Mammalian Hcf-1 Is A Conserved Co-Regulator Of The Longevity-Promoting Foxo Transcription Factors, And Is Required For Pancreatic Beta Cell Function

As the world's elderly population grows, and the incidence of age-related diseases increases, knowledge of the factors that affect longevity will be essential to develop therapies that counter the effects of aging. Aging is a highly complex phenomenon, but many genetic and environmental lifespan determinants have been characterized with the use of model organisms. Importantly, many of these longevity determinants function in human lifespan modulation. In the nematode C. elegans, the transcriptional regulator HCF-1 represses the insulin-responsive transcription factor DAF-16 to affect aging and stress responses. Whether mammalian HCF-1 homologs function in a conserved manner to regulate the mammalian DAF-16 homologs, known as FoxO transcription factors, has not yet been determined. My studies indicate that HCF-1 proteins interact with FoxO transcription factors, and regulate the transcriptional targets of FoxO in mammalian cells. Furthermore, while the DAF-16 co-regulator SIR-2.1 acts upstream of C. elegans HCF-1 to modulate lifespan, the mammalian homolog of SIR-2.1, SIRT1, targets mammalian HCF-1 for deacetylation. These findings highlight the well-conserved nature of the interaction between FoxO transcription factors and the FoxO co- regulators HCF-1 and SIRT1, and implicate HCF-1 as a novel longevity determinant in mammals. FoxO transcription factors are critical regulators of multiple physiological processes, including the maintenance of glucose homeostasis. In the pancreas, FoxO1 regulates [beta]-cell function through repression of the transcription factor Pdx1. My analyses indicate that HCF-1 is required for survival, proliferation and glucosestimulated insulin secretion in the INS-1 [beta]-cell line. Inactivation of HCF-1 leads to reduced Pdx1 gene transcription and resultant decreases in insulin gene transcription and cellular insulin content. However, while HCF-1 and FoxO1 physically interact in [beta]-cells, FoxO1 localization to the Pdx1 promoter is not increased by HCF-1 depletion, suggesting that HCF-1 promotes transcription of Pdx1 through a FoxO1-independent mechanism. Rather, I find that HCF-1 associates with the transcription factor E2F1, which is also known to affect Pdx1 expression. Both HCF-1 and E2F1 localize to the promoter of the Pdx1 gene, suggesting that HCF-1, in association with E2F1, directly promotes Pdx1 gene expression. Thus, my results implicate HCF-1 as a critical modulator of both mammalian glucose homoestasis and longevity.