Codoni Veronica, Blum Yuna, Civelek Mete, Proust Carole, Franzén Oscar, Björkegren Johan L M, Le Goff Wilfried, Cambien Francois, Lusis Aldons J, Trégouët David-Alexandre
Sorbonne 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.
Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095.
G3 (Bethesda). 2016 Oct 13;6(10):3361-3371. doi: 10.1534/g3.116.033894.
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) in macrophages from 86 mice of the Hybrid Mouse Diversity Panel. One of these modules was significantly [false discovery rate (FDR) = 8.9 × 10] enriched for genes belonging to the oxidative phosphorylation (OXPHOS) pathway. This pathway was also found significantly (FDR < 10) 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) 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.
巨噬细胞是参与众多病理生理途径的关键细胞，对其基因调控网络进行深入表征有助于更好地理解其功能障碍如何影响人类疾病。我们在此对人和小鼠之间的巨噬细胞基因表达数据进行了跨物种网络分析，以识别两个物种间保守的网络，并评估这些网络是否能揭示新的疾病相关调控机制。从684名进行全基因组巨噬细胞基因表达谱分析的个体样本中，我们识别出27组共表达基因（模块）。在杂交小鼠多样性面板的86只小鼠的巨噬细胞中，发现6个模块是保守的（P < 10）。其中一个模块显著[错误发现率（FDR）= 8.9 × 10]富集了属于氧化磷酸化（OXPHOS）途径的基因。该途径在阿尔茨海默病、帕金森病和亨廷顿病的易感基因中也显著（FDR < 10）富集。我们进一步进行了表达数量性状位点分析，以识别可调节人类巨噬细胞OXPHOS基因表达的单核苷酸多态性（SNP）。该分析确定PARK2 rs192804963为一个反式作用变体，影响（最小P值 = 4.3 × 10）人类大多数OXPHOS基因的表达。进一步的实验工作表明，在THP1人巨噬细胞中，PARK2基因敲低表达与OXPHOS基因表达增加相关。这项工作提供了强有力的新证据，表明PARK2参与了与氧化磷酸化相关的调控网络，并表明PARK2基因变异可能作为人类巨噬细胞OXPHOS基因表达的反式调节因子。
