Abstract
BACKGROUND: Transposable elements (TE) are mobile sequences in the human genome that change location, have variable expression and function as cis-regulating elements that modify the expression of the transcriptome. Based on the knowledge that the small airway epithelium (SAE) is the first site of early pathology caused by cigarette smoking, we hypothesized that smoking alters the expression of TE in the SAE and some smoker dysregulated SAE TE are associated with dysregulation of the SAE transcriptome. METHODS: RNA-Seq of cigarette smokers (n = 20) and nonsmokers (n = 26) and single cell RNA-seq (scRNA-seq) analysis of n = 3 smokers and nonsmokers all with normal lung function, was performed to quantify expression of TE. RESULTS: Compared to nonsmokers, cigarette smokers had 111 downregulated and 191 upregulated differentially expressed TE in the SAE. scRNA-seq showed that intermediate and differentiated club, mucus and ciliated cells had the highest number of dysregulated TE in smokers. Among the smoking-upregulated gene-TE pairs, genes involved in epithelial differentiation (EGF, MUCL1, MEP1A), immune responses and inflammation (IRGM, LUCAT1, LINCO1258), and tumorigenesis (AKR1B15). Conversely, smoking-downregulated gene-TE pairs included genes important for maintaining epithelial differentiation (DAPK1, CD81-AS1) and regulating immune functions (BTNL8, LTF, CFH, C4BPA, CCL17). Smoking-induced dysregulation of TE in the SAE of cigarette smokers in intermediate and differentiated cells was associated with dysregulation of genes in the SAE transcriptome. CONCLUSIONS: Understanding the impact of smoking on TE-mediated gene regulation may lead to the identification of new therapeutic targets for smoking-related lung diseases. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12931-026-03605-6.