Single cell RNA sequencing identifies IGFBP5 and QKI as ciliated epithelial cell genes associated with severe COPD

• Published in: Respiratory research Vol. 22; no. 1; pp. 100 - 13
• Main Authors: Li, Xiuying, Noell, Guillaume, Tabib, Tracy, Gregory, Alyssa D., Trejo Bittar, Humberto E., Vats, Ravi, Kaminski, Tomasz W., Sembrat, John, Snyder, Mark E., Chandra, Divay, Chen, Kong, Zou, Chunbin, Zhang, Yingze, Sundd, Prithu, McDyer, John F., Sciurba, Frank, Rojas, Mauricio, Lafyatis, Robert, Shapiro, Steve D., Faner, Rosa, Nyunoya, Toru
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 06.04.2021; BioMed Central; BMC
• Subjects: Adult; Aged; Air flow; Antibodies; Chronic obstructive pulmonary disease; Cigarette smoke; Clustering; Consortia; COPD; Cytotoxicity; Embedding; Emphysema; Emphysema, Pulmonary; Enrichment; Epithelial cells; Epithelial Cells - metabolism; Epithelial Cells - pathology; Epithelium; Female; Fibroblasts; Gene expression; Gene Expression Profiling - methods; Gene sequencing; Gene set enrichment analysis; Genes; Genetic aspects; Genetic research; Genomics; Health aspects; Humans; Insulin-Like Growth Factor Binding Protein 5 - biosynthesis; Insulin-Like Growth Factor Binding Protein 5 - genetics; Insulin-like growth factor-binding protein 5; Lung - metabolism; Lung - pathology; Lung diseases; Lung diseases, Obstructive; Lungs; Lymphocytes; Lymphocytes T; Macrophages; Male; Middle Aged; Monocytes; Obstructive lung disease; Ontology; Populations; Proteins; Pulmonary Disease, Chronic Obstructive - genetics; Pulmonary Disease, Chronic Obstructive - metabolism; Pulmonary Disease, Chronic Obstructive - pathology; Ribonucleic acid; Risk factors; RNA; RNA - genetics; RNA - metabolism; RNA sequencing; RNA-Binding Proteins - biosynthesis; RNA-Binding Proteins - genetics; Sequence Analysis, RNA - methods; Severity of Illness Index; Signatures; Single cell RNA-seq; Smoking; Transcription; Transcriptome - genetics; Transcriptomics; Young Adult; United States; Single cell RNA-seq; Cigarette smoke; COPD
• ISSN: 1465-993X; 1465-9921; 1465-993X
• DOI: 10.1186/s12931-021-01675-2

Whole lung tissue transcriptomic profiling studies in chronic obstructive pulmonary disease (COPD) have led to the identification of several genes associated with the severity of airflow limitation and/or the presence of emphysema, however, the cell types driving these gene expression signatures remain unidentified. To determine cell specific transcriptomic changes in severe COPD, we conducted single-cell RNA sequencing (scRNA seq) on n = 29,961 cells from the peripheral lung parenchymal tissue of nonsmoking subjects without underlying lung disease (n = 3) and patients with severe COPD (n = 3). The cell type composition and cell specific gene expression signature was assessed. Gene set enrichment analysis (GSEA) was used to identify the specific cell types contributing to the previously reported transcriptomic signatures. T-distributed stochastic neighbor embedding and clustering of scRNA seq data revealed a total of 17 distinct populations. Among them, the populations with more differentially expressed genes in cases vs. controls (log fold change >|0.4| and FDR = 0.05) were: monocytes (n = 1499); macrophages (n = 868) and ciliated epithelial cells (n = 590), respectively. Using GSEA, we found that only ciliated and cytotoxic T cells manifested a trend towards enrichment of the previously reported 127 regional emphysema gene signatures (normalized enrichment score [NES] = 1.28 and = 1.33, FDR = 0.085 and = 0.092 respectively). Among the significantly altered genes present in ciliated epithelial cells of the COPD lungs, QKI and IGFBP5 protein levels were also found to be altered in the COPD lungs. scRNA seq is useful for identifying transcriptional changes and possibly individual protein levels that may contribute to the development of emphysema in a cell-type specific manner.