daf-2;hcf-1

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Genetic mutants with daf-2, hcf-1 alterations

Names of genes are ordered alphabetically. For the order of interventions, please see the specific paper.

Temperature °C
25
Diet
NGM; OP51
Lifespan (days)
30.2
Lifespan change (compared to wild type)
108.28%
Phenotype
RNAi knock down of daf-2 in the hcf-1(ok559) mutant lived considerably longer than either the hcf-1(ok559) or daf-2 RNAi single mutant.
Lifespan comparisons
Double mutant daf-2(RNAi);hcf-1(ok559) has a lifespan of 30.2 days, while single mutant daf-2(RNAi) has a lifespan of 27.4 days, single mutant hcf-1(ok559) has a lifespan of 16.0 days and wild type has a lifespan of 14.5 days.
Type of interaction
See methods
Synergistic (positive)
Citation
View abstract
Li J et al., 2008, Caenorhabditis elegans HCF-1 functions in longevity maintenance as a DAF-16 regulator. PLoS Biol. 6(9):e233 18828672 Click here to select all mutants from this PubMed ID in the graph
Abstract
The transcription factor DAF-16/forkhead box O (FOXO) is a critical longevity determinant in diverse organisms, however the molecular basis of how its transcriptional activity is regulated remains largely unknown. We report that the Caenorhabditis elegans homolog of host cell factor 1 (HCF-1) represents a new longevity modulator and functions as a negative regulator of DAF-16. In C. elegans, hcf-1 inactivation caused a daf-16-dependent lifespan extension of up to 40% and heightened resistance to specific stress stimuli. HCF-1 showed ubiquitous nuclear localization and physically associated with DAF-16. Furthermore, loss of hcf-1 resulted in elevated DAF-16 recruitment to the promoters of its target genes and altered expression of a subset of DAF-16-regulated genes. We propose that HCF-1 modulates C. elegans longevity and stress response by forming a complex with DAF-16 and limiting a fraction of DAF-16 from accessing its target gene promoters, and thereby regulates DAF-16-mediated transcription of selective target genes. As HCF-1 is highly conserved, our findings have important implications for aging and FOXO regulation in mammals.

Names of genes are ordered alphabetically. For the order of interventions, please see the specific paper.

Temperature °C
25
Diet
NGM; OP51
Lifespan (days)
35.9
Lifespan change (compared to wild type)
158.27%
Phenotype
Interestingly, the daf-2(e1370);hcf-1(ok559) double mutant lived considerably longer than either the daf-2(e1370) or hcf-1(ok559) single mutant.
Lifespan comparisons
Double mutant daf-2(e1370);hcf-1(ok559) has a lifespan of 35.9 days, while single mutant hcf-1(ok559) has a lifespan of 18.6 days, single mutant daf-2(e1370) has a lifespan of 30.3 days and wild type has a lifespan of 13.9 days.
Type of interaction
See methods
Synergistic (positive)
Citation
View abstract
Li J et al., 2008, Caenorhabditis elegans HCF-1 functions in longevity maintenance as a DAF-16 regulator. PLoS Biol. 6(9):e233 18828672 Click here to select all mutants from this PubMed ID in the graph
Abstract
The transcription factor DAF-16/forkhead box O (FOXO) is a critical longevity determinant in diverse organisms, however the molecular basis of how its transcriptional activity is regulated remains largely unknown. We report that the Caenorhabditis elegans homolog of host cell factor 1 (HCF-1) represents a new longevity modulator and functions as a negative regulator of DAF-16. In C. elegans, hcf-1 inactivation caused a daf-16-dependent lifespan extension of up to 40% and heightened resistance to specific stress stimuli. HCF-1 showed ubiquitous nuclear localization and physically associated with DAF-16. Furthermore, loss of hcf-1 resulted in elevated DAF-16 recruitment to the promoters of its target genes and altered expression of a subset of DAF-16-regulated genes. We propose that HCF-1 modulates C. elegans longevity and stress response by forming a complex with DAF-16 and limiting a fraction of DAF-16 from accessing its target gene promoters, and thereby regulates DAF-16-mediated transcription of selective target genes. As HCF-1 is highly conserved, our findings have important implications for aging and FOXO regulation in mammals.

Names of genes are ordered alphabetically. For the order of interventions, please see the specific paper.

Temperature °C
25
Diet
NGM; OP51
Lifespan (days)
40.4
Lifespan change (compared to wild type)
174.83%
Phenotype
Interestingly, the daf-2(e1370);hcf-1(pk924) double mutant lived considerably longer than either the daf-2(e1370) or hcf-1(pk924) single mutant.
Lifespan comparisons
Double mutant daf-2(e1370);hcf-1(pk924) has a lifespan of 40.4 days, while single mutant hcf-1(pk924) has a lifespan of 19.3 days, single mutant daf-2(e1370) has a lifespan of 28.7 days and wild type has a lifespan of 14.7 days.
Type of interaction
See methods
Synergistic (positive)
Citation
View abstract
Li J et al., 2008, Caenorhabditis elegans HCF-1 functions in longevity maintenance as a DAF-16 regulator. PLoS Biol. 6(9):e233 18828672 Click here to select all mutants from this PubMed ID in the graph
Abstract
The transcription factor DAF-16/forkhead box O (FOXO) is a critical longevity determinant in diverse organisms, however the molecular basis of how its transcriptional activity is regulated remains largely unknown. We report that the Caenorhabditis elegans homolog of host cell factor 1 (HCF-1) represents a new longevity modulator and functions as a negative regulator of DAF-16. In C. elegans, hcf-1 inactivation caused a daf-16-dependent lifespan extension of up to 40% and heightened resistance to specific stress stimuli. HCF-1 showed ubiquitous nuclear localization and physically associated with DAF-16. Furthermore, loss of hcf-1 resulted in elevated DAF-16 recruitment to the promoters of its target genes and altered expression of a subset of DAF-16-regulated genes. We propose that HCF-1 modulates C. elegans longevity and stress response by forming a complex with DAF-16 and limiting a fraction of DAF-16 from accessing its target gene promoters, and thereby regulates DAF-16-mediated transcription of selective target genes. As HCF-1 is highly conserved, our findings have important implications for aging and FOXO regulation in mammals.

Search genes: daf-2 hcf-1

Entrez ID
Symbol
GenAge
Wormbase ID

175410
daf-2
View on GenAge (daf-2)
WBGene00000898

Insulin-like receptor subunit beta;Receptor protein-tyrosine kinase;hypothetical protein

Locus: CELE_Y55D5A.5

Wormbase description: daf-2 encodes a receptor tyrosine kinase that is the C. elegans insulin/IGF receptor ortholog; DAF-2 activity is required for a number of processes in C. elegans, including embryonic and larval development, formation of the developmentally arrested dauer larval stage (diapause), larval developmental timing, adult longevity, reproduction, fat storage, salt chemotaxis learning, and stress resistance, including response to high temperature, oxidative stress, and bacterial infection; DAF-2 signals through a conserved PI 3-kinase pathway to negatively regulate the activity of DAF-16, a Forkhead-related transcription factor, by inducing its phosphorylation and nuclear exclusion; in addition, DAF-2 negatively regulates the nuclear localization, and hence transcriptional activity, of SKN-1 in intestinal nuclei; amongst the 38 predicted insulin-like molecules in C. elegans, genetic and microarray analyses suggest that at least DAF-28, INS-1, and INS-7 are likely DAF-2 ligands; genetic mosaic and tissue-specific promoter studies indicate that daf-2 can function cell nonautonomously and within multiple cell types to influence dauer formation and adult lifespan, likely by regulating the production of secondary endocrine signals that coordinate growth and longevity throughout the animal; temporal analysis of daf-2 function indicates that daf-2 regulates lifespan, reproduction, and diapause independently, at distinct times during the animal's life cycle.

Entrez ID
Symbol
GenAge
Wormbase ID

177560
hcf-1
View on GenAge (hcf-1)
WBGene00001827

human HCF1 related

Locus: CELE_C46A5.9

Wormbase description: hcf-1 encodes the C. elegans ortholog of human host cell factor (HCF-1), a transcriptional regulator that associates with histone modification enzymes and plays a role in cell cycle progression; in C. elegans, hcf-1 plays a role in regulation of cell division and mitotic histone modification; in addition, HCF-1 functions in determination of adult lifespan as a negative regulator of DAF-16, with which it physically interacts; HCF-1 is a ubiquitously expressed protein that localizes to the nucleus.

Orthologs of daf-2;hcf-1 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Drosophila melanogaster	Hcf;InR
Mus musculus	Hcfc1;Insr
Mus musculus	Hcfc1;Igf1r
Mus musculus	Hcfc1;Insrr

Orthologs of daf-2 in SynergyAge

Show in SynergyAge
Species	Gene
Drosophila melanogaster	InR

Not in SynergyAge
Species	Gene
Mus musculus	Insr
Mus musculus	Igf1r
Mus musculus	Insrr

Orthologs of hcf-1 in SynergyAge

Show in SynergyAge
Species	Gene

Not in SynergyAge
Species	Gene
Drosophila melanogaster	Hcf
Mus musculus	Hcfc1