<em>FOXO3</em> LONGEVITY INTERACTOME ON HUMAN CHROMOSOME 6 — ASN Events
  1. Schedule
  2. Poster Session 2
  3. FOXO3 LONGEVITY INTERACTOME ON HUMAN CHROMOSOME 6

FOXO3 LONGEVITY INTERACTOME ON HUMAN CHROMOSOME 6 (#219)

Brian Morris 1 2 3 , Timothy Donlon 1 4 , Qimei He 2 5 , Randi Chen 2 , Kamal H Masaki 2 3 , Richard Allsopp 4 , D. Craig Willcox 2 4 6 , Ayako Elliott 2 , Bradley J Willcox 2 3
  1. University of Sydney, University Of Sydney, NSW, Australia
  2. Department of Research, Honolulu Heart Program/Honolulu-Asia Aging Study (HAAS), Kuakini Medical Center,, Honolulu, HI, USA
  3. Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA
  4. John A. Burns School of Medicine, , University of Hawaii , Honolulu, HI, USA
  5. Veterans Affairs Pacific Islands Health Care System, Honolulu, HI, USA
  6. Department of Human Welfare, , Okinawa, Japan , Okinawa International University, Okinawa, Japan

Background: Minor alleles of several FOXO3 polymorphismsn are associated with increased lifespan, as well as lower blood pressure, less hypertension, and reduced risk of death from coronary artery disease.

Aims: To determine the local genomic mechanisms by which FOXO3 exerts its health benefits.

Methods: Using leukocyte DNA from long-lived American subjects of Japanese ancestry we sequenced 7.2 Mb of chromosome 6q21 DNA surrounding FOXO3. SNPs were genotyped by Geneious®. The WashU Epigenome Browser public database and the program Juicebox were used to determine contact points.

Results: We identified all SNPs in FOXO3 and showed 41 were highly significant for 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 and chromatin looping, with sites in the FOXO3 promoter, and likely function together as a cis-regulatory unit. The SNPs were in a high degree of linkage disequilibrium in the Asian population, in which they define a specific longevity haplotype that is relatively common in Asians. The haplotype was less frequent in whites and virtually non-existent in blacks. We identified distant contact points between FOXO3 and neighboring genes, through long-range physical contacts via CCCTC-binding factor zinc finger protein (CTCF) binding sites, over a 7.2 Mb distance on chromosome 6. The 7.2 Mb achipelago was flanked by gene deserts. FOXO3 appeared to lie at the center of these contacts and of an early-replicating region on chromosome 6, suggesting that in addition to regulating the expression patterns of genes on other chromosomes, through its role as a transcription factor, FOXO3 may also function at the genomic level to help regulate neighboring genes by virtue of its central location in chromatin conformation.

Conclusion: We identified genotype-specific mechanisms affecting FOXO3 expression. Protective genotypes of FOXO3 form distinct conformations within the gene itself and between neighbouring genes. FOXO3 is at the hub of an interacting set of genes on chromosome 6 involved in cell and disease protection.

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