Transcriptomic analysis comparing mouse strains with extreme total lung capacities identifies novel candidate genes for pulmonary function

Abstract

BackgroundFailure to attain peak lung function by early adulthood is a risk factor for chronic lung diseases. Previously, we reported that C3H/HeJ mice have about twice total lung capacity (TLC) compared to JF1/MsJ mice. We identified seven lung function quantitative trait loci (QTL: Lfnq1-Lfnq7) in backcross/intercross mice derived from these inbred strains. We further demonstrated, superoxide dismutase 3, extracellular (Sod3), Kit oncogene (Kit) and secreted phosphoprotein 1 (Spp1) located on these Lfnqs as lung function determinants. Emanating from the concept of early origin of lung disease, we sought to identify novel candidate genes for pulmonary function by investigating lung transcriptome in C3H/HeJ and JF1/MsJ mice at the completion of embryonic development, bulk alveolar formation and maturity.MethodsDesign-based stereological analysis was performed to study lung structure in C3H/HeJ and JF1/MsJ mice. Microarray was used for lung transcriptomic analysis [embryonic day 18, postnatal days 28, 70]. Quantitative real time polymerase chain reaction (qRT-PCR), western blot and immunohistochemical analysis were used to confirm selected differences.ResultsStereological analysis revealed decreased alveolar number density, elastin to collagen ratio and increased mean alveolar volume in C3H/HeJ mice compared to JF1/MsJ. Gene ontology term “extracellular region” was enriched among the decreased JF1/MsJ transcripts. Candidate genes identified using the expression-QTL strategy include: ATP-binding cassette, sub-family G (WHITE), member 1 (Abcg1), formyl peptide receptor 1 (Fpr1), gamma-aminobutyric acid (GABA) B receptor, 1 (Gabbr1); histocompatibility 2 genes: class II antigen E beta (H2-Eb1), D region locus 1 (H2-D1), and Q region locus 4 (H2-Q4); leucine rich repeat containing 6 (testis) (Lrrc6), radial spoke head 1 homolog (Rsph1), and surfactant associated 2 (Sfta2). Noteworthy genes selected as candidates for their consistent expression include: Wnt inhibitor factor 1 (Wif1), follistatin (Fst), chitinase-like 1 (Chil1), and Chil3.ConclusionsComparison of late embryonic, adolescent and adult lung transcript profiles between mouse strains with extreme TLCs lead to the identification of candidate genes for pulmonary function that has not been reported earlier. Further mechanistic investigations are warranted to elucidate their mode of action in determining lung function.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-017-0629-3) contains supplementary material, which is available to authorized users.

Pneumonia: host susceptibility and shared genetics with pulmonary function and other traits

“…SFTA2 orthologs are present in all mammals. In a mouse model, Sfta2 was strongly down‐regulated after intratracheal injections of lipopolysaccharides ; it was also found to be implicated in lung function development . SFTA2 SNPs were associated with four of six PF phenotypes under study available through the Global Biobank Engine.…”

A candidate gene identification strategy utilizing mouse to human big-data mining: “3R-tenet” in COPD genetic research

“…This is mainly because complex traits are multi-gene controlled that do not follow Mendelian pattern of inheritance. Pulmonary function and COPD are classic examples of such phenomenon [ 4 – 18 ]. Yet we believe, transgenic models may continue to serve as important resources for studying gene-function relationships particularly in the field of respiratory research.…”

“…We previously identified mouse strains (C3H/HeJ and JF1/MsJ) with extreme total lung capacities [ 5 , 21 , 22 ]. Recently, we performed a large-scale microarray study (GSE80078) to compare the lung transcript expression profiles of C3H/HeJ and JF1/MsJ mice at the completion of: (I) embryonic lung development; (II) bulk alveolar formation and (III) lung growth and maturity [ 18 ]. The generated microarray data provides a publicly available resource for performing genetic association studies as well as functional and mechanistic investigations to understand pulmonary function development and chronic lung disease (eg.…”

“…The generated microarray data provides a publicly available resource for performing genetic association studies as well as functional and mechanistic investigations to understand pulmonary function development and chronic lung disease (eg. COPD) susceptibility [ 18 ]. Lung developmental pathways are recollected in genetic subroutines during repair and remodeling processes following lung injury.…”

“…A study by Lange et al [ 26 ] showed that forced expiratory volume in 1 s (FEV 1 ) in early adulthood is important for the genesis of COPD and that accelerated decline in FEV 1 is not an obligate feature of COPD. Therefore, in this work, we performed an in-silico study, testing the association of functional variations within human orthologs of mouse lung function candidate genes [ 18 ] in a publicly available RNAseq dataset of a COPD cohort [ 27 ].…”