Epigenetic dysregulation of IRF9 drives excessive interferon signaling in COPD.

Altered respiratory barrier integrity and impaired lung regeneration are hallmarks of chronic obstructive pulmonary disease (COPD). To investigate the molecular mechanisms driving the impaired regeneration of alveolar epithelial progenitors in COPD, we generated whole-genome DNA methylation and transcriptome maps of sorted human primary alveolar type 2 cells (AT2) at different disease stages. Our analysis revealed aberrant DNA methylation at specific gene promoters in AT2 during COPD, which was anticorrelated with gene expression changes. Interferon signaling was the top-upregulated pathway in COPD, associated with a concomitant loss of promoter-proximal DNA methylation. Integrated pathway analysis revealed transcription factor IRF9 as the master regulator of interferon signaling in COPD. Epigenetic regulation of the interferon pathway was validated by targeted DNA demethylation of the IRF9 gene, mimicking the effects observed in COPD-derived AT2. Our findings suggest that COPD-associated DNA methylation alterations in AT2 cells may impair internal regeneration programs in lung parenchyma.