Genome-wide dFOXO targets and topology of the transcriptomic response to stress and insulin signalling.
Genome-wide dFOXO targets and topology of the transcriptomic response to stress and insulin signalling.
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全基因组DFOXO靶标和对压力和胰岛素信号转导的转录组响应的拓扑。
DOI：
10.1038/msb.2011.36
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发表时间：
2011-06-21
影响因子：
9.9
通讯作者：
Partridge, Linda
中科院分区：
文献类型：
--
作者：
Alic, Nazif;Andrews, T. Daniel;Giannakou, Maria E.;Papatheodorou, Irene;Slack, Cathy;Hoddinott, Matthew P.;Cocheme, Helena M.;Schuster, Eugene F.;Thornton, Janet M.;Partridge, Linda
超过700个直接的转录目标的dFOXO转录因子中确定的成年果蝇。dFOXO结合基因在蠕虫和苍蝇之间是保守的，但dFOXO不是苍蝇中胰岛素信号变化的转录反应的唯一介体。FoxO转录因子受胰岛素/胰岛素样生长因子信号传导（IIS）抑制，是许多生物体过程（包括寿命）的关键参与者。使用基因组工具，我们发现了成年雌性果蝇中超过700个直接的dFOXO靶点。在野生型果蝇中，dFOXO是几种IIS组分和相互作用途径（如TOR）转录的直接必需品。dFOXO在成虫中占据的基因组位置与在幼虫或培养细胞中观察到的不同。这些位置在应激或IIS减少激活后保持不变，但结合增加，IIS遗传减少后激活了其他靶点。我们确定的IIS转录反应的一部分直接控制dFOXO和间接的影响，并表明IIS减少的转录反应的一部分不需要dFOXO。启动子分析显示加塔和其他叉头因子作为间接和dfoxo独立效应的候选介质。我们证明了果蝇和线虫之间dFOXO靶点的全基因组进化保守性，富含第二层调节剂，包括dHR 96/daf-12核激素受体。
Over 700 direct transcriptional targets of the dFOXO transcription factor are identified in the adult fruit fly. dFOXO-bound genes are conserved between worm and fly, but dFOXO is not the sole mediator of the transcriptional response to changes in insulin signalling in the fly. 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.
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影响因子：
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通讯作者：
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