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Identification of novel target genes in human lung tissue involved in chronic obstructive pulmonary disease.

ABSTRACT: Introduction:As part of a study aimed at illuminating at least some of the complex molecular events taking place in COPD, we screened tissues by means of transcriptome analyses. Materials and methods:Tissues were subjected to transcriptome analysis. Candidate genes were identified and validated by immunohistochemistry. Primary human lung cells were subjected to stimulation with cigarette smoke extract for further validation by real time PCR. Results:Six candidate genes were selected for further investigations: Aquaporin 3 (AQP3), extracellular matrix protein 1 (ECM1), four and a half LIM domain 1 (FHL1), milk fat globule epidermal growth factor 8 (MFGE8, lactadherin), phosphodiesterase 4D-interacting protein (PDE4DIP), and creatine transporter SLC6A8. All six proteins were allocated to distinct cell types by immunohistochemistry. Upon stimulation with cigarette smoke extract, human type II pneumocytes showed a dose-dependent down-regulation of MFGE8, while ECM1 and FHL1 also tended to be down-regulated. Although present, none of the candidates was regulated by cigarette smoke extract in primary human macrophages. Discussion:MFGE8 turned out to be an interesting new candidate gene in COPD deserving further studies.

SUBMITTER: Heinbockel L

PROVIDER: S-EPMC6065552 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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Identification of novel target genes in human lung tissue involved in chronic obstructive pulmonary disease.

Heinbockel Lena L Marwitz Sebastian S Schromm Andra B AB Watz Henrik H Kugler Christian C Ammerpohl Ole O Schnepf Karoline K Rabe Klaus F KF Droemann Daniel D Goldmann Torsten T

International journal of chronic obstructive pulmonary disease 20180726

<h4>Introduction</h4>As part of a study aimed at illuminating at least some of the complex molecular events taking place in COPD, we screened tissues by means of transcriptome analyses.<h4>Materials and methods</h4>Tissues were subjected to transcriptome analysis. Candidate genes were identified and validated by immunohistochemistry. Primary human lung cells were subjected to stimulation with cigarette smoke extract for further validation by real time PCR.<h4>Results</h4>Six candidate genes were ...[more]

PMID: 30100715

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Project description:Multiple gene expression studies have been performed in lung or airway tissues from subjects with chronic obstructive pulmonary disease (COPD). However, in comparison to genome-wide association studies (GWAS), there has been poor replication across these studies. We sought to perform gene expression profiling on a large sample of severe COPD cases and control smokers and use network methods to identify interacting genes and pathways. We collected surgically-resected lung tissue samples from subjects with severe COPD and controls with normal lung function; all subjects were former smokers. Gene expression profiling on homogenized lung tissue was performed using Illumina HumanHT-12 BeadChips. Protein and RNA binding studies, RNA-interference, a murine smoking model, and expression quantitative trait locus analyses were used to identify genes and proteins that may interact with three known COPD GWAS genes: IREB2, HHIP and FAM13A. Weighted Gene Co-Expression Network Analysis (WGCNA) was used to define co-expressed gene modules. Comparing 111 COPD cases and 40 control smokers, 214 genes were differentially expressed; none of these genes were at significant GWAS loci. However, the top differentially expressed gene was HMGB1, which interacts with AGER, a gene implicated through COPD GWAS. The genes differentially expressed in lung tissue showed strong enrichment for putative interactors of IREB2 and HHIP, with less support for FAM13A, based on the gene sets from the in vitro, in vivo, and in silico studies. In the WGCNA, the module most highly associated for COPD was enriched for B-cell pathways, which shared seventeen genes with the results of the Hhip+/- mouse smoking model. As in other common diseases, genes at COPD GWAS loci were not differentially expressed with COPD status; however, using a combination of network methods, experimental studies of interaction and careful phenotype definition, we found differential expression of putative interactors of these genes, and we replicated previous human and mouse microarray results involving B cell pathways.

Dataset Information

Identification of novel target genes in human lung tissue involved in chronic obstructive pulmonary disease.

Publications

Identification of novel target genes in human lung tissue involved in chronic obstructive pulmonary disease.

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