FOXO3 longevity interactome on chromosome 6

Abstract

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.

Identification and characterization of two functional variants in the human longevity gene FOXO3

“…In view of the diverse functions of CTCF, including transcriptional activation, enhancer-blocking and insulator properties and its influence on chromatin organisation 27 , FOXO3 rs12206094 might affect gene expression of neighboring genes or may even act interchromosomally. Experimental evidence for this hypothesis has recently been published 44 .…”

Genetic Architecture of Subcortical Brain Structures in Over 40,000 Individuals Worldwide

“…The most significant variant located 9Kb downstream from DRAM1 was also associated with a CpG site proximate to active TSS upstream of that gene in several mature brain tissues (Table S5 and Figure S3.B). F0X03 has been recently identified as pivotal in an astrocyte network conserved across humans and mice involved in stress, sleep, and Huntington’s disease 62 , and has been related to longevity 63 . In Drosophila , a F0X03 ortholog regulates dendrite number and length in the peripheral nervous system 64 , and in the zebrafish, Danio rario, Foxo3a knockdown led to apoptosis and mispatterning of the embryonic CNS 65 .…”

Review and meta-analysis of genetic polymorphisms associated with exceptional human longevity

“…The investigated FOXO3A SNP, rs2802292, is located in intron 2 and is a cis-eQTL for a nearby long non-coding RNA, LINC0022, of which little is known. Recently, the presence of the G allele was found to be protective for coronary artery disease mortality in older populations (~76 yrs age), including Japanese and Caucasians (Willcox et al, 2017). The exact mechanism by which such a protective effect occurs is unclear but different lines of evidence suggest FOXO3 may have beneficial cardiovascular effects (Willcox et al, 2017).…”

“…Indeed, the authors suggest that this set of genes, 'the FOXO3 longevity interactome' may act as an 'ageing hub' (Willcox et al, 2017). The role of rs2802292 as an eQTL of LINC0022 also deserves attention (see Suppl.).…”