Proteogenomic analysis of aneuploidy reveals divergent types of gene expression regulation across cellular pathways

How cells control gene expression is a fundamental question. The relative contribution of protein-level and transcript-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 transcript and protein abundances of SCNA-containing genes, we provide insights into the rules of gene regulation. While gene compensation mainly occurs at the protein level across tumor types, genes gained or lost show surprisingly low protein compensation in lung and high RNA compensation in colon cancer. Protein complex genes have a strong protein-level regulation while non-complex genes have a strong transcript-level regulation. Exceptions are plasma membrane protein complexes showing a very low protein-level regulation. Strikingly, we find a strong negative association between the degree of transcript-level and protein-level regulation across genes and pathways. Moreover, genes participating in the same pathway show similar degree of transcript- and protein-level regulation. Pathways including translation, splicing and mitochondrial function show a stronger protein-level regulation while cell adhesion and migration pathways show a stronger transcript-level regulation. These results suggest that the evolution of gene regulation is shaped by functional constraints and that many cellular pathways tend to evolve a predominant mechanism of gene regulation, possibly due to energetic constraints. HighlightsO_LIProteogenomic analyses of cancer SCNAs reveal tissue specificity in gene compensation. C_LIO_LIGenes gained or lost show surprisingly low protein compensation in lung cancer and unexpected RNA compensation in colon cancer. C_LIO_LIWe use DNA-RNA and RNA-protein correlations to infer the degree of RNA-level and protein-level regulation. C_LIO_LIProtein complex genes and non-complex genes show high protein-level and RNA-level regulation, respectively. C_LIO_LIPlasma membrane complexes are an exception showing more RNA-level than protein-level regulation than other complex genes. C_LIO_LIGenes participating in the same pathway show similar degree of RNA-level and protein-level regulation. C_LIO_LIThere is a strong negative relationship between the RNA- and protein-level regulation among pathways, suggesting that they are regulated either at the protein or at the RNA level. C_LIO_LIGenes involved in RNA processing and protein synthesis are upregulated in highly aneuploid tumors, especially at the protein level. C_LI