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

Respiratory Research

Research

George D. Leikauf¹  Alicia Madurga²  Dorothea Hühn³  Holger Schulz⁴  Martin Irmler⁵  Johannes Beckers⁶  Swapna Upadhyay⁷  Lars Lunding⁸  Heinz Fehrenbach⁹  Leema George^1,10  Ankita Mitra^1,10  Sangeetha Vishweswaraiah^1,10  Tania A. Thimraj^1,10  Koustav Ganguly^1,11 

[1] Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, 15219, Pittsburgh, PA, USA;Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center (UGMLC), 35392, Giessen, Germany;Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Centre Giessen and Marburg, Philipps-University Marburg, Marburg, Germany;Present address: Lahn-Dill-Kliniken, Klinikum Wetzlar, Medizinische Klinik II, Forsthausstraße 1, D-35578, Wetzlar, Germany;Institute of Epidemiology I, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, 85764, Neuherberg, Munich, Germany;Comprehensive Pneumology Center Munich (CPC-M), Munich, Germany;Institute of Experimental Genetics, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, 85764, Neuherberg, Munich, Germany;Institute of Experimental Genetics, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, 85764, Neuherberg, Munich, Germany;German Center for Diabetes Research (DZD), 85764, Neuherberg, Germany;Experimental Genetics, Technische Universität München, 85354, Freising, Germany;Lung and Airway Research, Institute of Environmental Medicine, Karolinska Institutet, Box 287, SE-171 77, Stockholm, Sweden;Institute of Lung Biology and Disease, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, 85764, Neuherberg, Munich, Germany;Priority Area Asthma & Allergy, Division of Asthma Exacerbation & Regulation, Research Center Borstel, Airway Research Center North (ARCN), 23845, Borstel, Germany;Priority Area Asthma & Allergy, Division of Experimental Pneumology, Research Center Borstel, Airway Research Center North (ARCN), 23845, Borstel, Germany;SRM Research Institute, SRM University, 603203, Chennai, India;SRM Research Institute, SRM University, 603203, Chennai, India;Lung and Airway Research, Institute of Environmental Medicine, Karolinska Institutet, Box 287, SE-171 77, Stockholm, Sweden;Institute of Lung Biology and Disease, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, 85764, Neuherberg, Munich, Germany;Work Environment Toxicology; Institute of Environmental Medicine, Karolinska Institutet, Box 287, SE-171 77, Stockholm, Sweden;

关键词: Transcriptomics;    Lung development;    Chronic obstructive pulmonary disease;    Asthma;    WNT Signaling;   

DOI  :  10.1186/s12931-017-0629-3

 received in 2017-04-25, accepted in 2017-07-25,  发布年份 2017

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© The Author(s). 2017