A systems approach to mapping transcriptional networks controlling surfactant homeostasis

Division of Pulmonary Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
BMC Genomics (Impact Factor: 3.99). 07/2010; 11(1):451. DOI: 10.1186/1471-2164-11-451
Source: PubMed

ABSTRACT 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.
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.
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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Available from: Pooja Kadambi, May 13, 2014
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    • "In summary, our previous network model identified the important role of SREBP as a regulatory hub controlling a lung lipid transcriptional network [14]. The present study was designed to further define the dynamic roles of SREBP during perinatal lung development and maturation. "
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    • "Less information is available regarding dynamic and combinatorial regulation of target genes by multiple TFs that are likely to mediate the complex process of perinatal lung maturation. We recently developed a systems approach integrating previous studies and identified the interactive nature of the factors that form a genetic network regulating surfactant homeostasis [16]. Murray et al. compared gestational lengths of 15 inbred mouse strains and found significant variability among inbred strains, while the intra-strain variation was low, supporting the concept that gestational length is genetically controlled [17], [18]. "
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