Multi-omics analysis identifies drivers of protein phosphorylation

• Published in: Genome Biology Vol. 24; no. 1; p. 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: Journal Article
• Language: English
• Published: England BioMed Central 21.03.2023; BMC
• 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); Phosphorylation; Quantitative trait loci (QTL); Collaborative Cross; Medation analysis; Multi-omics; Phosphorylation regulation
• ISSN: 1474-760X; 1474-7596; 1474-760X
• DOI: 10.1186/s13059-023-02892-2

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.