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Open Access Research article

An overlapping set of genes is regulated by both NFIB and the glucocorticoid receptor during lung maturation

Mathieu Lajoie1, Yu-Chih Hsu2, Richard M Gronostajski2 and Timothy L Bailey1*

Author Affiliations

1 Institute for Molecular Bioscience, The University of Queensland, 306 Carmody Road, St Lucia 4072, Australia

2 Department of Biochemistry and Developmental Genomics Group, University at Buffalo, 701 Ellicott St., 14203 Buffalo, USA

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BMC Genomics 2014, 15:231  doi:10.1186/1471-2164-15-231

Published: 25 March 2014

Abstract

Background

Lung maturation is a late fetal developmental event in both mice and humans. Because of this, lung immaturity is a serious problem in premature infants. Disruption of genes for either the glucocorticoid receptor (Nr3c1) or the NFIB transcription factors results in perinatal lethality due to lung immaturity. In both knockouts, the phenotype includes excess cell proliferation, failure of saccularization and reduced expression of markers of epithelial differentiation. This similarity suggests that the two genes may co-regulate a specific set of genes essential for lung maturation.

Results

We analyzed the roles of these two transcription factors in regulating transcription using ChIP-seq data for NFIB, and RNA expression data and motif analysis for both. Our new ChIP-seq data for NFIB in lung at E16.5 shows that NFIB binds to a NFI motif. This motif is over-represented in the promoters of genes that are under-expressed in Nfib-KO mice at E18.5, suggesting an activator role for NFIB. Using available microarray data from Nr3c1-KO mice, we further identified 52 genes that are under-expressed in both Nfib and Nr3c1 knockouts, an overlap which is 13.1 times larger than what would be expected by chance. Finally, we looked for enrichment of 738 recently published transcription factor motifs in the promoters of these putative target genes and found that the NFIB and glucocorticoid receptor motifs were among the most enriched, suggesting that a subset of these genes may be directly activated by Nfib and Nr3c1.

Conclusions

Our data provide the first evidence for Nfib and Nr3c1 co-regulating genes related to lung maturation. They also establish that the in vivo DNA-binding specificity of NFIB is the same as previously seen in vitro, and highly similar to that of the other NFI-family members NFIA, NFIC and NFIX.

Keywords:
Lung development; Nr3c1; Glucocorticoid receptor; Nfib; Regulation of transcription; ChIP-seq analysis; Expression analysis; Motif analysis; Transcription factor