FOXO3 cell resilience gene neighborhood

The forkhead transcription factor Foxo3 negatively regulates natural killer cell function and viral clearance in myocarditis

“…Thus, we wanted to analyze if variants in the FOXO3 gene have different effects on metformin response and FOXO3 activation potential. Therefore, we analyzed variants that are considered to have an influence on aging and inflammation and to have higher FOXO3 mRNA level (9,112,156,158,204). We detected no influence of a single SNP on the metformin induced FOXO3 activation in human immune cells (Figure 38).…”

“…This clustering was stronger in cells with the minor SNP genotype GG (rs2802292) compared with the common genotype TT. This was accompanied by the observation that lymphoid cell lines derived from SNP carriers expressed more FOXO3 mRNA upon induction than cell lines derived from non-carriers (158).…”

“…Several studies have ruled out the fact that SNPs in the FOXO3 gene are associated with higher mRNA levels of FOXO3 (9,112,156,158,159). Furthermore, results have come up showing that FOXO3 expression increases in human blood with age.…”

Recent advances in understanding the role of FOXO3

“…Two recent studies provide insight into how the longevity variants of FOXO3 may act at the molecular and cellular levels. In carriers of the G allele of a longevity variant of FOXO3 , the FOXO3 gene was physically closer to its neighboring genes, and when exposed to stress, FOXO3 mRNA expression in lymphoblastoid cell lines derived from carriers increased more than in cell lines derived from non-carriers 62 . In line with those findings, another study showed that the same genetic variant has enhancer functions and that the G allele allows the creation of a novel transcription factor binding site, which induces FOXO3 mRNA expression in response to diverse stress stimuli 63 .…”

“…One mechanism of action of the FOXO3 SNPs was only recently uncovered and involves a complex “interactome” whereby cellular stress causes FOXO3 to move close and physically interacts with no fewer than 46 flanking genes on chromosome 6 64 . Rather than just FOXO3 , the strong association of FOXO3 with longevity might rely on the central position of FOXO3 in a chromatin domain containing essential genes involved in cell resilience, including autophagy, stress response, energy/nutrient sensing, cell proliferation, apoptosis, and stem cell maintenance 62 – 64 .…”