Characterization of DNA methylation changes associated with lung and right ventricle dysfunction in pulmonary hypertension

Pulmonary arterial hypertension (PAH) is a lethal vasculopathy associated with pulmonary arteries remodeling and right ventricle (RV) dysfunction. Epigenetic dysregulation, including altered DNA methylation, promotes PAH. However, the DNA methylation changes associated with PAH and their functional consequences on transcriptomic reprogramming remain unexplored in human PAH RV and lungs. We conducted an exploratory study in human lung and RV samples to characterize the DNA methylome and transcriptomic changes associated with PAH in both organs. Impaired DNA methylation landscape observed in PAH lungs and RV correlates with adverse pulmonary vascular remodeling, RV fibrosis, and markers of disease severity (e.g. NT-proBNP). PAH differentially methylated genes and differentially expressed transcripts regulate biological functions related to inflammation, fibrosis, heart contraction, blood vessel development. Moreover, we observed substantial lung/RV transcriptomic and methylomic changes overlap in PAH. Thus, PAH is associated with specific DNA methylation changes associated with the disease severity.