LSC Abstract – Epigenome-wide mapping of histone modification landscape in human pulmonary arterial hypertension

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Genome-wide alteration in the epigenetic regulatory network that facilitates normal cells to acquire pro-proliferative, pro-inflammatory phenotype remains unexplored in pulmonary arterial hypertension (PAH). Our objective is to employ next generation sequencing (NGS) approaches to identify disease-specific epigenetic signatures in idiopathic PAH (IPAH). Comprehensive analysis of gene/protein expression (donor/IPAH: pulmonary artery adventitial fibroblasts (PAAF, n=4); pulmonary arteries(n=8)) confirmed upregulation of histone deacetylases HDAC1, HDAC2 and acetyltransferases P300, PCAF, GCN5 in IPAH. Cell-specific transcriptome profiling using RNA sequencing (RNA-seq) revealed differential expression of 2572 genes (2-fold) in IPAH-PAAF, which are enriched for oxygen sensing, development, cytokine, MAPK, TGF-β and cancer (KEGG). Chromatin immunoprecipitation coupled with NGS (ChIP-seq) was employed to determine genome-wide differential distribution of RNA polymerase-II, HDAC1, HDAC2, P300, PCAF and histone modifications associated with, active promoters(H3K9/K14Ac, H3K4me3, acetyl-H4), heterochromatin(H3K27me3, H3K9me3), enhancer elements(H3K27ac, H3K4me1). Combinatorial analysis of chromatin-state maps and transcriptome profiles revealed substantial association of epigenetic signature with differentially expressed genes (e.g.,IL-6). Integrative analysis of vascular cell-specific, high-throughput epigenomics data provides insights into the mechanistic link between the recruitment of histone modifiers and regulatory network of histone modifications that co-operatively regulate aberrant transcriptional responses in PAH, and may open new avenues for targeted therapeutic intervention. This abstract has been presented previously at the European Respiratory Society9s Lung Science Conference in March 2016.

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