Abstract 9929: Epigenome-Wide-Association-Study Characterizes DNA Methylation Changes Associated With Lung and Right Ventricle Dysfunction in Pulmonary Hypertension

Abstract

Background: Pulmonary arterial hypertension (PAH) is a lethal vasculopathy associated with pulmonary arteries remodeling and right ventricle (RV) dysfunction. Epigenetic dysregulation, including altered DNA methylation (DNAm), promotes PAH. However, the DNAm changes associated with PAH remain unexplored in human PAH RV and lungs. We conducted an exploratory study using human lung and RV samples to characterize the DNA methylome and transcriptomic changes associated with PAH. Methods/Results: We observed that PAH is associated with substantial changes in the DNAm landscape in both organs. We identified 88 identical differentially methylated probe (DMP) in both PAH Lungs and RV. Functionally, we observed that 65, and 76 of those DMP correlate with myocardial fibrosis and adverse pulmonary vascular remodeling, respectively. Then we clustered DMP onto functional differentially methylated region (DMR) and reported that 41% and 11.5% of the genes carrying a DMR are differentially expressed in PAH RV and lungs, respectively. Gene ontology analysis suggests that both impaired DNAm (DNA methylome) and genes expression (RNA sequencing) observed in PAH regulate biological functions related to inflammation, fibrosis, cell proliferation and vascular remodeling. Impaired DNAm landscape observed in PAH RV and lung is associated with the disease severity and contributes to 4.1% and 2.7% of the whole transcriptomic reprograming associated with PAH development in RV and lungs samples, respectively. Despite the modest overlap between DNAm and transcriptomic changes, we observed that DNAm affects genes and molecular pathways involved in PAH development. Conclusion: Although exploratory, our study is the first to characterize the DNAm and transcriptomic change associated with PAH in human RV and lung. Our data suggest that impaired DNAm landscape might contribute to the disease development/severity.