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Chronic Obstructive Pulmonary Disease (COPD) is a complex disease. Genetic, epigenetic, and environmental factors are known to contribute to COPD risk and disease progression. Therefore we developed a systematic approach to identify key regulators of COPD that integrates genome-wide DNA methylation, gene expression, and phenotype data in lung tissue from COPD and control samples. Our integrative analysis identified 126 key regulators of COPD. We identified  EPAS1  as the only key regulator whose downstream genes significantly overlapped with multiple genes sets associated with COPD disease severity.  EPAS1  is distinct in comparison with other key regulators in terms of methylation profile and downstream target genes. Genes predicted to be regulated by  EPAS1  were enriched for biological processes including signaling, cell communications, and system development. We confirmed that EPAS1 protein levels are lower in human COPD lung tissue compared to non-disease controls and that  Epas1  gene expression is reduced in mice chronically exposed to cigarette smoke. As  EPAS1  downstream genes were significantly enriched for hypoxia responsive genes in endothelial cells, we tested  EPAS1  function in human endothelial cells.  EPAS1  knockdown by siRNA in endothelial cells impacted genes that significantly overlapped with  EPAS1  downstream genes in lung tissue including hypoxia responsive genes, and genes associated with emphysema severity. Our first integrative analysis of genome-wide DNA methylation and gene expression profiles illustrates that not only does DNA methylation play a ‘causal’ role in the molecular pathophysiology of COPD, but it can be leveraged to directly identify novel key mediators of this pathophysiology.

Integrative Analysis of DNA Methylation and Gene Expression Data Identifies EPAS1 as a Key Regulator of COPD