The longevity SNP rs2802292 uncovered: HSF1 activates stress-dependent expression of FOXO3 through an intronic enhancer

Valentina Grossi, Giovanna Forte, Paola Sanese, Alessia Peserico, Tugsan Tezil, Martina Lepore Signorile, Candida Fasano, Rosaura Lovaglio, Rosanna Bagnulo, Daria C Loconte, Francesco C Susca, Nicoletta Resta, Cristiano Simone

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)5587-5600
Number of pages14
JournalNucleic Acids Research
Volume46
Issue number11
DOIs
Publication statusPublished - Jun 20 2018

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Single Nucleotide Polymorphism
Alleles
Nucleic Acid Regulatory Sequences
5' Untranslated Regions
Disease Susceptibility
DNA Repair
Introns
Oxidation-Reduction
Transcription Factors
Binding Sites
Cell Line
Survival
Population

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The longevity SNP rs2802292 uncovered : HSF1 activates stress-dependent expression of FOXO3 through an intronic enhancer. / 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.

In: Nucleic Acids Research, Vol. 46, No. 11, 20.06.2018, p. 5587-5600.

Research output: Contribution to journalArticle

Grossi, V, Forte, G, Sanese, P, Peserico, A, Tezil, T, Lepore Signorile, M, Fasano, C, Lovaglio, R, Bagnulo, R, Loconte, DC, Susca, FC, Resta, N & Simone, C 2018, 'The longevity SNP rs2802292 uncovered: HSF1 activates stress-dependent expression of FOXO3 through an intronic enhancer', Nucleic Acids Research, vol. 46, no. 11, pp. 5587-5600. https://doi.org/10.1093/nar/gky331
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. / The longevity SNP rs2802292 uncovered : HSF1 activates stress-dependent expression of FOXO3 through an intronic enhancer. In: Nucleic Acids Research. 2018 ; Vol. 46, No. 11. pp. 5587-5600.
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AU - Peserico, Alessia

AU - Tezil, Tugsan

AU - Lepore Signorile, Martina

AU - Fasano, Candida

AU - Lovaglio, Rosaura

AU - Bagnulo, Rosanna

AU - Loconte, Daria C

AU - Susca, Francesco C

AU - Resta, Nicoletta

AU - Simone, Cristiano

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N2 - 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.

AB - 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.

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