title: 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.
authors.affiliation: Institute of Healthy Ageing, and GEE, University College London, London, United Kingdom.
authors.forename: Nazif
authors.initials: N
authors.lastname: Alic
authors.affiliation: Institute of Healthy Ageing, and GEE, University College London, London, United Kingdom.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Giannakou
authors.affiliation: Institute of Healthy Ageing, and GEE, University College London, London, United Kingdom; EMBL - European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.
authors.forename: Irene
authors.initials: I
authors.lastname: Papatheodorou
authors.affiliation: Institute of Healthy Ageing, and GEE, University College London, London, United Kingdom; Max Planck Institute for Biology of Ageing, Cologne, Germany.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Hoddinott
authors.affiliation: EMBL - European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.
authors.forename: T Daniel
authors.initials: TD
authors.lastname: Andrews
authors.affiliation: Institute of Healthy Ageing, and GEE, University College London, London, United Kingdom; Max Planck Institute for Biology of Ageing, Cologne, Germany.
authors.forename: Ekin
authors.initials: E
authors.lastname: Bolukbasi
authors.affiliation: Institute of Healthy Ageing, and GEE, University College London, London, United Kingdom; Max Planck Institute for Biology of Ageing, Cologne, Germany.
authors.forename: Linda
authors.initials: L
authors.lastname: Partridge
mesh_terms: D000818:Animals; D001665:Binding Sites; D016000:Cluster Analysis; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000502:physiology*; D005216:Fat Body; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D008017:Life Expectancy; D050356:Lipid Metabolism; D009928:Organ Specificity / Q000235:genetics; D011485:Protein Binding; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; C477334:FOXO protein, Drosophila; D051858:Forkhead Transcription Factors; D014157:Transcription Factors