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| Status |
Public on Jul 01, 2024 |
| Title |
CRISPR activation screens identify the SWI-SNF ATPases as suppressors of ferroptosis [NGS3789_snRNA] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Ferroptosis is an iron-dependent cell death mechanism characterized by an accumulation of toxic lipid peroxides and membrane rupture. The glutathione dependent enzyme, GPX4 (glutathione peroxidase 4), prevents ferroptosis by reducing these lipid peroxides into non-toxic lipid alcohols. Ferroptosis induction by GPX4 inhibition has emerged as a vulnerability of cancer cells, thus highlighting the need to identify ferroptosis regulators that may be exploited therapeutically. Through genome-wide screens and a series of genetic, genomic, and quantitative imaging approaches, we identify the SWI-SNF ATPases BRM and BRG1 as ferroptosis suppressors. Mechanistically, they directly bind to and catalytically increase chromatin accessibility at NRF2 target loci, thus boosting NRF2 transcriptional output. This primes cells to counter lipid peroxidation and confers resistance to GPX4 inhibition and ferroptosis. Importantly, we demonstrate that the BRM/BRG1-ferroptosis connection can be leveraged to enhance the paralog dependency of BRG1-mutant lung cancer cells on BRM, especially in lines that are less sensitive to BRM inhibition or degradation. Our data reveal ferroptosis induction as a potential avenue for broadening the efficacy of BRM degraders/inhibitors and define a specific genetic context for exploiting GPX4 dependency.
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| Overall design |
Single cell multiome profiling of BRM-inducible KP4 cells treated with or without doxycycline to induce BRM overexpression (snRNA-seq).
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| Contributor(s) |
Bhat KP, Ye X, Vilas CK, Durinck S |
| Citation(s) |
38870012 |
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| Submission date |
Oct 12, 2023 |
| Last update date |
Sep 22, 2024 |
| Contact name |
Marc Hafner |
| E-mail(s) |
hafner.marc@gene.com
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| Organization name |
Genentech
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| Department |
Oncology Bioinformatics
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| Street address |
Building 45-1, 1 DNA Way
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| City |
South San Francisco |
| State/province |
CA |
| ZIP/Postal code |
94080 |
| Country |
USA |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (2) |
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| This SubSeries is part of SuperSeries: |
| GSE245249 |
CRISPR activation screens identify the SWI-SNF ATPases as suppressors of ferroptosis |
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| Relations |
| BioProject |
PRJNA1027457 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE245242_NGS3789_BRM_expression_status.csv.gz |
36.3 Kb |
(ftp)(http) |
CSV |
| GSE245242_NGS3789_cell_density.csv.gz |
114.8 Kb |
(ftp)(http) |
CSV |
| GSE245242_NGS3789_louvain_clusters.csv.gz |
40.9 Kb |
(ftp)(http) |
CSV |
| GSE245242_NGS3789_umap_coordinates.csv.gz |
113.9 Kb |
(ftp)(http) |
CSV |
| GSE245242_RAW.tar |
375.9 Mb |
(http)(custom) |
TAR (of MTX, TSV) |
SRA Run Selector |
| Raw data are available in SRA |
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