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PreprintCited by 26Advanced Proteomics Techniques and ApplicationsCancer Genomics and DiagnosticsRNA Research and Splicing

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

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Cheng, Pan, Zhao, Xin, Katsnelson, Lizabeth, Moya, Raquel, Shwetar, Jasmine, Fenyö, David, Davoli, Teresa·2021·eLife
DOI 10.1101/2021.12.07.471176PMC PMC9491860

Preprint — published as 10.7554/elife.75227

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Abstract

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. Highlights: Proteogenomic analyses of cancer SCNAs reveal tissue specificity in gene compensation. Genes gained or lost show surprisingly low protein compensation in lung cancer and unexpected RNA compensation in colon cancer. We use DNA-RNA and RNA-protein correlations to infer the degree of RNA-level and protein-level regulation. Protein complex genes and non-complex genes show high protein-level and RNA-level regulation, respectively. Plasma membrane complexes are an exception showing more RNA-level than protein-level regulation than other complex genes. Genes participating in the same pathway show similar degree of RNA-level and protein-level regulation. There 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. Genes involved in RNA processing and protein synthesis are upregulated in highly aneuploid tumors, especially at the protein level.

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    “For this analysis we considered the cellular pathways utilized in the Schwanhausser et al. 2011 (Schwanhäusser et al., 2011) using the msigdb GSEA database to identify the genes in each pathway (v7.”
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Metadata

Authors
Cheng, P., Zhao, X., Katsnelson, L., Moya, R., Shwetar, J., Fenyö, D., & Davoli, T.
Affiliations
NYU Langone Health (US)
Corresponding author
Davoli, Teresa
ORCID
Venue
eLife
Publisher
openRxiv
Published
2021-12-09
Volume
11
ISSN
2050-084X (ISSN-L)
DOI
10.1101/2021.12.07.471176
PMC
PMC9491860
OpenAlex
W4296569450
Cited by
26
References
1
Citations by year
2026: 3 · 2025: 5 · 2024: 10 · 2023: 7 · 2022: 1
FWCI
2.08
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • eLife (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Mark Foundation For Cancer Research (C5470, C5470/A27144)
  • Cancer Research UK (C5470/A27144)
  • Deutsche Forschungsgemeinschaft (322977937)
  • National Institutes of Health
  • European Research Council (818846 - ImmuNiche - ERC-2018-COG)
  • National Cancer Institute (U24CA210972, CA248631, K99CA212621, R00CA212621, CA212621, R37CA248631, P30CA016087)
  • National Institute of General Medical Sciences (T32GM136542)
Topics
  • Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
Keywords
proteogenomics, somatic copy number alterations, gene expression regulation, plasma membrane proteins, cellular pathways, gene regulatory evolution, translation (biology), splicing, mitochondrial function, cell adhesion, cell migration, tumor versus normal tissue comparison
MeSH terms
Proteogenomics, Aneuploidy, Humans, Membrane Proteins, Neoplasms, RNA

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