title: Genome-wide dFOXO targets and topology of the transcriptomic response to stress and insulin signalling.
abstract: FoxO transcription factors, inhibited by insulin/insulin-like growth factor signalling (IIS), are crucial players in numerous organismal processes including lifespan. Using genomic tools, we uncover over 700 direct dFOXO targets in adult female Drosophila. dFOXO is directly required for transcription of several IIS components and interacting pathways, such as TOR, in the wild-type fly. The genomic locations occupied by dFOXO in adults are different from those observed in larvae or cultured cells. These locations remain unchanged upon activation by stresses or reduced IIS, but the binding is increased and additional targets activated upon genetic reduction in IIS. We identify the part of the IIS transcriptional response directly controlled by dFOXO and the indirect effects and show that parts of the transcriptional response to IIS reduction do not require dfoxo. Promoter analyses revealed GATA and other forkhead factors as candidate mediators of the indirect and dfoxo-independent effects. We demonstrate genome-wide evolutionary conservation of dFOXO targets between the fly and the worm Caenorhabditis elegans, enriched for a second tier of regulators including the dHR96/daf-12 nuclear hormone receptor.
authors.affiliation: Institute of Healthy Ageing, and GEE, University College London, London, UK.
authors.forename: Nazif
authors.initials: N
authors.lastname: Alic
authors.forename: T Daniel
authors.initials: TD
authors.lastname: Andrews
authors.forename: Maria E
authors.initials: ME
authors.lastname: Giannakou
authors.forename: Irene
authors.initials: I
authors.lastname: Papatheodorou
authors.forename: Cathy
authors.initials: C
authors.lastname: Slack
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Hoddinott
authors.forename: Helena M
authors.initials: HM
authors.lastname: Cochemé
authors.forename: Eugene F
authors.initials: EF
authors.lastname: Schuster
authors.forename: Janet M
authors.initials: JM
authors.lastname: Thornton
authors.forename: Linda
authors.initials: L
authors.lastname: Partridge
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D004330:Drosophila / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D050980:GATA Transcription Factors / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods*; D049750:Genome, Insect; D007328:Insulin / Q000378:metabolism*; D018384:Oxidative Stress; D010641:Phenotype; D015398:Signal Transduction; D013002:Somatomedins / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D029721:Drosophila Proteins; C477334:FOXO protein, Drosophila; D051858:Forkhead Transcription Factors; D050980:GATA Transcription Factors; D007328:Insulin; D013002:Somatomedins