FOXO 3 longevity interactome on chromosome 6

Summary FOXO 3 has been implicated in longevity in multiple populations. By DNA sequencing in long‐lived individuals, we identified all single nucleotide polymorphisms ( SNP s) in FOXO 3 and showed 41 were associated with longevity. Thirteen of these had predicted alterations in transcription factor binding sites. Those SNP s appeared to be in physical contact, via RNA polymerase II binding chromatin looping, with sites in the FOXO 3 promoter, and likely function together as a cis ‐regulatory unit. The SNP s 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 FOXO 3 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 FOXO 3 toward neighboring genes. FOXO 3 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, FOXO 3 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 FOXO 3 ‘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 FOXO 3 variants promote longevity and healthy aging.