The longevity SNP rs2802292 uncovered: HSF1 activates stress-dependent expression of FOXO3 through an intronic enhancer. Issue 11 (4th May 2018)

• Record Type: Journal Article
• Authors: Grossi, Valentina; Forte, Giovanna; Sanese, Paola; Peserico, Alessia; Tezil, Tugsan; Lepore Signorile, Martina; Fasano, Candida; Lovaglio, Rosaura; Bagnulo, Rosanna; Loconte, Daria C; Susca, Francesco C; Resta, Nicoletta; Simone, Cristiano
• Is Part Of: Nucleic acids research. Volume 46:Issue 11(2018)
• Page Start: 5587
• Page End: 5600
• Publication Date: 2018-05-04
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gky331
• Languages: English
• ISSNs: 0305-1048

Abstract

Abstract: The HSF and FOXO families of transcription factors play evolutionarily conserved roles in stress resistance and lifespan. In humans, the rs2802292 G-allele at FOXO3 locus has been associated with longevity in all human populations tested; moreover, its copy number correlated with reduced frequency of age-related diseases in centenarians. At the molecular level, the intronic rs2802292 G-allele correlated with increased expression of FOXO3, suggesting that FOXO3 intron 2 may represent a regulatory region. Here we show that the 90-bp sequence around the intronic single nucleotide polymorphism rs2802292 has enhancer functions, and that the rs2802292 G-allele creates a novel HSE binding site for HSF1, which induces FOXO3 expression in response to diverse stress stimuli. At the molecular level, HSF1 mediates the occurrence of a promoter–enhancer interaction at FOXO3 locus involving the 5′UTR and the rs2802292 region. These data were confirmed in various cellular models including human HAP1 isogenic cell lines (G/T). Our functional studies highlighted the importance of the HSF1-FOXO3-SOD2/CAT/GADD45A cascade in cellular stress response and survival by promoting ROS detoxification, redox balance and DNA repair. Our findings suggest the existence of an HSF1-FOXO3 axis in human cells that could be involved in stress response pathways functionally regulating lifespan and disease susceptibility.