Clark H. Smith Brain Tumour Centre, Arnie Charbonneau Cancer Institute, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N 4N1, Canada.
Department of Biochemistry and Molecular Biology Calgary, University of Calgary, Calgary, AB T2N 4N1, Canada.
G3 (Bethesda). 2022 Dec 1;12(12). doi: 10.1093/g3journal/jkac263.
When exposed to low oxygen or hypoxia, animals must alter their metabolism and physiology to ensure proper cell-, tissue-, and whole-body level adaptations to their hypoxic environment. These alterations often involve changes in gene expression. While extensive work has emphasized the importance of the HIF-1 alpha transcription factor on controlling hypoxia gene expression, less is known about other transcriptional mechanisms. We previously identified the transcription factor FOXO as a regulator of hypoxia tolerance in Drosophila larvae and adults. Here, we use an RNA-sequencing approach to identify FOXO-dependent changes in gene expression that are associated with these tolerance effects. We found that hypoxia altered the expression of over 2,000 genes and that ∼40% of these gene expression changes required FOXO. We discovered that hypoxia exposure led to a FOXO-dependent increase in genes involved in cell signaling, such as kinases, GTPase regulators, and regulators of the Hippo/Yorkie pathway. Among these, we identified homeodomain-interacting protein kinase as being required for hypoxia survival. We also found that hypoxia suppresses the expression of genes involved in ribosome synthesis and egg production, and we showed that hypoxia suppresses tRNA synthesis and mRNA translation and reduces female fecundity. Among the downregulated genes, we discovered that FOXO was required for the suppression of many ribosomal protein genes and genes involved in oxidative phosphorylation, pointing to a role for FOXO in limiting energetically costly processes such as protein synthesis and mitochondrial activity upon hypoxic stress. This work uncovers a widespread role for FOXO in mediating hypoxia changes in gene expression.
当动物暴露在低氧或缺氧环境中时，它们必须改变新陈代谢和生理机能，以确保细胞、组织和全身水平适应其低氧环境。这些改变通常涉及基因表达的变化。虽然大量研究强调了 HIF-1α转录因子在控制缺氧基因表达方面的重要性，但对于其他转录机制知之甚少。我们之前已经确定 FOXO 转录因子是果蝇幼虫和成虫缺氧耐受的调节因子。在这里，我们使用 RNA 测序方法来确定与这些耐受效应相关的 FOXO 依赖性基因表达变化。我们发现，缺氧改变了超过 2000 个基因的表达，其中约 40%的基因表达变化需要 FOXO。我们发现，缺氧暴露导致参与细胞信号转导的基因（如激酶、GTPase 调节剂和 Hippo/Yorkie 途径调节剂）的 FOXO 依赖性增加。在这些基因中，我们确定了同源域相互作用蛋白激酶是缺氧存活所必需的。我们还发现，缺氧抑制了核糖体合成和卵子产生所涉及的基因的表达，并且我们表明，缺氧抑制 tRNA 合成和 mRNA 翻译，并降低雌性生育能力。在下调的基因中，我们发现 FOXO 是许多核糖体蛋白基因和参与氧化磷酸化的基因表达抑制所必需的，这表明 FOXO 在限制蛋白质合成和线粒体活性等能量消耗过程中发挥作用缺氧应激。这项工作揭示了 FOXO 在介导缺氧基因表达变化方面的广泛作用。
