Caenorhabditis Elegans Host Cell Factor 1 Modulates Organismal Longevity And Stress Responses Via Coordinated Interactions With Multiple Nuclear Transcription Factors And Regulators

Abstract

Aging is a complex process influenced by the environment and genotype. Numerous conserved genetic pathways and factors have been identified as key mediators of lifespan and stress responses in the nematode C. elegans. Host cell factor-1 (HCF-1) is a longevity and stress response modulator in worms. Mammalian HCF-1 is a vital transcriptional regulator which scaffolds diverse transcriptional regulatory complexes and controls gene expression. In C. elegans, HCF-1 is a repressor of the critical longevity determinant DAF-16, the homolog of mammalian FOXO transcription factors. The molecular partners of HCF-1 and the mechanisms whereby it modulates lifespan and stress responses have not been fully elucidated. My work implicated HCF-1 as a critical player in the regulatory mechanism linking DAF-16 and its coactivator SIR-2.1 in worms. Genetic analyses revealed that hcf-1 acts downstream of sir-2.1 to influence lifespan and oxidative stress response. Gene expression profiling uncovered a striking 80% overlap between the HCF-1- and SIR-2.1-regulated DAF16 target genes. Subsequent GO-term analyses of HCF-1 and SIR-2.1-coregulated DAF-16 targets suggested that HCF-1 and SIR-2.1 together regulate specific aspects of DAF-16mediated transcription important for aging and stress responses. My findings uncover a novel interaction between the key longevity determinants SIR-2.1 and HCF-1, and provide new insights into the complex regulation of DAF-16. SKN-1 transcription factor is an evolutionarily conserved protector against oxidative and xenobiotic stress and is a well-established pro-longevity factor. I demonstrated that SKN1 contributes to the enhanced oxidative stress resistance incurred by hcf-1 inactivation in a manner parallel to DAF-16. This functional interaction between HCF-1 and SKN-1 specifically occurs under excessive oxidant stress as SKN-1 is dispensable for the thermotolerance and long lifespan of hcf-1 mutants. HCF-1 represses the activation of SKN-1 to inhibit SKN-1 target genes involved in cellular detoxification pathways. To control SKN-1 activity, HCF-1 prevents nuclear accumulation of SKN-1 in response to oxidative stress. My findings reveal a new, context-specific regulatory relationship between the stress-response factors HCF-1 and SKN-1. Given that HCF-1, DAF-16, SIR-2.1, and SKN-1 are functionally conserved between C. elegans and mammals, my findings have important implications for the regulation of mammalian counterparts of these factors by HCF proteins