TY - JOUR
T1 - FOXO3 on the Road to Longevity
T2 - Lessons From SNPs and Chromatin Hubs
AU - Sanese, Paola
AU - Forte, Giovanna
AU - Disciglio, Vittoria
AU - Grossi, Valentina
AU - Simone, Cristiano
PY - 2019
Y1 - 2019
N2 - Health span is driven by a precise interplay between genes and the environment. Cell response to environmental cues is mediated by signaling cascades and genetic variants that affect gene expression by regulating chromatin plasticity. Indeed, they can promote the interaction of promoters with regulatory elements by forming active chromatin hubs. FOXO3 encodes a transcription factor with a strong impact on aging and age-related phenotypes, as it regulates stress response, therefore affecting lifespan. A significant association has been shown between human longevity and several FOXO3 variants located in intron 2. This haplotype block forms a putative aging chromatin hub in which FOXO3 has a central role, as it modulates the physical connection and activity of neighboring genes involved in age-related processes. Here we describe the role of FOXO3 and its single-nucleotide polymorphisms (SNPs) in healthy aging, with a focus on the enhancer region encompassing the SNP rs2802292, which upregulates FOXO3 expression and can promote the activity of the aging hub in response to different stress stimuli. FOXO3 protective effect on lifespan may be due to the accessibility of this region to transcription factors promoting its expression. This could in part explain the differences in FOXO3 association with longevity between genders, as its activity in females may be modulated by estrogens through estrogen receptor response elements located in the rs2802292-encompassing region. Altogether, the molecular mechanisms described here may help establish whether the rs2802292 SNP can be taken advantage of in predictive medicine and define the potential of targeting FOXO3 for age-related diseases.
AB - Health span is driven by a precise interplay between genes and the environment. Cell response to environmental cues is mediated by signaling cascades and genetic variants that affect gene expression by regulating chromatin plasticity. Indeed, they can promote the interaction of promoters with regulatory elements by forming active chromatin hubs. FOXO3 encodes a transcription factor with a strong impact on aging and age-related phenotypes, as it regulates stress response, therefore affecting lifespan. A significant association has been shown between human longevity and several FOXO3 variants located in intron 2. This haplotype block forms a putative aging chromatin hub in which FOXO3 has a central role, as it modulates the physical connection and activity of neighboring genes involved in age-related processes. Here we describe the role of FOXO3 and its single-nucleotide polymorphisms (SNPs) in healthy aging, with a focus on the enhancer region encompassing the SNP rs2802292, which upregulates FOXO3 expression and can promote the activity of the aging hub in response to different stress stimuli. FOXO3 protective effect on lifespan may be due to the accessibility of this region to transcription factors promoting its expression. This could in part explain the differences in FOXO3 association with longevity between genders, as its activity in females may be modulated by estrogens through estrogen receptor response elements located in the rs2802292-encompassing region. Altogether, the molecular mechanisms described here may help establish whether the rs2802292 SNP can be taken advantage of in predictive medicine and define the potential of targeting FOXO3 for age-related diseases.
U2 - 10.1016/j.csbj.2019.06.011
DO - 10.1016/j.csbj.2019.06.011
M3 - Review article
C2 - 31303978
VL - 17
SP - 737
EP - 745
JO - Computational and Structural Biotechnology Journal
JF - Computational and Structural Biotechnology Journal
SN - 2001-0370
ER -