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Genetic Screen for Cell Fitness in High or Low Oxygen Highlights Mitochondrial and Lipid Metabolism
Open accessAbstract
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.
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“Many autophagy-related genes were also common hits in the two screens (Fig. 2 d,e), such as WIPI2, ATG9A, ATG13, ATG14, and BECN1, suggesting an important role of autophagy in maintaining redox homeostasis in cells, as reported in previous studies31–33.”
From Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis (2021) · cites this paper as [33]
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“Many autophagy-related genes were also common hits in the two screens (Fig. 2 d,e), such as WIPI2, ATG9A, ATG13, ATG14, and BECN1, suggesting an important role of autophagy in maintaining redox homeostasis in cells, as reported in previous studies31–33.”
From Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis (2021) · cites this paper as [33]
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Metadata
- Authors
- Jain, I. H., Calvo, S. E., Markhard, A. L., Skinner, O. S., To, T.-L., Ast, T., & Mootha, V. K.
- Affiliations
- Broad Institute (US)
- Corresponding author
- Mootha, Vamsi K.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2020-04
- Volume
- 181
- Issue
- 3
- Pages
- 716-727.e11
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC7293541
- OpenAlex
- W3014660178
- Semantic Scholar
- f5cf6ffc17c0afcf964c1821338eea659750c183
- Cited by
- 224
- References
- 71
- Citations by year
- 2026: 30 · 2025: 42 · 2024: 33 · 2023: 37 · 2022: 30 · 2021: 37 · 2020: 14
- FWCI
- 10.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- National Institutes of Health (1F32GM133047-01)
- J. Willard and Alice S. Marriott Foundation
- U.S. Department of Energy
- Howard Hughes Medical Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- oxygen homeostasis, hypoxia, cell fitness, genome-wide CRISPR screen, mitochondrial metabolism, lipid metabolism, complex I, peroxisomes, lipogenesis, hypoxia-inducible factor, reactive oxygen species
- MeSH terms
- Hypoxia, Genetic Testing, Humans, Lipids, Mitochondria, Oxygen, Signal Transduction, Cell Hypoxia, Reactive Oxygen Species, K562 Cells, Lipid Metabolism, Genome-Wide Association Study, HEK293 Cells, Transcriptome
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