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Preservation Analysis of Macrophage Gene Coexpression Between Human and Mouse Identifies PARK2 as a Genetically
Veronica Codoni1, Yuna Blum2, Mete Civelek3
1Sorbonne Universités, Université Pierre et Marie Curie, Paris 06, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche en Santé 1166, F-75013 Paris, France Institute for Cardiometabolism and Nutrition, F-75013 Paris, France.
Abstract:
Macrophages are key players involved in numerous pathophysiological pathways and an in-depth characterization of their gene regulatory networks can help in better understanding how their dysfunction may impact on human diseases. We here conducted a cross-species network analysis of macrophage gene expression data between human and mouse to identify conserved networks across both species, and assessed whether such networks could reveal new disease-associated regulatory mechanisms. From a sample of 684 individuals processed for genome-wide macrophage gene expression profiling, we identified 27 groups of coexpressed genes (modules). Six modules were found preserved (P < 10-4) in macrophages from 86 mice of the Hybrid Mouse Diversity Panel. One of these modules was significantly [false discovery rate (FDR) = 8.9 × 10-11] enriched for genes belonging to the oxidative phosphorylation (OXPHOS) pathway. This pathway was also found significantly (FDR < 10-4) enriched in susceptibility genes for Alzheimer, Parkinson, and Huntington diseases. We further conducted an expression quantitative trait loci analysis to identify SNP that could regulate macrophage OXPHOS gene expression in humans. This analysis identified the PARK2 rs192804963 as a trans-acting variant influencing (minimal P-value = 4.3 × 10-8) the expression of most OXPHOS genes in humans. Further experimental work demonstrated that PARK2 knockdown expression was associated with increased OXPHOS gene expression in THP1 human macrophages. This work provided strong new evidence that PARK2 participates to the regulatory networks associated with oxidative phosphorylation and suggested that PARK2 genetic variations could act as a trans regulator of OXPHOS gene macrophage expression in humans.
Insights
This study reveals conserved gene networks in macrophages across species, linking oxidative phosphorylation (OXPHOS) to neurodegenerative diseases. PARK2 genetic variations were identified as key regulators of OXPHOS gene expression in human macrophages.
Area of Science:
- Immunology
- Genetics
- Neuroscience
Background:
- Macrophages are crucial in disease pathogenesis.
- Understanding macrophage gene regulation is vital for disease insight.
- Cross-species analysis can uncover conserved regulatory mechanisms.
Purpose of the Study:
- To identify conserved gene regulatory networks in human and mouse macrophages.
- To assess if these networks reveal disease-associated mechanisms.
- To investigate the role of PARK2 in regulating oxidative phosphorylation in macrophages.
Main Methods:
- Genome-wide gene expression profiling in 684 human individuals.
- Cross-species network analysis comparing human and mouse macrophage data.
- Expression quantitative trait loci (eQTL) analysis and PARK2 knockdown experiments.
Main Results:
- Identified 27 coexpressed gene modules, with six conserved between human and mouse macrophages.
- One conserved module was significantly enriched for oxidative phosphorylation (OXPHOS) genes.
- Discovered that PARK2 rs192804963 acts as a trans-acting variant regulating OXPHOS gene expression in human macrophages.
- PARK2 knockdown increased OXPHOS gene expression in human macrophages.
Conclusions:
- Conserved macrophage gene networks link OXPHOS to Alzheimer's, Parkinson's, and Huntington's diseases.
- PARK2 genetic variations are implicated as trans regulators of OXPHOS gene expression in macrophages.
- This finding provides new evidence for PARK2's role in macrophage regulatory networks relevant to neurodegenerative diseases.
