Transcriptional Programs Controlling Perinatal Lung Maturation

Abstract

The timing of lung maturation is controlled precisely by complex genetic and cellular programs. Lung immaturity following preterm birth frequently results in Respiratory Distress Syndrome (RDS) and Broncho-Pulmonary Dysplasia (BPD), which are leading causes of mortality and morbidity in preterm infants. Mechanisms synchronizing gestational length and lung maturation remain to be elucidated. In this study, we designed a genome-wide mRNA expression time-course study from E15.5 to Postnatal Day 0 (PN0) using lung RNAs from C57BL/6J (B6) and A/J mice that differ in gestational length by ∼30 hr (B6<A/J). Comprehensive bioinformatics and functional genomics analyses were used to identify key regulators, bioprocesses and transcriptional networks controlling lung maturation. We identified both temporal and strain dependent gene expression patterns during lung maturation. For time dependent changes, cell adhesion, vasculature development, and lipid metabolism/transport were major bioprocesses induced during the saccular stage of lung development at E16.5–E17.5. CEBPA, PPARG, VEGFA, CAV1 and CDH1 were found to be key signaling and transcriptional regulators of these processes. Innate defense/immune responses were induced at later gestational ages (E18.5–20.5), STAT1, AP1, and EGFR being important regulators of these responses. Expression of RNAs associated with the cell cycle and chromatin assembly was repressed during prenatal lung maturation and was regulated by FOXM1, PLK1, chromobox, and high mobility group families of transcription factors. Strain dependent lung mRNA expression differences peaked at E18.5. At this time, mRNAs regulating surfactant and innate immunity were more abundantly expressed in lungs of B6 (short gestation) than in A/J (long gestation) mice, while expression of genes involved in chromatin assembly and histone modification were expressed at lower levels in B6 than in A/J mice. The present study systemically mapped key regulators, bioprocesses, and transcriptional networks controlling lung maturation, providing the basis for new therapeutic strategies to enhance lung function in preterm infants.

Diseases of Pulmonary Surfactant Homeostasis

“…Many of the signaling and transcriptional mechanisms regulating early lung branching remain highly active in late gestation as the fetal lung undergoes sacculation, and airway epithelial cells differentiate to produce pulmonary surfactant (16). During the canalicular, saccular, and alveolar periods of lung morphogenesis, pulmonary mesenchymal cells differentiate to form fibroblasts, lipofibroblasts, pericytes, matrix-associated fibroblasts, smooth muscle, and endothelial cells in the distal lung.…”

Age, Sexual Dimorphism, and Disease Associations in the Developing Human Fetal Lung Transcriptome

“…We have previously used genome-wide gene expression profiling to describe characteristic lung development genes in a small set of human lung samples (6). Similarly, animal studies performed by us and others have shown the validity of this approach to identify the key regulators of fetal lung development (6,7). Elucidating these genomic contributions to lung development will help determine molecular pathways involved in the development of lung disease and identify potential therapeutic targets.…”

Alveolar Development and Disease

“…Bioinformatic analysis of lung RNA expression array data obtained after gene targeting or mutation of these critical transcription factors demonstrated their importance in perinatal lung maturation and surfactant synthesis(10-12, 15, 16). As a critical regulator of perinatal lung maturation, NKX2-1 is predicted to function with other transcription factors, e.g., HOPX, ETV5, GATA6, GRHL, FOXP2, and HMGA2, that together regulate many aspects of lung maturation, including alveolar type I/type II cell differentiation and surfactant synthesis(12). The direct binding of TTF-1 to cis-acting regulatory sites on target genes was identified by genome wide CHromatin ImmunoPrecipitation (CHIP) assays(17,18) demonstrating its binding to sequences in the ABCA3, SFTPA, SFTPB, and SFTPC genes.…”