Multi-omics analysis identifies drivers of protein phosphorylation

Tian Zhang, Harvard Medical School
Gregory R. Keele, Jackson Laboratory
Isabela Gerdes Gyuricza, Jackson Laboratory
Matthew Vincent, Jackson Laboratory
Catherine Brunton, Jackson Laboratory
Timothy A. Bell, The University of North Carolina at Chapel Hill
Pablo Hock, The University of North Carolina at Chapel Hill
Ginger D. Shaw, The University of North Carolina at Chapel Hill
Steven C. Munger, Jackson Laboratory
Fernando Pardo Manuel de Villena, The University of North Carolina at Chapel Hill
Martin T. Ferris, The University of North Carolina at Chapel Hill
Joao A. Paulo, Harvard Medical School
Steven P. Gygi, Harvard Medical School
Gary A. Churchill, Jackson Laboratory


Background: 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. Results: 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. Conclusions: 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.