Highlights
- CRISPR screens at 21%, 5%, and 1% O 2 highlight 322 genes, most unconnected to HIF
- Low O 2 buffers loss of mitochondrial and Fe-S biosynthetic pathways
- Low O 2 exacerbates loss of pathways in lipid and peroxisomal metabolism
- Screen nominates genetic diseases that may benefit from O 2-modulation
Summary
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.
