FOXO3 on the Road to Longevity: Lessons From SNPs and Chromatin Hubs

Abstract

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.

Keywords: 3C, Chromosome conformation capture; 5′UTR, Five prime untranslated region; ACH, Active chromatin hub; Aging; Chromatin hub; ER, Estrogen receptor; ERE, Estrogen-responsive element; FHRE, Forkhead response element; FOXO3; FOXO3, Forkhead box 3; GPx, Glutathione peroxidase; GWAS, Genome-wide association study; HPS, Hamartomatous polyposis syndrome; HSE, Heat shock element; HSF1, Heat shock factor 1; IGF-1, Insulin growth factor-1; LD, Linkage disequilibrium; Longevity; PHTS, PTEN hamartoma tumor syndrome; PJS, Peutz-Jeghers syndrome; ROS, Reactive oxygen species; SNP; SNP, Single nucleotide polymorphism; SNV, Single nucleotide variant; SOD2, Superoxide dismutase 2; TAD, Topologically associated domain.

Graphical abstract

Fig. 1

Genomic region encompassing FOXO3 longevity SNPs (a) FOXO3 Ref Seq canonical transcript is mapped on the genomic region of chromosome 6 (UCSC Genome Browser, GRCh38). Single-nucleotide polymorphisms (SNPs) associated with longevity are mapped according to the genomic coordinates of the human reference genome and are marked with filled blue triangles. The rs2802292 SNP is highlighted and marked with a filled blue-sky triangle. Linkage disequilibrium (LD) correlation between rs2802292 and other SNPs is indicated by filled circles: green circles, LD between rs2802292, rs2802288, rs768023, rs2253310, rs2802288, rs12202234, rs17069665, rs12212067, rs9398171, rs3800230 and rs1935952; yellow circles, LD between rs2802292, rs2764264, and rs13217795; pink circles, LD between rs2802292 and rs10457180. (b) chr6:108,587,295-108,587,340. rs2802292 genomic location is marked with a vertical red arrow, and a blue-sky circle indicates the G/T alternative alleles. Transcription factor response elements (for ESR1, SP1, HSF1, and GATA1), previously identified by in silico analysis [91], are shown as filled orange rectangles. The rs2802292 G-allele creates a unique binding site for HSF1, while the T-allele fails to do so. The start and the end nucleotide positions for each transcription factor response element are indicated according to the genomic coordinates of the UCSC Genome Browser (GRCh38).

Fig. 2

Enhancer role of the region encompassing rs2802292 in response to stress stimuli. The rs2802292 locus has enhancer functions. FOXO3 effect on lifespan extension may be dependent on the accessibility of this region to transcription factors that positively regulate FOXO3 transcription. The presence of the G-allele creates a HSF1 binding site, which induces promoter-enhancer interaction by chromatin looping, thereby fostering FOXO3 expression and the activity of the aging hub. In female individuals, the association with longevity may be dependent on estrogen-mediated ER activity in this region. Green and red flags on chromatin (nucleosomes and DNA filament) indicate active and inactive epigenetic marks, respectively, which regulate the accessibility of regulatory and binding elements to transcription factors. HSF1: heat shock factor 1; ER: estrogen receptor; E2: estradiol; HSE: heat shock element; ERE: estrogen responsive element; 5’UTR: five prime untranslated region. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)