Date Published: July 19, 2017
Publisher: John Wiley and Sons Inc.
Author(s): Timothy A. Donlon, Brian J. Morris, Randi Chen, Kamal H. Masaki, Richard C. Allsopp, D. Craig Willcox, Ayako Elliott, Bradley J. Willcox.
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.
Forkhead/winged helix box gene, group O (FoxO) proteins are a set of evolutionarily conserved transcription factors involved in sensing and maintaining energy homeostasis. At the cellular level, they play roles in regulation of gluconeogenesis and glycogenolysis by insulin signaling, protection against environmental and biological stressors, cell proliferation, differentiation, survival, cell cycle arrest, apoptosis, DNA repair, inhibition and promotion of differentiation, immune cell regulation, carcinogenesis, and stem cell quiescence/maintenance [see reviews: (Morris et al., 2015; Martins et al., 2016)]. They function at both the protein–protein level and at the DNA–protein level, where they bind with other elements to promote cell‐specific gene regulation. At the whole body level, FoxOs regulate a wide array of processes that include cell growth and proliferation, tumor suppression and cell cycle regulation (via Smad‐dependent transforming growth factor β), muscle homeostasis (via phosphoinositide‐3 kinase), and regulation of carbohydrate and lipid metabolism [see review: (van der Vos & Coffer, 2008)].
T.A.D., B.J.W., and K.H.M. designed the research; T.A.D., B.J.W., R.C., K.H.M., and A.E. performed the research; T.A.D. contributed new reagents/analytic tools; R.C. analyzed data; and T.A.D., B.J.M., B.J.W., K.H.M., and D.C.W. wrote the manuscript.
This work was supported by contract N01‐HC‐05102 from the National Heart, Lung, and Blood Institute and contract N01‐AG‐4‐2149 and Grants 5 U01 AG019349‐05 and R01 AG027060‐01 (Hawaii Lifespan Study) from the National Institute on Aging. Authors BJW and TAD declare that they currently hold a US patent (number 20130295566) entitled ‘Method of Using FOXO3A Polymorphisms and Haplotypes to Predict and Promote Healthy Aging and Longevity’.