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Multi-omics analysis identifies drivers of protein phosphorylation.

ABSTRACT: 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.

SUBMITTER: Zhang T

PROVIDER: S-EPMC10031968 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Multi-omics analysis identifies drivers of protein phosphorylation.

Zhang Tian T Keele Gregory R GR Gyuricza Isabela Gerdes IG Vincent Matthew M Brunton Catherine C Bell Timothy A TA Hock Pablo P Shaw Ginger D GD Munger Steven C SC de Villena Fernando Pardo-Manuel FP Ferris Martin T MT Paulo Joao A JA Gygi Steven P SP Churchill Gary A GA

Genome biology 20230321 1

<h4>Background</h4>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.<h4>Results</h4>We quantified phosphopeptides, proteins, and transcripts in heart, liver, and kidney tissue samples of mice from 58 strains of the Collaborative Cross ...[more]

PMID: 36944993

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Project description:BackgroundLigamentum flavum hypertrophy (LFH) is a primary contributor to lumbar spinal stenosis. However, a thorough understanding of the cellular and molecular mechanisms driving LFH fibrotic progression remains incomplete.MethodsSingle-cell RNA sequencing (scRNA-seq) was performed to construct the single-cell map of human ligamentum flavum (LF) samples. An integrated multi-omics approach, encompassing scRNA-seq, bulk RNA sequencing (bulk RNA-seq), and Mendelian randomization (MR), was applied to conduct comprehensive functional analysis. Clinical tissue specimens and animal models were employed to further confirm the multi-omics findings.ResultsScRNA-seq provided a single-cell level view of the fibrotic microenvironment in LF, revealing significantly increased proportions of fibroblasts, myofibroblasts, and macrophages in LFH. Using transmission electron microscopy, single-cell gene set scoring, and MR analysis, ferroptosis was identified as a critical risk factor and pathway within LFH. Subcluster analysis of fibroblasts revealed functional heterogeneity among distinct subpopulations, highlighting the functional characteristics and the metabolic dynamics of fibroblast with a high ferroptosis score (High Ferro-score FB). The quantification of gene expression at single-cell level revealed that ferroptosis increased along with fibrosis in LFH specimens, a finding further validated in both human and mice tissue sections. Consistently, bulk RNA-seq confirmed increased proportions of fibroblasts and macrophages in LFH specimens, underscoring a strong correlation between these cell types through Spearman correlation analysis. Notably, subcluster analysis of the mononuclear phagocytes identified a specific subset of SPP1+ macrophages (SPP1+ Mac) enriched in LFH, which exhibited activation of fibrosis and ferroptosis-related metabolic pathways. Cell-cell communication analysis highlighted that SPP1+ Mac exhibited the strongest outgoing and incoming interactions among mononuclear phagocytes in the LFH microenvironment. Ligand-receptor analysis further revealed that the SPP1-CD44 axis could serve as a key mediator regulating the activity of High Ferro-score FB. Multiplex immunofluorescence confirmed substantial Collagen I deposition and reduced Ferritin Light Chain expression in regions with SPP1-CD44 co-localization in LFH specimens.ConclusionsOur findings indicated that SPP1+ Mac may contribute to LFH fibrosis by regulating ferroptosis in High Ferro-score FB through the SPP1-CD44 axis. This study enhances our understanding of the cellular and molecular mechanisms underlying LFH progression, potentially improving early diagnostic strategies and identifying new therapeutic targets.

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Multi-omics analysis identifies drivers of protein phosphorylation.

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Multi-omics analysis identifies drivers of protein phosphorylation.

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