A systems approach to mapping transcriptional networks controlling surfactant homeostasis.
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.
Xu
Yan
Y
Division of Pulmonary Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA. Yan.Xu@cchmc.org
Zhang
Minlu
M
Wang
Yanhua
Y
Kadambi
Pooja
P
Dave
Vrushank
V
Lu
Long J
LJ
Whitsett
Jeffrey A
JA
D000818:Animals; D053263:Gene Regulatory Networks; D006706:Homeostasis; D008168:Lung / Q000378:metabolism*; D051379:Mice; D011663:Pulmonary Surfactants / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
D011663:Pulmonary Surfactants; D014157:Transcription Factors