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Cell-specific expression of lung disease risk-related genes in the human small airway epithelium.

ABSTRACT: BACKGROUND:The human small airway epithelium (SAE) plays a central role in the early events in the pathogenesis of most inherited and acquired lung disorders. Little is known about the molecular phenotypes of the specific cell populations comprising the SAE in humans, and the contribution of SAE specific cell populations to the risk for lung diseases. METHODS:Drop-seq single-cell RNA-sequencing was used to characterize the transcriptome of single cells from human SAE of nonsmokers and smokers by bronchoscopic brushing. RESULTS:Eleven distinct cell populations were identified, including major and rare epithelial cells, and immune/inflammatory cells. There was cell type-specific expression of genes relevant to the risk of the inherited pulmonary disorders, genes associated with risk of chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis and (non-mutated) driver genes for lung cancers. Cigarette smoking significantly altered the cell type-specific transcriptomes and disease risk-related genes. CONCLUSIONS:This data provides new insights into the possible contribution of specific lung cells to the pathogenesis of lung disorders.

SUBMITTER: Zuo WL

PROVIDER: S-EPMC7389881 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Cell-specific expression of lung disease risk-related genes in the human small airway epithelium.

Zuo Wu-Lin WL Rostami Mahboubeh R MR Shenoy Shushila A SA LeBlanc Michelle G MG Salit Jacqueline J Strulovici-Barel Yael Y O'Beirne Sarah L SL Kaner Robert J RJ Leopold Philip L PL Mezey Jason G JG Schymeinsky Juergen J Quast Karsten K Visvanathan Sudha S Fine Jay S JS Thomas Matthew J MJ Crystal Ronald G RG

Respiratory research 20200729 1

<h4>Background</h4>The human small airway epithelium (SAE) plays a central role in the early events in the pathogenesis of most inherited and acquired lung disorders. Little is known about the molecular phenotypes of the specific cell populations comprising the SAE in humans, and the contribution of SAE specific cell populations to the risk for lung diseases.<h4>Methods</h4>Drop-seq single-cell RNA-sequencing was used to characterize the transcriptome of single cells from human SAE of nonsmokers ...[more]

PMID: 32727470

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Project description:Cystatin A (gene: CSTA), is up-regulated in non-small-cell lung cancer (NSCLC) and dysplastic vs normal human bronchial epithelium. In the context that chronic obstructive pulmonary disease (COPD), a small airway epithelium (SAE) disorder, is independently associated with NSCLC (especially squamous cell carcinoma, SCC), but only occurs in a subset of smokers, we hypothesized that genetic variation, smoking and COPD modulate CSTA gene expression levels in SAE, with further up-regulation in SCC. Gene expression was assessed by microarray in SAE of 178 individuals [healthy nonsmokers (n=60), healthy smokers (n=82), and COPD smokers (n=36)], with corresponding large airway epithelium (LAE) data in a subset (n=52). Blood DNA was genotyped by SNP microarray. Twelve SNPs upstream of the CSTA gene were all significantly associated with CSTA SAE gene expression (p<0.04 to 5 x 10-4). CSTA gene expression levels in SAE were higher in COPD smokers (28.4 ± 2.0) than healthy smokers (19.9 ± 1.4, p<10-3), who in turn had higher levels than nonsmokers (16.1 ± 1.1, p<0.04). CSTA LAE gene expression was also smoking-responsive (p<10-3). Using comparable publicly available NSCLC expression data, CSTA was up-regulated in SCC vs LAE (p<10-2) and down-regulated in adenocarcinoma vs SAE (p<10-7). All phenotypes were associated with significantly different proportional gene expression of CSTA to cathepsins. The data demonstrate that regulation of CSTA expression in human airway epithelium is influenced by genetic variability, smoking, and COPD, and is further up-regulated in SCC, all of which should be taken into account when considering the role of CSTA in NSCLC pathogenesis. CSTA gene expression was assessed in the small airway epithelium obtained by bronchoscopy from 178 individuals, including healthy nonsmokers (n= 60) and healthy smokers (n= 118) and the large airway epithelium from healthy nonsmokers (n=21) and healthy smokers(n=31). *** Processed data not provided for all gene expression records. *** Blood DNA from the majority of these individuals was genotyped and an association analysis of gene expression with genotypes of all 48 SNPs within 100 kb of CSTA was performed in PLINK, and tested for significance following 103 permutations within ancestral clusters. Supplementary file (linked below) reports genotypes of all 48 SNPs within 100 kb of the CSTA gene for the 112 genotyping Samples.

Dataset Information

Cell-specific expression of lung disease risk-related genes in the human small airway epithelium.

Publications

Cell-specific expression of lung disease risk-related genes in the human small airway epithelium.

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