High-resolution epigenetic profiling identifies novel regulators of COPD in human lung fibroblasts

Patients with chronic obstructive pulmonary disease (COPD) are still waiting for curative treatments. Considering environmental causes of COPD and disease phenotypes, we hypothesized that COPD will be associated with altered epigenetic signaling in lung cells. We generated genome-wide DNA methylation maps at single CpG resolution of primary human lung fibroblasts from ex-smokers and COPD patients. Epigenetic landscape is markedly changed in lung fibroblasts across COPD stages, with DNA methylation changes occurring predominantly in regulatory regions. RNA sequencing of matched fibroblasts demonstrated dysregulation of genes involved in proliferation, DNA repair and matrix organization. Notably, we identified epigenetic and transcriptional dysregulation already in mild COPD, providing unique insights into early disease. Integration of profiling data identified 110 candidate regulators of disease phenotypes. Using phenotypic screens, we linked the function of multiple candidates to repair processes in the lung. Our study provides first integrative high-resolution epigenetic and transcriptomic maps of human lung fibroblasts across COPD stages. We reveal novel signatures associated with COPD onset and progression and identify candidate regulators involved in the pathogenesis of chronic respiratory diseases.