Combined genome-wide transcriptomic and epigenetic profiling across disease stages identifies novel regulators of COPD in human lung fibroblasts

Despite decades of intensive research, patients with COPD are still desperately waiting for curative treatments. For these to be developed, better understanding of molecular changes driving disease development is required. Based on key features and the environmental cause of COPD (cigarette smoke), we hypothesised that the disease will be triggered by altered epigenetic signalling in lung cells. Using cutting-edge, low-input whole genome bisulfite sequencing technology, we generated first unbiased DNA methylation maps of parenchymal fibroblasts isolated from lungs of smoker controls and COPD patients, both with early and established disease. We demonstrate that epigenetic landscape is severely changed in fibroblasts across COPD stages, with methylation changes occurring predominantly in regulatory regions, including promoters and enhancers. RNA-seq analysis of matched fibroblasts demonstrated dysregulation of genes involved in proliferation, DNA repair and extracellular matrix organisation. Excitingly, we identify differentially methylated regions and gene subsets dysregulated already in mild COPD patients, providing unique insight into early disease. Integration of profiling data, together with upstream regulator analysis identified 112 candidate regulators of COPD phenotypes. Using high-content phenotypic screens in primary lung fibroblasts from normal and COPD donors, we linked the function of multiple of these genes to key processes in COPD, establishing them as potential novel targets for therapy. Interestingly, many of these candidates are epigenetic factors, emphasising the critical role of epigenetic regulation in COPD.