Epigenetic deregulation in AT2 cells impairs alveolar regeneration in COPD.

Understanding processes driving the regeneration of alveolar progenitors in the human lung is essential to define novel therapeutic strategies aimed at restoring lung function altered in COPD and other chronic lung diseases. Considering the environmental cause of COPD and disease phenotypes, including defective cell renewal and differentiation, we hypothesized that COPD will be driven by altered epigenetic signalling in lung cells. Using whole-genome bisulfite sequencing, we generated the first genome-wide DNA methylation maps at single CpG resolution of FACS-isolated human alveolar type 2 cells across different disease stages. We reveal novel transcriptomic and epigenetic signatures associated with COPD, establishing a roadmap for further dissection of molecular mechanisms driving alveolar regeneration. We demonstrate that the epigenetic landscape is severely changed in COPD, with changes occurring predominantly in regulatory regions, including promoters and enhancers. We uncovered strong anti-correlation between gene expression and promoter methylation in key COPD-relevant pathways, indicating that epigenetic changes may drive inefficient alveolar repair in COPD. Using DNA methylation inhibitors and state-of-the-art CRISPR-based epigenetic editing, we validated the link between methylation loss and activation of key pathways regulating alveolar stem cell renewal. Our data demonstrate that epigenetic regulation in COPD is an exciting research field that should be explored in-depth, as it can provide important insights into COPD-driving cell populations and associated mechanisms.