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Genome-wide CRISPR-Cas9 screen analyzed by SLIDER identifies network of repressor complexes that regulate TRIM24
Lalit R Patel1,2,3, Sabrina A Stratton4, Megan McLaughlin5
1Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Iscience
|July 10, 2023
Summary
Researchers identified key regulators of TRIM24, an oncogenic protein overexpressed in many cancers. This discovery sheds light on how TRIM24 is controlled and offers new avenues for cancer research.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- The oncogenic protein TRIM24 is frequently overexpressed in human tumors, correlating with poor patient prognosis.
- Despite its prevalence, TRIM24 rarely undergoes genetic alterations like mutations or rearrangements, suggesting regulatory mechanisms are key to its overexpression.
Purpose of the Study:
- To identify novel regulators of TRIM24 expression.
- To elucidate the regulatory network controlling TRIM24 in cancer.
Main Methods:
- Genome-wide CRISPR-Cas9 screening coupled with fluorescence-activated cell sorting (FACS).
- Development and application of the SLIDER scoring system for CRISPR screen analysis.
Main Results:
- Nominated 220 negative regulators of TRIM24.
- Identified the KAP1 corepressor, CNOT deadenylase, and GID/CTLH E3 ligase complexes as critical negative regulators.
- Demonstrated that knockout of components of these complexes leads to TRIM24 overexpression.
Conclusions:
- Uncovered a regulatory network controlling TRIM24 expression.
- Identified novel therapeutic targets and biological contexts for TRIM24 in cancer.
- Validated SLIDER as a broadly applicable tool for FACS-based CRISPR screen analysis.
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