Genetic Screen for Cell Fitness in High or Low Oxygen Highlights Mitochondrial and Lipid Metabolism
Genetic Screen for Cell Fitness in High or Low Oxygen Highlights Mitochondrial and Lipid Metabolism
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DOI：
10.1016/j.cell.2020.03.029
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发表时间：
2020-04-30
期刊：
影响因子：
64.5
通讯作者：
Mootha, Vamsi K.
中科院分区：
文献类型：
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作者：
Jain, Isha H.;Calvo, Sarah E.;Mootha, Vamsi K.
人类细胞能够感知并适应氧气水平的变化。历史上，这一领域的研究主要集中在低氧诱导因子(HIF)信号和活性氧(ROS)。在这里，我们在21%、5%和1%的氧气条件下进行全基因组CRISPR生长筛选，以系统地识别在高氧(213个基因)或低氧(109个基因)中具有相对适合性缺陷的基因敲除，大多数基因与HIF或ROS没有已知的联系。许多被认为是必不可少的线粒体途径的敲除，包括复合体I和铁-S生物合成中的酶，在低氧条件下生长得相对较好，因此可以在低氧条件下得到缓冲。相反，在某些类型的细胞中，脂质生物合成和过氧化物体基因的敲除只会在低氧条件下导致健康缺陷。我们的资源提名了严重程度可能受氧调节的遗传病，并将数百个基因与氧稳态联系在一起。
Human cells are able to sense and adapt to variations in oxygen levels. Historically, much research in this field has focused on hypoxia-inducible factor (HIF) signaling and reactive oxygen species (ROS). Here, we perform genome-wide CRISPR growth screens at 21%, 5%, and 1% oxygen to systematically identify gene knockouts with relative fitness defects in high oxygen (213 genes) or low oxygen (109 genes), most without known connection to HIF or ROS. Knockouts of many mitochondrial pathways thought to be essential, including complex I and enzymes in Fe-S biosynthesis, grow relatively well at low oxygen and thus are buffered by hypoxia. In contrast, in certain cell types, knockout of lipid biosynthetic and peroxisomal genes causes fitness defects only in low oxygen. Our resource nominates genetic diseases whose severity may be modulated by oxygen and links hundreds of genes to oxygen homeostasis.