DAF-16, the C. elegans ortholog of the evolutionarily conserved FOXO transcription factors, is a key mediator of longevity. DAF-16 acts as a central integrator of diverse environmental and cellular stimuli, and mounts a transcriptional response to modulate stress responses and lifespan. Although multiple pathways and factors that affect the function of DAF-16 have been identified, the precise molecular mechanisms determining the specific transcriptional responses by DAF-16 have yet to be discovered. We recently identified the C. elegans host cell factor 1 (
hcf-1) as a novel longevity determinant and as a transcriptional co-repressor of DAF-16 (Li J. et al, 2008, PLoS Biol). While not much is known about C. elegans HCF-1, the mammalian ortholog of HCF-1 is known to regulate the activities of several transcription factors by assembling appropriate transcriptional complexes. Loss of C. elegans
hcf-1 results in a robust lifespan extension and resistance to oxidative and UV-stress that is dependent on
daf-16. HCF-1 antagonizes the transcriptional activity of DAF-16 in the nucleus by physically associating with DAF-16 and limiting its access to select target gene promoters. To test if
hcf-1 also requires the activity of
sir-2.1, another key longevity determinant that acts as a
daf-16 cofactor, we performed epistasis analysis between
hcf-1 and
sir-2.1. Our preliminary results indicate that loss of
sir-2.1 suppressed the longevity and UV-stress-resistance phenotypes of
hcf-1 mutants. In addition,
sir-2.1 was necessary for the elevated expression of superoxide-dismutase 3 (
sod-3), a DAF-16 target gene, in
hcf-1 mutants. Co-immunoprecipitation experiments revealed that HCF-1 and SIR-2.1 proteins physically associate. Using gene-expression microarray analysis, we identified genes regulated by DAF-16 in response to HCF-1. In agreement with our hypothesis that HCF-1 modulates specific functions of DAF-16, we found that the HCF-1/DAF-16 target genes constituted only a subset of known DAF-16 target genes altered in response to insulin/IGF signaling (Shaw WM et al, 2007, Curr Biol). Interestingly, comparison of
daf-16-dependent gene expression changes in long-lived
hcf-1 mutants to those in long-lived
sir-2.1 overexpressing strains (CTM, unpublished results) revealed a >90% overlap of similarly regulated genes. Therefore, our results suggest that HCF-1 modulates longevity and stress responses through antagonizing the transcriptional activities of DAF-16 and SIR-2.1.