Proteogenomic analysis of cancer aneuploidy and normal tissues reveals divergent modes of gene regulation across cellular pathways

How cells control gene expression is a fundamental question. The relative contribution of protein-level and RNA-level regulation to this process remains unclear. Here, we perform a proteogenomic analysis of tumors and untransformed cells containing somatic copy number alterations (SCNAs). By reveali...

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Bibliographic Details
Published in:eLife 2022-09, Vol.11
Main Authors: Cheng, Pan, Zhao, Xin, Katsnelson, Lizabeth, Camacho-Hernandez, Elaine M, Mermerian, Angela, Mays, Joseph C, Lippman, Scott M, Rosales-Alvarez, Reyna Edith, Moya, Raquel, Shwetar, Jasmine, Grun, Dominic, Fenyo, David, Davoli, Teresa
Format: Article
Language:English
Subjects:
Analysis
Aneuploidy
Cancer
Cancer Biology
Cell adhesion
Cell cycle
Cell migration
Computational and Systems Biology
Consortia
Copy number
Divergence
Gene expression
Gene regulation
Genes
Genetic aspects
Genetic regulation
Genetic research
Genetic translation
Genomes
Membrane proteins
Mitochondria
protein regulation
Proteins
proteogenomic
RNA
RNA processing
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Summary:How cells control gene expression is a fundamental question. The relative contribution of protein-level and RNA-level regulation to this process remains unclear. Here, we perform a proteogenomic analysis of tumors and untransformed cells containing somatic copy number alterations (SCNAs). By revealing how cells regulate RNA and protein abundances of genes with SCNAs, we provide insights into the rules of gene regulation. Protein complex genes have a strong protein-level regulation while non-complex genes have a strong RNA-level regulation. Notable exceptions are plasma membrane protein complex genes, which show a weak protein-level regulation and a stronger RNA-level regulation. Strikingly, we find a strong negative association between the degree of RNA-level and protein-level regulation across genes and cellular pathways. Moreover, genes participating in the same pathway show a similar degree of RNA- and protein-level regulation. Pathways including translation, splicing, RNA processing, and mitochondrial function show a stronger protein-level regulation while cell adhesion and migration pathways show a stronger RNA-level regulation. These results suggest that the evolution of gene regulation is shaped by functional constraints and that many cellular pathways tend to evolve one predominant mechanism of gene regulation at the protein level or at the RNA level.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.75227