Epigenomic and transcriptomic analyses of epithelial ovarian cancer

Profiling of active chromatin and gene expression in primary ovarian cancer specimens Overall design: To catalogue the landscape of active chromatin in primary tissues representing the major histological subtypes of OC, we performed ChIP-seq for acetylated lysine 27 of histone H3 protein (H3K27ac), a mark of active promoters and enhancers, on 20 primary tissue specimens, specifically 5 CCOCs, 5 EnOCs, 5 HGSOCs, and 5 MOCs. We observed inter-histotype heterogeneity among the 20 epigenomic landscapes (union set = 295,349 peaks, encompassing 11.6% of the genome). As expected, the common peaks (n = 12,954) shared across all histologies were enriched in promoter regions when compared to the whole genome (odds ratio = 86, P < 0.001, Fisher's exact test); in contrast, the histotype-specific regions defining CCOC (n = 5,401), EnOC (n = 20), HGSOC (n = 6,583) and MOC (n = 2,134) fall predominantly in enhancers. Using a matched RNA-sequence (RNA-Seq) dataset for 19 (out of 20) tumor specimens, we identified 1,214 differentially expressed genes (DEGs) specific for CCOC, just 16 DEGs for EnOC, 519 DEGs for HGSOC and 371 DEGs for MOC. Both analyses, H3K27ac ChIP-Seq and RNA-Seq, suggest a lack of specificity for EnOCs. Genes flanking histotype-specific peaks of active chromatin were consistently expressed at higher levels in the relevant histotype; conversely, genes flanking depleted regions were under-expressed in a histotype-specific manner, indicating that the different enhancer landscapes of OC histotypes regulate histotype-specific patterns of gene expression in cis.