人体细胞能够感知和适应氧水平的变化。历史上,该领域的许多研究集中在缺氧诱导因子(HIF)信号和活性氧(ROS)上。这里,我们以21%的比例进行全基因组CRISPR生长筛选,5%,和1%的氧气,以系统地识别在高氧(213个基因)或低氧(109个基因)中具有相对适应性缺陷的基因敲除,大多数没有已知的连接到HIF或ROS。许多线粒体途径的敲除被认为是必不可少的,包括复合物I和Fe-S生物合成中的酶,在低氧条件下生长相对良好,因此受到缺氧的缓冲。相比之下,在某些细胞类型中,脂质生物合成和过氧化物酶体基因的敲除仅在低氧下会导致适应性缺陷。我们的资源提名了严重程度可能受氧气调节的遗传疾病,并将数百个基因与氧气稳态联系起来。
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.