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

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. © 2014 alic et al.