit of the CCR4‐NOT complex,ccf‐1, as a requirement for theC. eleganstranscriptional response to cadmium and acrylamide stress. Using whole‐transcriptome RNA sequencing, we show that the knockdown ofccf‐1attenuates the activation of a broad range of stress‐protective genes in response to cadmium and acrylamide, including those encoding heat shock proteins and xenobiotic detoxification. Consistently, survival assays show that the knockdown ofccf‐1decreasesC. elegansstress resistance and normal lifespan. A yeast 2‐hybrid screen using a CCF‐1 bait identified the homeobox transcription factor PAL‐1 as a physical interactor. Knockdown ofpal‐1inhibits the activation ofccf‐1 dependent stress genes and reducesC. elegansstress resistance. Gene expression analysis reveals that knockdown ofccf‐1andpal‐1attenuates the activation ofelt‐2andelt‐3under stress that encode master transcriptional co‐regulators of stress response in theC. elegans, and that overexpression of ELT‐2 can suppressccf‐1's requirement for gene transcription in a stress‐dependent manner. Our findings reveal a new role for CCR4‐NOT in the environmental stress response and define its role in stress resistance and longevity inC. elegans.

    more » « less
  3. FOXO transcription factors regulate development, longevity, and stress-resistance across species. The C. elegans FOXO ortholog, daf-16, has three major isoforms with distinct promoters and N-termini. Different combinations of isoforms regulate different processes. Adverse environments can induce dauer diapause after the second larval molt. During dauer, daf-16 blocks specification of vulval precursor cells, including EGFR/Ras-mediated 1˚ fate specification and LIN-12/Notch-mediated 2˚ fate specification. Using isoform-specific mutants, we find that daf-16a and daf-16f are functionally redundant for the block to the expression of 1˚ fate markers. In contrast, all three isoforms contribute to blocking the expression of 2˚ fate markers. 
    more » « less
  4. Plasticity in multicellular organisms involves signaling pathways converting contexts—either natural environmental challenges or laboratory perturbations—into context-specific changes in gene expression. Congruently, the interactions between the signaling molecules and transcription factors (TF) regulating these responses are also context specific. However, when a target gene responds across contexts, the upstream TF identified in one context is often inferred to regulate it across contexts. Reconciling these stable TF–target gene pair inferences with the context-specific nature of homeostatic responses is therefore needed. The induction of the Caenorhabditis elegans genes lipl-3 and lipl-4 is observed in many genetic contexts and is essential to survival during fasting. We find DAF-16/FOXO mediating lipl-4 induction in all contexts tested; hence, lipl-4 regulation seems context independent and compatible with across-context inferences. In contrast, DAF-16–mediated regulation of lipl-3 is context specific. DAF-16 reduces the induction of lipl-3 during fasting, yet it promotes it during oxidative stress. Through discrete dynamic modeling and genetic epistasis, we define that DAF-16 represses HLH-30/TFEB—the main TF activating lipl-3 during fasting. Contrastingly, DAF-16 activates the stress-responsive TF HSF-1 during oxidative stress, which promotes C. elegans survival through induction of lipl-3 . Furthermore, the TF MXL-3 contributes to the dominance of HSF-1 at the expense of HLH-30 during oxidative stress but not during fasting. This study shows how context-specific diverting of functional interactions within a molecular network allows cells to specifically respond to a large number of contexts with a limited number of molecular players, a mode of transcriptional regulation we name “contextualized transcription.” 
    more » « less
  5. Ashrafi, Kaveh (Ed.)
    Animals integrate changes in external and internal environments to generate behavior. While neural circuits detecting external cues have been mapped, less is known about how internal states like hunger are integrated into behavioral outputs. Here, we use the nematode C . elegans to examine how changes in internal nutritional status affect chemosensory behaviors. We show that acute food deprivation leads to a reversible decline in repellent, but not attractant, sensitivity. This behavioral change requires two conserved transcription factors MML-1 (MondoA) and HLH-30 (TFEB), both of which translocate from the intestinal nuclei to the cytoplasm during food deprivation. Next, we identify the insulin-like peptide INS-31 as a candidate ligand relaying food-status signals from the intestine to other tissues. Further, we show that neurons likely use the DAF-2 insulin receptor and AGE-1/PI-3 Kinase, but not DAF-16/FOXO to integrate these intestine-released peptides. Altogether, our study shows how internal food status signals are integrated by transcription factors and intestine-neuron signaling to generate flexible behaviors via the gut-brain axis. 
    more » « less