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.
Highlights
Lung immaturity is a major cause of morbidity and mortality in premature infants and is commonly associated with Respiratory Distress Syndrome (RDS) and Broncho-Pulmonary Dysplasia (BPD)
Lung development is a highly regulated and coordinated process typified by stage specific changes in structure and function that occur as the structural processes including branching morphogenesis, angiogenesis, sacculation, alveologenesis and cytodifferentiation [4,5]
Dynamic lung mRNA expression profiling from B6 and A/J mice were compared to identify: 1) genes and bioprocesses commonly altered in both strains during lung maturation, 2) transcription factors and signaling molecules (TF/SMs) that changed at different stages of lung maturation, 3) pathways and transcriptional networks controlling lung maturation, and 4) strain dependent effects on lung maturation
Summary
Lung immaturity is a major cause of morbidity and mortality in premature infants and is commonly associated with RDS and BPD. Despite the impact of prematurity on related lung diseases following pre-term birth, mechanisms linking gestational length and lung maturation remain to be elucidated. Lung development is a highly regulated and coordinated process typified by stage specific changes in structure and function that occur as the structural processes including branching morphogenesis, angiogenesis, sacculation, alveologenesis and cytodifferentiation [4,5]. Formation of the gas exchange region of the lung begins at approximately E15, and increases dramatically prior to birth. During this stage, the fetal lung undergoes remarkable structural, biochemical, and functional changes including sacculation and septation to form alveoli
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