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Decoding RNA Metabolism by RNA-linked CRISPR Screening in Human Cells.
Patrick J Nugent1,2, Heungwon Park1, Cynthia L Wladyka3
1Basic Sciences Division and Computational Biology Section of the Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle WA, USA.
Biorxiv : the Preprint Server for Biology
|August 2, 2024
Summary
Researchers developed a new CRISPR screening method (ReLiC) to identify gene regulators of RNA metabolism. This approach reveals how gene networks control RNA splicing, translation, and decay, impacting cell growth and disease.
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
Background:
- Human cells utilize thousands of RNA-associated proteins for RNA metabolism.
- The complete set of regulators for most RNA metabolic events is largely unknown.
- Understanding these regulators is crucial for comprehending cellular function and disease.
Purpose of the Study:
- To develop a massively parallel screening approach to comprehensively identify regulators of RNA metabolism.
- To investigate the interplay between gene networks controlling RNA splicing, translation, and decay.
- To explore the coupling between cellular growth and mRNA translation, and identify drug targets.
Main Methods:
- Development and application of a RNA-linked CRISPR (ReLiC) screening approach.
- Knockout screening of 2,092 human genes encoding RNA-associated proteins.
- Integration with biochemical fractionation of polysomes and chemogenomic profiling.
Main Results:
- ReLiC screens revealed modular interactions within gene networks governing mRNA splicing, translation, and decay.
- Pathway-specific coupling between growth fitness and mRNA translation was identified.
- Differential regulation of intron retention and exon skipping was captured, and translational regulators upstream of mRNA decay were deciphered.
Conclusions:
- ReLiC is a versatile platform for discovering and dissecting regulatory principles of human RNA metabolism.
- The study identified novel insights into the complex regulation of RNA metabolic processes.
- Findings have implications for understanding cellular responses to drugs and disease states.
