Transcriptional programs controlling perinatal lung maturation.

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.

肺成熟的时间是由复杂的基因和细胞程序精确控制的。早产之后的肺不成熟常常导致呼吸窘迫综合征（RDS）和支气管肺发育不良（BPD），这是早产儿死亡和发病的主要原因。使妊娠期长度和肺成熟同步的机制仍有待阐明。在这项研究中，我们利用来自C57BL/6J（B6）和A/J小鼠的肺RNA设计了一项从胚胎第15.5天（E15.5）到出生后第0天（PN0）的全基因组mRNA表达时间进程研究，这两种小鼠的妊娠期长度相差约30小时（B6＜A/J）。综合生物信息学和功能基因组学分析被用于识别控制肺成熟的关键调节因子、生物过程和转录网络。我们确定了肺成熟过程中随时间和品系变化的基因表达模式。对于时间依赖性变化，细胞黏附、脉管系统发育以及脂质代谢/转运是在胚胎第16.5 - 17.5天肺发育的囊泡期诱导的主要生物过程。CEBPA、PPARG、VEGFA、CAV1和CDH1被发现是这些过程的关键信号和转录调节因子。先天防御/免疫反应在妊娠后期（E18.5 - 20.5）被诱导，STAT1、AP1和EGFR是这些反应的重要调节因子。与细胞周期和染色质组装相关的RNA表达在产前肺成熟过程中受到抑制，并由FOXM1、PLK1、染色质框和高迁移率族转录因子家族调节。品系依赖性肺mRNA表达差异在E18.5达到峰值。此时，调节表面活性物质和先天免疫的mRNA在B6（妊娠期短）小鼠的肺中比在A/J（妊娠期长）小鼠的肺中表达更丰富，而参与染色质组装和组蛋白修饰的基因在B6小鼠中的表达水平比在A/J小鼠中低。本研究系统地绘制了控制肺成熟的关键调节因子、生物过程和转录网络，为提高早产儿肺功能的新治疗策略提供了基础。