FOXO3 longevity interactome on chromosome 6

• Published in: Aging cell Vol. 16; no. 5; pp. 1016 - 1025
• Main Authors: Donlon, Timothy A., Morris, Brian J., Chen, Randi, Masaki, Kamal H., Allsopp, Richard C., Willcox, D. Craig, Elliott, Ayako, Willcox, Bradley J.
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.10.2017; John Wiley and Sons Inc
• Subjects: African Continental Ancestry Group; Aged; Aged, 80 and over; Asian Continental Ancestry Group; Base Sequence; Binding Sites; Case-Control Studies; Cellular stress response; Chromatin; Chromatin - chemistry; Chromatin - metabolism; Chromosome 6; Chromosomes; Chromosomes, Human, Pair 6 - chemistry; Chromosomes, Human, Pair 6 - metabolism; DNA binding proteins; DNA sequencing; DNA-directed RNA polymerase; European Continental Ancestry Group; Female; fluorescence in situ hybridization; Forkhead Box Protein O3 - genetics; Forkhead Box Protein O3 - metabolism; FOXO3; FOXO3 protein; Gene expression; Genes; Genetic aspects; Genetic transcription; gene–gene interactions; Genome, Human; Haplotypes; Healthy Aging - ethnology; Healthy Aging - genetics; Healthy Aging - metabolism; Heat-Shock Proteins - genetics; Heat-Shock Proteins - metabolism; Humans; Laminin - genetics; Laminin - metabolism; Longevity; Longevity - genetics; Male; Membrane Proteins - genetics; Membrane Proteins - metabolism; Nucleotide sequencing; Original; Phenotype; Polymorphism, Single Nucleotide; Protein Binding; RNA; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Synteny; transcription factor binding; Transcription factors; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Zinc finger proteins; transcription factor binding; fluorescence in situ hybridization; FOXO3; single nucleotide polymorphisms; gene-gene interactions
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/acel.12625

Summary FOXO3 has been implicated in longevity in multiple populations. By DNA sequencing in long‐lived individuals, we identified all single nucleotide polymorphisms (SNPs) in FOXO3 and showed 41 were associated with longevity. Thirteen of these had predicted alterations in transcription factor binding sites. Those SNPs appeared to be in physical contact, via RNA polymerase II binding chromatin looping, with sites in the FOXO3 promoter, and likely function together as a cis‐regulatory unit. The SNPs exhibited a high degree of LD in the Asian population, in which they define a specific longevity haplotype that is relatively common. The haplotype was less frequent in whites and virtually nonexistent in Africans. We identified distant contact points between FOXO3 and 46 neighboring genes, through long‐range physical contacts via CCCTC‐binding factor zinc finger protein (CTCF) binding sites, over a 7.3 Mb distance on chromosome 6q21. When activated by cellular stress, we visualized movement of FOXO3 toward neighboring genes. FOXO3 resides at the center of this early‐replicating and highly conserved syntenic region of chromosome 6. Thus, in addition to its role as a transcription factor regulating gene expression genomewide, FOXO3 may function at the genomic level to help regulate neighboring genes by virtue of its central location in chromatin conformation via topologically associated domains. We believe that the FOXO3 ‘interactome’ on chromosome 6 is a chromatin domain that defines an aging hub. A more thorough understanding of the functions of these neighboring genes may help elucidate the mechanisms through which FOXO3 variants promote longevity and healthy aging.