TY - JOUR T1 - High-resolution transcriptomic and epigenetic profiling identifies novel regulators of COPD phenotypes in human lung fibroblasts JF - bioRxiv DO - 10.1101/2022.03.28.486023 SP - 2022.03.28.486023 AU - Uwe Schwartz AU - Maria Llamazares Prada AU - Stephanie T. Pohl AU - Mandy Richter AU - Raluca Tamas AU - Michael Schuler AU - Corinna Keller AU - Vedrana Mijosek AU - Thomas Muley AU - Marc A. Schneider AU - Karsten Quast AU - Joschka Hey AU - Claus P. Heußel AU - Arne Warth AU - Hauke Winter AU - Özdemirhan Serçin AU - Harry Karmouty-Quintana AU - Felix Herth AU - Ina Koch AU - Giuseppe Petrosino AU - Balca R. Mardin AU - Dieter Weichenhan AU - Tomasz P. Jurkowski AU - Charles D. Imbusch AU - Benedikt Brors AU - Vladimir Benes AU - Brigit Jung AU - David Wyatt AU - Heiko Stahl AU - Christoph Plass AU - Renata Z. Jurkowska Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/03/29/2022.03.28.486023.abstract N2 - Patients with chronic obstructive pulmonary disease (COPD) are still waiting for curative treatments. Considering the environmental cause of COPD (e.g., cigarette smoke) and disease phenotypes, including stem-cell senescence and impaired differentiation, 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 (HLFs) isolated from distal parenchyma of ex-smoker controls and COPD patients, with both mild and severe disease. The epigenetic landscape is markedly changed in lung fibroblasts across COPD stages, with DNA methylation changes occurring predominantly in regulatory regions, including promoters and enhancers. RNA sequencing of matched fibroblasts demonstrated dysregulation of genes involved in proliferation, DNA repair, and extracellular matrix organization. Notably, we identified epigenetic and transcriptional dysregulation already in mild COPD patients, providing unique insights into early disease. Integration of profiling data identified 110 candidate regulators of disease phenotypes, including epigenetic factors. Using phenotypic screens, we verified the regulator capacity of multiple candidates and linked them to repair processes in the human lung.Our study provides first integrative high-resolution epigenetic and transcriptomic maps of human lung fibroblasts across stages of COPD. We reveal novel transcriptomic and epigenetic signatures associated with COPD onset and progression and identify new candidate regulators involved in the pathogenesis of chronic respiratory diseases. The presence of various epigenetic factors among the candidates demonstrates that epigenetic regulation in COPD is an exciting research field that holds promise for novel therapeutic avenues for patients. ER -