Transcriptomic analysis of lung tissue from cigarette smoke induced emphysema murine models and human COPD show shared and distinct pathways
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE87292 | GEO | 2017/09/05
SECONDARY ACCESSION(S): PRJNA344029
REPOSITORIES: GEO
Similar Datasets
Project description:BACKGROUND: The HHIP gene, encoding Hedgehog interacting protein, has been implicated in chronic obstructive pulmonary disease (COPD) by genome-wide association studies (GWAS), and our subsequent studies identified a functional upstream genetic variant that decreased HHIP transcription. However, little is known about how HHIP contributes to COPD pathogenesis. METHODS: Here, we exposed Hhip haploinsufficient mice (Hhip+/-) to cigarette smoke (CS) for 6 months to model the biological consequences caused by CS in human COPD risk-allele carriers at the HHIP locus. Gene expression profiling in murine lungs was performed followed by an integrative network inference analysis, PANDA (Passing Attributes between Networks for Data Assimilation) analysis. RESULTS: We detected more severe airspace enlargement in Hhip+/- mice vs. wild-type littermates (Hhip+/+) exposed to CS. Gene expression profiling in murine lungs suggested enhanced lymphocyte activation pathways in CS-exposed Hhip+/- vs. Hhip+/+ mice, which was supported by increased numbers of lymphoid aggregates and enhanced activation of CD8+ T cells after CS-exposure in the lungs of Hhip+/- mice compared to Hhip+/+ mice. Mechanistically, results from PANDA network analysis suggested a rewired and dampened Klf4 signaling network in Hhip+/- mice after CS exposure. CONCLUSIONS: In summary, HHIP haploinsufficiency exaggerated CS-induced airspace enlargement, which models CS-induced emphysema in human smokers carrying COPD risk alleles at the HHIP locus. Network modeling suggested rewired lymphocyte activation signaling circuits in the HHIP haploinsufficiency state. Total RNA was obtained from the lung tissue of C57BL/6J mice exposed to cigarette smoke (CS) or filtered air (air) for 6 months. Six mice from each of four groups with different genotypes (Hhip+/+ or Hhip+/-) and treatments (air or CS) were randomly chosen for gene expression profiling
2015-01-21 | E-GEOD-65124 | biostudies-arrayexpress
Project description:BACKGROUND: The HHIP gene, encoding Hedgehog interacting protein, has been implicated in chronic obstructive pulmonary disease (COPD) by genome-wide association studies (GWAS), and our subsequent studies identified a functional upstream genetic variant that decreased HHIP transcription. However, little is known about how HHIP contributes to COPD pathogenesis. METHODS: Here, we exposed Hhip haploinsufficient mice (Hhip+/-) to cigarette smoke (CS) for 6 months to model the biological consequences caused by CS in human COPD risk-allele carriers at the HHIP locus. Gene expression profiling in murine lungs was performed followed by an integrative network inference analysis, PANDA (Passing Attributes between Networks for Data Assimilation) analysis. RESULTS: We detected more severe airspace enlargement in Hhip+/- mice vs. wild-type littermates (Hhip+/+) exposed to CS. Gene expression profiling in murine lungs suggested enhanced lymphocyte activation pathways in CS-exposed Hhip+/- vs. Hhip+/+ mice, which was supported by increased numbers of lymphoid aggregates and enhanced activation of CD8+ T cells after CS-exposure in the lungs of Hhip+/- mice compared to Hhip+/+ mice. Mechanistically, results from PANDA network analysis suggested a rewired and dampened Klf4 signaling network in Hhip+/- mice after CS exposure. CONCLUSIONS: In summary, HHIP haploinsufficiency exaggerated CS-induced airspace enlargement, which models CS-induced emphysema in human smokers carrying COPD risk alleles at the HHIP locus. Network modeling suggested rewired lymphocyte activation signaling circuits in the HHIP haploinsufficiency state.
2015-01-21 | GSE65124 | GEO
Project description:Chronic obstructive pulmonary disease (COPD) is characterized by a progressive decline in lung function, caused by exposure to exogenous particles, mainly cigarette smoke (CS). COPD pathogenesis is initiated and perpetuated by an abnormal CS-induced inflammatory response of the lungs, involving both innate and adaptive immunity. Specifically, B cells organized in iBALT structures, as well as macrophages, accumulate in the lungs and contribute to CS-induced emphysema, but the mechanisms thereof remain unclear. Here, we demonstrate that B cell-deficient mice are significantly protected against CS-induced emphysema. Chronic CS exposure led to increased lung compliance, total lung capacity, and mean linear chord length in WT, but not B cell-deficient mice, associated with an increased size and number of iBALT structures. The increased accumulation of macrophages around iBALT and in emphysematous alveolar areas in CS-exposed WT mice coincided with upregulated MMP12 expression. In vitro co-culture experiments using B cells and macrophages demonstrated that B cell-derived IL-10 drives macrophage activation and MMP12 upregulation. In summary, B cell function in iBALT formation in CS-induced emphysema provides a new innovative mechanism, which could be explored as a target for therapeutic intervention in COPD patients.
2014-12-04 | GSE52509 | GEO
Project description:Chronic obstructive pulmonary disease (COPD) is characterized by a progressive decline in lung function, caused by exposure to exogenous particles, mainly cigarette smoke (CS). COPD pathogenesis is initiated and perpetuated by an abnormal CS-induced inflammatory response of the lungs, involving both innate and adaptive immunity. Specifically, B cells organized in iBALT structures, as well as macrophages, accumulate in the lungs and contribute to CS-induced emphysema, but the mechanisms thereof remain unclear. Here, we demonstrate that B cell-deficient mice are significantly protected against CS-induced emphysema. Chronic CS exposure led to increased lung compliance, total lung capacity, and mean linear chord length in WT, but not B cell-deficient mice, associated with an increased size and number of iBALT structures. The increased accumulation of macrophages around iBALT and in emphysematous alveolar areas in CS-exposed WT mice coincided with upregulated MMP12 expression. In vitro co-culture experiments using B cells and macrophages demonstrated that B cell-derived IL-10 drives macrophage activation and MMP12 upregulation. In summary, B cell function in iBALT formation in CS-induced emphysema provides a new innovative mechanism, which could be explored as a target for therapeutic intervention in COPD patients. Expression data of mice treated with cigarette smoke. Lung tissue was analysed at four and six months of age.
2014-12-04 | E-GEOD-52509 | biostudies-arrayexpress
Project description:Chronic obstructive pulmonary disease (COPD) is a complex pulmonary disorder primarily induced by cigarette smoking, and characterized by persistent airflow limitation. The mouse represents an important model for studying COPD pathologies such as lung emphysema. In this respect, a number of mechanistic studies have been performed, however the approaches were mostly focused on single gene analysis or characterization of cellular, inflammatory or histopathological changes without attempting a more comprehensive interpretation. In the present study we aimed at applying systems biology approach to identify genome-wide molecular mechanisms indicative of cigarette smoke (CS)-induced lung emphysema. The lung transcriptomes of five mouse models (C57BL/6, ApoE-/-, A/J, CD1, and Nrf2-/-), that are known to be susceptible to CS-induced emphysema development, were analyzed following prolonged (5-6 months) CS exposure. The investigation resulted in the confirmation of many existing mechanistic explanations underlying smoke-induced lung emphysema, including increased transcriptional activity of NF-?B, and increased levels of TNF-a, IFN-g, and IL-1b. More importantly, we predicted mechanisms without currently well-documented roles, including increased transcriptional activity of PU.1, STAT1, C/EBP, FOXM1, YY1 and N-cor, and increased IL-17 cytokine expression, and reduced protein expression of ITGB6 and CFTR. We also corroborated, by using targeted proteomic approaches, several predictions such as reduced expression of ITGB6 and increased expression of BRCA1, C/EBPs, PU.1, TNF-a, IL-1b or CSF2. We believe this study will provide more insights into better understanding of CS-induced molecular processes underlying emphysema development in mice that may eventually be relevant in humans.
2014-11-28 | E-MTAB-2756 | biostudies-arrayexpress
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.
2017-03-29 | GSE76925 | GEO
Project description:Fibroblast growth factor (FGF) 10 is essential for lung morphogenesis and polymorphisms in the Fgf10 region are linked with higher susceptibility towards COPD in human patients. We found that FGF10 signaling is impaired in lung septal wall compartment from COPD patients. Mice with impaired FGF10 signaling (Fgf10+/-) were more prone to develop cigarette smoke (CS)-induced emphysema and pulmonary hypertension (PH). Furthermore, FGF10 overexpression could successfully reverse cigarette smoke-induced emphysema and PH in mice.
2024-04-01 | GSE230854 | GEO
Project description:We hypothesize that gene expression in the CS-exposed lungs of this strain (A/J) of mice would be able to give clues about the molecular mechanism of emphysema development, thus contributing to this phenotype. More specifically, although imbalance in oxidants/antioxidants and proteinase/antiproteinase pathways drives the pathogenesis of COPD, the molecular mechanisms involved in the development of emphysema are poorly understood. In order to test this hypothesis at the gene expression level, we utilized microarray analysis to examine transcriptional differences between CS-exposed and Air-exposed groups of mice. Keywords: comparative expression profiling
2009-03-23 | GSE8790 | GEO
Project description:Chronic Obstructive Pulmonary Disease (COPD) is a respiratory disorder that is the result of extended exposure of the airways to noxious stimuli, principally cigarette smoke (CS). The mechanisms through which COPD evolves are not fully understood though it is believed that the disease process includes a genetic component since not all smokers develop COPD. To investigate the mechanism leading to the development of COPD/emphysema, we performed an experiment in which whole genome gene expression and several COPD-relevant biological endpoints (MMP-9, MMP activity, TIMP-1 and lung weight) were measured in lung tissue after exposure to two doses of CS for various periods of time. A novel and powerful method, known as reverse engineering and forward simulation (REFS(TM)), was employed to identify key molecular drivers by integrating gene expression data and 4 measured COPD-relevant endpoints. An ensemble of molecular networks was generated using REFS(TM). Simulations showed that this ensemble could successfully recover the measured experimental data for gene expression and measured COPD-relevant endpoints. This ensemble of networks was then further employed to simulate thousands of in silico gene knockdown experiments. Based on the in silico gene knockdown, thirty-three molecular key drivers for the above four COPD-relevant endpoints were identified, with the majority of them being enriched in inflammation, emphysema and COPD.
2014-05-14 | E-MTAB-1426 | biostudies-arrayexpress
Project description:Background: The identification of causal variants responsible for disease associations from genome-wide association studies (GWAS) facilitates functional understanding of the disease mechanisms implicated by GWAS. One of the earliest GWAS associations to COPD spans an intragenic region within FAM13A, but the causal variants at this loci have not yet been identified. Massively parallel reporter assays (MPRA) can be used to prioritize functional regulatory variants in a high-throughput manner. Methods: We used an integrated approach using fine-mapping in over 10,000 subjects from COPD GWAS studies, two MPRA experiments, traditional reporter assays, chromatin conformation capture, and CRISPR-based gene editing to characterize COPD-associated regulatory variants in FAM13A in human bronchial epithelial cell lines. Results: Conditional genetic association and fine mapping analyses identified two independent COPD association signals in FAM13A. MPRA identified 45 common functional regulatory variants, and six COPD-associated putative functional variants were prioritized for further functional investigation. Three variants demonstrated significant activity in traditional reporter assays, and one variant, rs2013701, was selected for further testing in the endogenous genomic context based on a direction of effect consistent with postulated mechanisms of FAM13A-mediated COPD susceptibility. CRISPR-based genome editing for this variant confirmed allele-specific effects on FAM13A expression and altered rates of cellular proliferation, providing multiple levels of functional characterization for this COPD-associated variant. Conclusions: Comprehensive screening for regulatory variants near FAM13A identified the presence of extensive functional regulatory variation within a 250kb window of FAM13A in HBECs. Focused functional evaluation of the COPD-associated functional variants in LD with the two independent association signals in this region prioritized the common variant rs2013701, for which multiple parallel lines of functional evidence confirm allelic effects on FAM13A regulation.
2019-01-19 | GSE109452 | GEO