Preservation Analysis of Macrophage Gene Coexpression Between Human and Mouse Identifies PARK2 as a Genetically Controlled Master Regulator of Oxidative Phosphorylation in Humans
| Autor: | François Cambien, Johan Björkegren, Yuna Blum, Veronica Codoni, Wilfried Le Goff, Oscar Franzén, Mete Civelek, David-Alexandre Trégouët, Carole Proust, Aldons J. Lusis |
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| Přispěvatelé: | HAL UPMC, Gestionnaire, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), University of Virginia, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Karolinska Institutet [Stockholm], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of California-University of California, University of Virginia [Charlottesville] |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Genotype Ubiquitin-Protein Ligases Quantitative Trait Loci Gene regulatory network Regulator Investigations Biology QH426-470 Gene Expression Regulation Enzymologic Oxidative Phosphorylation Workflow Evolution Molecular Mice 03 medical and health sciences 0302 clinical medicine Species Specificity [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry Molecular Biology/Genomics [q-bio.GN] Gene expression Genetics Animals Humans Macrophage Gene Regulatory Networks Molecular Biology Gene trans genetic effects Genetics (clinical) Gene knockdown Gene Expression Profiling cross-species comparison Computational Biology High-Throughput Nucleotide Sequencing gene expression network analysis macrophages Gene expression profiling 030104 developmental biology Gene Expression Regulation eQTL analysis Expression quantitative trait loci [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry Molecular Biology/Genomics [q-bio.GN] Transcriptome 030217 neurology & neurosurgery Genome-Wide Association Study |
| Zdroj: | G3: Genes, Genomes, Genetics, Vol 6, Iss 10, Pp 3361-3371 (2016) G3 G3, 2016, 6 (10), pp.3361-3371. ⟨10.1534/g3.116.033894⟩ G3: Genes|Genomes|Genetics G3, Genetics Society of America, 2016, 6 (10), pp.3361-3371. ⟨10.1534/g3.116.033894⟩ |
| ISSN: | 2160-1836 |
| DOI: | 10.1534/g3.116.033894 |
| Popis: | Cardiogenics Consortium, IDEM Leducq Consortium CADGenomics; International audience; 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 24) in macrophages from 86 mice of the Hybrid Mouse Diversity Panel. One of these modules was significantly [false discovery rate (FDR) = 8.9 · 10 211 ] enriched for genes belonging to the oxidative phosphorylation (OXPHOS) pathway. This pathway was also found significantly (FDR , 10 24) 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 transacting variant influencing (minimal P-value = 4.3 · 10 28) 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. |
| Databáze: | OpenAIRE |
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