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. 2010 Jul 26:11:451.
doi: 10.1186/1471-2164-11-451.

A systems approach to mapping transcriptional networks controlling surfactant homeostasis

Yan Xu  1 , Minlu Zhang, Yanhua Wang, Pooja Kadambi, Vrushank Dave, Long J Lu, Jeffrey A Whitsett
Affiliations

A systems approach to mapping transcriptional networks controlling surfactant homeostasis

Yan Xu et al. BMC Genomics. .

Abstract

Background: Pulmonary surfactant is required for lung function at birth and throughout life. Lung lipid and surfactant homeostasis requires regulation among multi-tiered processes, coordinating the synthesis of surfactant proteins and lipids, their assembly, trafficking, and storage in type II cells of the lung. The mechanisms regulating these interrelated processes are largely unknown.

Results: We integrated mRNA microarray data with array independent knowledge using Gene Ontology (GO) similarity analysis, promoter motif searching, protein interaction and literature mining to elucidate genetic networks regulating lipid related biological processes in lung. A Transcription factor (TF)-target gene (TG) similarity matrix was generated by integrating data from different analytic methods. A scoring function was built to rank the likely TF-TG pairs. Using this strategy, we identified and verified critical components of a transcriptional network directing lipogenesis, lipid trafficking and surfactant homeostasis in the mouse lung.

Conclusions: Within the transcriptional network, SREBP, CEBPA, FOXA2, ETSF, GATA6 and IRF1 were identified as regulatory hubs displaying high connectivity. SREBP, FOXA2 and CEBPA together form a common core regulatory module that controls surfactant lipid homeostasis. The core module cooperates with other factors to regulate lipid metabolism and transport, cell growth and development, cell death and cell mediated immune response. Coordinated interactions of the TFs influence surfactant homeostasis and regulate lung function at birth.

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Figures

Figure 1
Figure 1
Identification of over-represented TFBSs in each gene cluster. Upstream genomic sequence (3 kb) was searched for TFBS in evolutionarily conserved regions (ECR) that are over-represented in a gene cluster. Proximal promoter regions (1.2 kb) were searched for over-represented TFBS in the cluster. We also determined the over-represented TFBS frequency in the proximal promoter region for each gene in the cluster. The relative importance of a TFBS was determined by the average ranking order of ECR, prompter and frequency analysis and normalized to -2.5 to 2.5. A heatmap was generated based on the normalized relative importance of TFBSs. ND: Frequency was not determined if the TFBS was not enriched in the promoter region of the gene cluster compared to all promoters in the mouse genome used as the background set (p-value > 0.05).
Figure 2
Figure 2
Graphic representation of a subnetwork consisting of predicted TF-TG pairs with the highest connectivity. The graphic representation of a subnetwork consisting of predicted TF-TG pairs with confidence cutoff as 0.60 and the top 6 TFs with the highest connectivity. SREBP, HNF3, ETSF, CEBP, GATA and IRFF were identified as regulatory hubs in this network. The network has 183 nodes and 386 links. Round nodes represent TGs, red diamond nodes represent TFs. Blue edges indicate the TF-TG predictions from C1, red edges for C2, green for C28, yellow for both C1 and C2, brown for both C1 and C28, light blue for both C2 and C28, and pink edges for TF-TG predication from C1, C2, and C28. The thickness of the edge corresponds to the frequency of the TF-TG prediction from all three clusters.
Figure 3
Figure 3
Graphic representation of a CEBPA-SREBP centered sub-network. The graphic representation of a CEBPA-SREBP centered sub-network, showing the potential connections between SREBP, CEBPA and their predicted gene targets. 3A represents top ranked common gene targets for CEBP and SREBP and 3B represents top ranked unique gene targets for CEBP or SREBP. Solid line represented literature-validated relationships and dotted lines represent predicted relationships. Known markers of lung maturation and function are highlighted in purple.
Figure 4
Figure 4
Promoter reporter assay of predicted C/EBPA and SREBP targets in transient transfection of MLE-15 cells. Schematic representation of the ≥1 kb Slc34a2, Elovl1 and Zdhhc3 promoter-luciferase constructs made in pGL3 reporter plasmids are depicted above the graphs. C/EBPα (green) and SREBP1c (red) represent consensus motifs on each mouse gene promoter. Transcription start sites are shown at +1 bp. The dose response effects of C/EBPα and SREBP1c expression after co-transfection with fixed amounts of the promoter-reporter constructs were assessed in MLE-15 cells, an immortalized mouse lung epithelial cell line, as measured by luciferase activity in 6-well plates. Values represent two independent experiments carried out in duplicate with means ± S.D. (n = 6).
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