Abstract Rationale Chronic obstructive pulmonary disease (COPD), the 6th leading cause of death in the US, is a chronic inflammatory lung disorder affecting the airways and alveoli. Based on the knowledge that the small airway epithelium (SAE) is the 1st site of COPD-related early pathology caused by cigarette smoking and that transposable elements (TE) expression in the SAE of healthy nonsmokers and smokers demonstrates that smoking is associated with upregulation of several TE positioned near autosomal inflammatory genes, we hypothesized that dysregulation of TE in the transcriptome of the SAE plays a role in dysregulating inflammation related genes in the SAE in COPD. If correct, SAE TE dysregulation could be a novel target for therapy for COPD. Methods Illumina HiSeq 4000 RNAseq analysis was used to assess the TE and the expressed transcriptome of the SAE (10th to 12th order bronchi), collected by flexible bronchoscopy and brushing, of smokers (S) =11, nonsmokers (NS) =20, and COPD-smokers (COPD-S) n = 17. The bioinformatics tool Telescope was used for RNAseq TE analysis, TE expression with ≥5 counts in ≥ 3 samples was compared using DESeq2 among S vs NS and COPD vs NS. Genes with Benjamini-Hochberg adjusted p value 0.05 and fold-change ≥1.5 were considered differentially expressed. Identification of the link between differentially expressed TE and the SAE transcriptome related to inflammation was based on the location of TE in the chromosome, the directionality of regulation and fold-change in expression between COPD-S vs NS and S vs NS. Results Compared to NS, there were 374 downregulated and 493 upregulated differentially expressed TE in the SAE of S, and 73 downregulated and 294 upregulated differentially expressed TE in COPD-S SAE. Of the differentially expressed TE, a total of 187 were shared between COPD and S. Of these, 161 and 26 were found to be upregulated and downregulated, respectively in both conditions. Among overlapping TE and genes in COPD-S vs NS and S vs NS, n = 31 TE and n = 26 genes nearby were upregulated including 16 genes that play a role in lung inflammation such as ADAMTS17, ADH7, AKR1B10, AKR1C2, CYP1B1, CYP1B1-AS1, GCLC, MUCL1, ME1, MEP1A, PON3, HRH1, JAKMIP3, LUCAT1, EPHB1and FUT3. Conclusions Assessment of the role of TE in the pathogenesis of COPD offers a potential new avenue for biomarker discovery and therapeutic intervention. Understanding the impact of COPD on TE-mediated gene regulation may lead to the identification of new therapeutic targets for COPD-related lung diseases. This abstract is funded by: KL2TR002385
Rostami et al. (Fri,) studied this question.