JunD-AP1 regulatory network analysis during macrophage activation in a rat model of crescentic glomerulonephritisReport as inadecuate




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BMC Systems Biology

, 7:93

Empirical systems biology

Abstract

BackgroundFunction and efficiency of a transcription factor TF are often modulated by interactions with other proteins or TFs to achieve finely tuned regulation of target genes. However, complex TF interactions are often not taken into account to identify functionally active TF-targets and characterize their regulatory network. Here, we have developed a computational framework for integrated analysis of genome-wide ChIP-seq and gene expression data to identify the functional interacting partners of a TF and characterize the TF-driven regulatory network. We have applied this methodology in a rat model of macrophage dependent crescentic glomerulonephritis Crgn where we have previously identified JunD as a TF gene responsible for enhanced macrophage activation associated with susceptibility to Crgn in the Wistar-Kyoto WKY strain.

ResultsTo evaluate the regulatory effects of JunD on its target genes, we analysed data from two rat strains WKY and WKY.LCrgn2 that show 20-fold difference in their JunD expression in macrophages. We identified 36 TFs interacting with JunD-Jun and JunD-ATF complexes i.e., AP1 complex, which resulted in strain-dependent gene expression regulation of 1,274 target genes in macrophages. After lipopolysaccharide LPS stimulation we found that 2.4 fold more JunD-ATF-target genes were up-regulated as compared with JunD-Jun-target genes. The enriched 314 genes up-regulated by AP1 complex during LPS stimulation were most significantly enriched for immune response P = 6.9 × 10 and antigen processing and presentation functions P = 2.4 × 10, suggesting a role for these genes in macrophage LPS-stimulated activation driven by JunD interaction with Jun-ATF.

ConclusionsIn summary, our integrated analyses revealed a large network of TFs interacting with JunD and their regulated targets. Our data also suggest a previously unappreciated contribution of the ATF complex to JunD-mediated mechanisms of macrophage activation in a rat model of crescentic glomerulonephritis.

Electronic supplementary materialThe online version of this article doi:10.1186-1752-0509-7-93 contains supplementary material, which is available to authorized users.

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Author: Prashant K Srivastava - Richard P Hull - Jacques Behmoaras - Enrico Petretto - Timothy J Aitman

Source: https://link.springer.com/



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