The derepression of transposable elements in lung cells is associated with the inflammatory response and gene activation in idiopathic pulmonary fibrosis.
Academic Article
Overview
abstract
BACKGROUND: Transposable elements (TEs) are repetitive sequences of viral origin that compose almost half of the human genome. These elements are tightly controlled within cells, and if activated, they can cause changes in both gene regulation and immune viral responses that have been associated with several chronic inflammatory diseases in humans. As oxidants are potent activators of TEs, and because oxidative injury is a major risk factor in relation to idiopathic pulmonary fibrosis (IPF), we hypothesized that TEs might be involved in the regulation of gene expression and so contribute to inflammation in cases of IPF. IPF is a fatal lung disease that involves the gradual replacement of the alveolar tissue with fibrotic scars as well as the accumulation of inflammatory cells in the lower respiratory tract. Although IPF is known to occur as a result of the complex interaction between age, environmental risk factors (i.e., oxidative stress) and genetics, the relative contributions of these factors to the disease remain unclear. To determine whether TEs are associated with IPF, we compared the transcriptional profiles of the genes and TEs of lung cells obtained from both healthy donors and IPF patients. RESULTS: We quantified TE and gene expression levels using a published bulk RNA-seq dataset containing 24 subjects (16 donors and eight IPF patients), including three lung-cell types per subject, as well as an scRNA-seq dataset concerning 16 subjects (eight donors and eight IPF patients). We found evidence of TE dysregulation in the alveolar type II lung cells and alveolar macrophages of the IPF patients. In addition, the activation of the LINE1 family of elements in IPF is associated with the increased expression of TE cellular regulators (MOV10, IFI16, SAMHD1, and APOBECG3), interferon-stimulating genes (ISG15, IFI6, IFI27, IFI44, and OAS1), chemokines (CX3CL1 and CXCL9), and interleukins (IL15RA). We also propose that TE derepression might be involved in the regulation of previously reported IPF candidate genes (MUC5B, CHL1, SPP1, and MMP7). CONCLUSION: Based on our findings, we propose that TE derepression plays an important role in the regulation of gene expression and can also prompt both the recruitment of inflammatory processes and the disruption of the immunological balance, which can lead to chronic inflammation in IPF.
