Preservation Analysis of Macrophage Gene Coexpression Between Human and Mouse Identifies PARK2 as a Genetically Controlled Master Regulator of Oxidative Phosphorylation in Humans

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.

LncRNA and mRNA profiling during activation of tilapia macrophages by HSP70 and Streptococcus agalactiae antigen

“…We also found that regulatory pathway containing “phosphorylation” was the most enriched number pathway involved in both lncRNA and mRNA categories, highlighting its regulatory roles during TPMs activation. Previous reports showed that phosphorylation was associated with glycolysis during macrophage polarization [ 42 , 46 , 47 ]. This allows the speculation establish that glucose metabolic pathway and phosphorylation pathway might be connected and quite important in TPMs similar to mammals.…”

A Genome Wide Association Study on plasma FV levels identified PLXDC2 as a new modifier of the coagulation process

“…Of interest, in a recent plasma proteomic profiling study, 22 the F5 rs6027 and PLXDC2 rs927826 variants we found here associated TA B L E 3 Association of rs927826 genotypes with plasma FV antigen (FV:Ag) and activity (FV:C) in a sample of 60 patients from the MARTHA cohort NA: Expressions were not available Corresponding publication for each study: a [12]; b [13]; c [14]; d [15]; e [16]; f [17] F I G U R E 1 Impact of PLXDC2 gene silencing on F5 gene expression in liver. Abbreviation: KD = siRNA KnockDown.…”

“…We further examined the correlation between PLXDC2 and F5 gene expression in several genome-wide gene expression data from multiple cell lines and tissues. [12][13][14][15][16][17] In all investigated resources except macrophages, we observed positive correlations between PLXDC2 and F5 expressions, the strongest correlation (r = .45, P = 3.94 × 10 −14 ) being observed in liver ( Figure S5) where FV synthesis mainly occurs (Table 4). We also assessed the correlation of liver PLXDC2 expression with that of other coagulation genes expressed in the liver (F2, F7 and F10).…”

K-Module Algorithm: An Additional Step to Improve the Clustering Results of WGCNA Co-Expression Networks

“…Genes involved in the regulation of inflammatory responses and gene–environment interactions were identified in macrophages from a set of mouse inbred strains, termed the hybrid mouse diversity panel (HMDP), while confounding factors such as environmental variation were minimized, making these datasets ideal for network biology and module identification. Macrophages were exposed to oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphatidylcholine (OxPAPC) or control treatment conditions [ 24 , 25 , 26 ]. Here, we analyzed the control and OxPAPC treatment data (329 samples), which were normalized using the robust multi-array average (RMA) method.…”