Temporal dynamics of the developing lung transcriptome in three common inbred strains of laboratory mice reveals multiple stages of postnatal alveolar development

Abstract

To characterize temporal patterns of transcriptional activity during normal lung development, we generated genome wide gene expression data for 26 pre- and post-natal time points in three common inbred strains of laboratory mice (C57BL/6J, A/J, and C3H/HeJ). Using Principal Component Analysis and least squares regression modeling, we identified both strain-independent and strain-dependent patterns of gene expression. The 4,683 genes contributing to the strain-independent expression patterns were used to define a murine Developing Lung Characteristic Subtranscriptome (mDLCS). Regression modeling of the Principal Components supported the four canonical stages of mammalian embryonic lung development (embryonic, pseudoglandular, canalicular, saccular) defined previously by morphology and histology. For postnatal alveolar development, the regression model was consistent with four stages of alveolarization characterized by episodic transcriptional activity of genes related to pulmonary vascularization. Genes expressed in a strain-dependent manner were enriched for annotations related to neurogenesis, extracellular matrix organization, and Wnt signaling. Finally, a comparison of mouse and human transcriptomics from pre-natal stages of lung development revealed conservation of pathways associated with cell cycle, axon guidance, immune function, and metabolism as well as organism-specific expression of genes associated with extracellular matrix organization and protein modification. The mouse lung development transcriptome data generated for this study serves as a unique reference set to identify genes and pathways essential for normal mammalian lung development and for investigations into the developmental origins of respiratory disease and cancer. The gene expression data are available from the Gene Expression Omnibus (GEO) archive (GSE74243). Temporal expression patterns of mouse genes can be investigated using a study specific web resource (http://lungdevelopment.jax.org).

Genome-wide enrichment of damaging de novo variants in patients with isolated and complex congenital diaphragmatic hernia

“…Genome wide expression levels were previously assessed during lung development at 26 time points throughout murine lung development in three inbred strains (GEO Series GSE74243), providing stage-specific transcriptional profiles (Beauchemin et al 2016). We used unsupervised hierarchical clustering of the 71 genes with de novo variants in our cohorts to identify their expression pattern during in the embryonic, pseudoglandular, and canalicular phases (Figure 3).…”

“…Stages in lung development are indicated by purple (embryonic), cyan (pseudoglandular), green (canalicular), yellow (saccular), and orange (alveolar). Normalization methods are as in (Beauchemin et al 2016)…”

Endothelial Sash1 Is Required for Lung Maturation through Nitric Oxide Signaling

“…These data were compared to expression data from normal developing lung to assess whether the immature phenotype observed could be more widely generalized, including the endothelium. We analyzed custom gene sets made from pairwise comparisons of lung differentially expressed genes during lung development (Beauchemin et al, 2016;Xu et al, 2012). The gene signature of Sash1 À/À lungs was enriched in genes associated with an earlier developmental time point when compared to WT ( Figure 3A).…”

Mouse genetic background impacts susceptibility to hyperoxia‐driven perturbations to lung maturation

“…A spectrum of mouse strains is currently used in studies on BPD, including C57BL/6, BALB/c, A/J, C3H/He, FVB/N, and DBA/2 inbred strains. That different strains are widely used is important, because both strain‐independent and strain‐dependent patterns of gene expression have been noted in the lungs of C57BL/6J, A/J, and C3H/HeJ strains in a genome‐wide analysis of 26 time‐points between embryonic day (E)9.5 and postnatal day (P)56 . Thus, the dynamics of gene expression during lung development can be strain dependent.…”