Interplay of dFOXO and Two ETS-Family Transcription Factors Determines Lifespan in Drosophila melanogaster

Abstract

Forkhead box O (FoxO) transcription factors (TFs) are key drivers of complex transcriptional programmes that determine animal lifespan. FoxOs regulate a number of other TFs, but how these TFs in turn might mediate the anti-ageing programmes orchestrated by FoxOs in vivo is unclear. Here, we identify an E-twenty six (ETS)-family transcriptional repressor, Anterior open (Aop), as regulated by the single Drosophila melanogaster FoxO (dFOXO) in the adult gut. AOP, the functional orthologue of the human Etv6/Tel protein, binds numerous genomic sites also occupied by dFOXO and counteracts the activity of an ETS activator, Pointed (Pnt), to prevent the lifespan-shortening effects of co-activation of dFOXO and PNT. This detrimental synergistic effect of dFOXO and PNT appears to stem from a mis-regulation of lipid metabolism. At the same time, AOP activity in another fly organ, the fat body, has further beneficial roles, regulating genes in common with dfoxo, such as the secreted, non-sensory, odorant binding protein (Obp99b), and robustly extending lifespan. Our study reveals a complex interplay between evolutionarily conserved ETS factors and dFOXO, the functional significance of which may extend well beyond animal lifespan.

FOXO regulates RNA interference in Drosophila and protects from RNA virus infection

“…Using a cutoff of fourfold enrichment over input, we identified ∼2,200 genes that were bound by dFOXO (Dataset S1). The number of targets agrees well with previously reported dFOXO ChIP studies (20)(21)(22)(23). Comparisons with the previous ChIP studies of dFOXO binding indicate that the genes bound in this model most closely resemble those found in starved larva or the adult fat body (Dataset S2) (20)(21)(22)(23).…”

“…1A). Using the same approach, similar sequences were identified in three of the four previous studies (20)(21)(22)(23) (Fig. S1).…”

Genetics and Pharmacology of Longevity

“…They pointed toward additional factors like GATA, other forkheads, and dHR96 as potential regulators downstream of dFOXO (Alic, Andrews, et al, 2011). Additionally, the regulation of secondary transcriptional activators/repressors might be tissue-specific, differentially regulating life span (Alic, Giannakou, et al, 2014). Therefore, it is important to understand not only the transcriptional response in specific tissues where genetic manipulations are performed, but also how neighboring (or even distant) tissues respond and modulate organismal survival.…”

Mapping the path to a longer life

“…The authors also show that the extension of fly lifespan by ERK or PI3K inhibition is not additive, which suggests that the two branches of the pathway might converge on modulating the expression of common genes that regulate lifespan 10 . Inhibition of ERK activates AOP, whereas inhibition of PI3K activates FOXO; both transcription factors do indeed bind a common subset of genes, but the exact targets that control lifespan are unknown 10 (Fig.…”

“…Inhibition of ERK activates AOP, whereas inhibition of PI3K activates FOXO; both transcription factors do indeed bind a common subset of genes, but the exact targets that control lifespan are unknown 10 (Fig. 1).…”