Multi-omics analysis identifies drivers of protein phosphorylation

Phosphorylation of proteins is a key step in the regulation of many cellular processes including activation of enzymes and signaling cascades. The abundance of a phosphorylated peptide (phosphopeptide) is determined by the abundance of its parent protein and the proportion of target sites that are p...

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Published in:Genome Biology 2023-03, Vol.24 (1), p.52-52, Article 52
Main Authors: Zhang, Tian, Keele, Gregory R, Gyuricza, Isabela Gerdes, Vincent, Matthew, Brunton, Catherine, Bell, Timothy A, Hock, Pablo, Shaw, Ginger D, Munger, Steven C, de Villena, Fernando Pardo-Manuel, Ferris, Martin T, Paulo, Joao A, Gygi, Steven P, Churchill, Gary A
Format: Article
Language:English
Subjects:
Animals
Collaborative Cross
Diabetes mellitus (non-insulin dependent)
Diabetes Mellitus, Type 2 - genetics
Gender differences
Gene expression
Genetic analysis
Genomes
Heart
Influence
Kidneys
Kinases
Liver
Males
Medation analysis
Mice
Mitochondria
Multi-omics
Multiomics
Peptides
Peptides - genetics
Phosphatase
Phosphorylation
Phosphorylation regulation
Polygenic inheritance
Proteins
Pyruvic acid
Quantitative Trait Loci
Quantitative trait loci (QTL)
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Summary:Phosphorylation of proteins is a key step in the regulation of many cellular processes including activation of enzymes and signaling cascades. The abundance of a phosphorylated peptide (phosphopeptide) is determined by the abundance of its parent protein and the proportion of target sites that are phosphorylated. We quantified phosphopeptides, proteins, and transcripts in heart, liver, and kidney tissue samples of mice from 58 strains of the Collaborative Cross strain panel. We mapped ~700 phosphorylation quantitative trait loci (phQTL) across the three tissues and applied genetic mediation analysis to identify causal drivers of phosphorylation. We identified kinases, phosphatases, cytokines, and other factors, including both known and potentially novel interactions between target proteins and genes that regulate site-specific phosphorylation. Our analysis highlights multiple targets of pyruvate dehydrogenase kinase 1 (PDK1), a regulator of mitochondrial function that shows reduced activity in the NZO/HILtJ mouse, a polygenic model of obesity and type 2 diabetes. Together, this integrative multi-omics analysis in genetically diverse CC strains provides a powerful tool to identify regulators of protein phosphorylation. The data generated in this study provides a resource for further exploration.
ISSN:1474-760X
1474-7596
1474-760X
DOI:10.1186/s13059-023-02892-2