Abstract 5372: Alterations in the chromatin accessibility in nonalcoholic steatohepatitis-associated hepatocellular carcinoma

Abstract Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Accumulated evidence in the past decade has stablished that NASH, in addition to other well-identified risk factors, is becoming a major cause of HCC in United States. In the present study, we investigated cancer-associated chromatin alterations in the Stelic Animal Model (STAM) of NASH-related HCC. Using Assay for Transposase-Accessible Chromatin with high throughput sequencing (ATAC-seq), we identified 1666 differentially opened chromatin regions in HCC tumor tissue as compared to normal livers. Annotation of these regions showed that they were associated with 1773 differentially expressed genes, which were enriched in lipid and steroid metabolism, obesity, and cancer. Among the differentially opened chromatin regions, 10% resided within 5 kb from the transcription start site (TSS), while the remaining 90% were located distal to the TSS (> 5 kb). By combining ATAC-seq and transcriptomic profiles, we demonstrated that 182 of the up-regulated genes were associated with open chromatin regions in tumor tissue. Furthermore, 24 of these up-regulated genes, including Apoa4, Nupr1, Anxa2, and Igfbp1, had accessible chromatin regions located proximal to the TSS. Importantly, analysis of histone modifications at the open chromatin regions of the over-expressed cancer-related Apoa4 and Anxa2 genes demonstrated enrichment by H3K4 mono-methylation (H3H4me1) and H3K27 acetylation (H3K27ac), histone marks that associated with the active gene promoters (H3K27ac) and enhancers (H3Kme1 and H3K27ac). In conclusion, these data provide evidence for alterations in the chromatin accessibility in tumor tissue and potential role of open chromatin regions in the over-expression of critical cancer-related genes in HCC. Citation Format: Mekonnen Lemma Dechassa. Alterations in the chromatin accessibility in nonalcoholic steatohepatitis-associated hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5372. doi:10.1158/1538-7445.AM2017-5372