JunD/AP1 regulatory network analysis during macrophage activation in a rat model of crescentic glomerulonephritis

Title: JunD/AP1 regulatory network analysis during macrophage activation in a rat model of crescentic glomerulonephritis
Authors: Srivastava, PK
Hull, RP
Behmoaras, J
Petretto, E
Aitman, TJ
Item Type: Journal Article
Abstract: Background: Function 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. Results: To 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 × 10-4) and antigen processing and presentation functions (P = 2.4 × 10-5), suggesting a role for these genes in macrophage LPS-stimulated activation driven by JunD interaction with Jun/ATF. Conclusions: In 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.
Issue Date: 22-Sep-2013
Date of Acceptance: 12-Sep-2013
URI: http://hdl.handle.net/10044/1/57213
DOI: https://dx.doi.org/10.1186/1752-0509-7-93
ISSN: 1752-0509
Publisher: BioMed Central
Journal / Book Title: BMC Systems Biology
Volume: 7
Copyright Statement: © Srivastava et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Science & Technology
Life Sciences & Biomedicine
Mathematical & Computational Biology
Disease Models, Animal
Macrophage Activation
Protein Interaction Mapping
Proto-Oncogene Proteins c-jun
Species Specificity
Transcription Factor AP-1
Transcription, Genetic
1199 Other Medical And Health Sciences
Publication Status: Published
Article Number: ARTN 93
Appears in Collections:Clinical Sciences
Molecular Sciences
Department of Medicine
Faculty of Medicine

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