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

Abstract

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.

Increased RNA and protein degradation is required for counteracting transcriptional burden and proteotoxic stress in human aneuploid cells

“…Intriguingly, the effect of aneuploidy on RNA metabolism is not limited to the gained chromosomes or to protein complex genes, as we did not observe increased RNA degradation of transcripts from such genes. These findings are consistent with recent reports that dosage compensation of protein complex genes mostly occurs at the protein regulation level 5,6 . How aneuploid cells evolve to alter their global RNA metabolism in response to changes in gene dosage remains to be fully understood.…”

“…Although this stoichiometric control has been extensively studied at the protein level in the context of aneuploidy — in both untransformed 7–10,12,17,19,55–57 and cancer cells 4,5 – the role and the impact of RNA metabolism regulation in controlling gene expression is only beginning to emerge as another important layer of regulation 23,58,59 . Interestingly, dosage compensation at the mRNA level seems to be minimal in yeast 13,20 , but has been recently observed in human cells 4,6 .…”

“…The degree of gene dosage compensation varies across different cellular contexts 1 , yet it is clear that in human aneuploid cancer cells the effect of aneuploidy is attenuated by such buffering mechanisms. Recent studies have revealed that many proteins do not change their expression by the degree expected based on their DNA levels [2][3][4][5][6] . The mechanisms that allow for dosage compensation, and the potential cellular vulnerabilities that result from them, remain under-explored.…”

Multilevel gene expression changes in lineages containing adaptive copy number variants

“…We also observed that the number of significantly divergent genes (including both amplified and unamplified) decreases at each successive level of expression, from a median of ∼1500 per strain for RNA, to ∼1100 for ribosome abundance, to ∼600 per strain for protein abundance. Again, this agrees with previous reports of buffering of divergent gene expression at the translational (McManus et al 2014; Wang and Chen 2019; Kusnadi et al 2022) and post-translational levels (Wang et al 2018; Cheng et al 2022; Jiang et al 2023).…”

Gene dosage compensation: Origins, criteria to identify compensated genes, and mechanisms including sensor loops as an emerging systems‐level property in cancer

“…For instance, genes involved in translation processes and RNA processing are more susceptible to regulation at protein level, and in the other hand, genes related to structural and cellular adhesion have a stronger RNA regulation; suggesting genes that evolved with similarities in function might have also co-evolved with the same type of compensation strategies. 43 Additionally, it was found that for every gene evaluated either it showed protein or RNA regulation (i.e., genes with compensation at protein level presented very low or null RNA compensation and the same for RNA-compensated genes showing no protein regulation). Cheng and collaborators explained this with the co-evolution hypothesis, where final protein destination might be a strong indicator of the regulation gene pathway; for example, once cell adhesion proteins-including the ones working in complexes-are transported, protein regulation may be a difficult target, leaving RNA compensation as the most viable regulation pathway.…”