IDDF2018-ABS-0153 Super-enhancer-associated master transcriptional circuitry in nafld-hcc development

Abstract

Background Hepatocellular carcinoma (HCC) has become a prominent global health threat due to its occurrence, lethality and dismal survival rates. Increasing prevalence of obesity and diabetes-induced non-alcoholic fatty liver disease (NAFLD) and metabolic syndromes have been found culpable for the rise of HCC initiation, via disruption of liver microenvironment. Super enhancers, which are characterised by high density of transcription binding sites, high-level transcription regulation and response to external stimulation, determine cell fate during oncogenesis. Master transcription factors translate microenvironmental changes into super enhancer remodelling and activation, which subsequently changes the gene expression profile and define cell identity. This project aims at profiling the super enhancer status in the context of NAFLD-associated HCC and to unveil the master transcription factors responsible for diet-induced HCC progression. Methods Nanoscale chromatin immunoprecipitation sequencing (nano ChIP-seq) against histone marks H3K27ac, H3K4me1 and H3K4me3 in 6 pairs of primary human NAFLD-HCC tumours and their adjacent non-tumour tissues revealed potential oncogenic super enhancers. Global mRNA expression was detected by RNA sequencing (RNA-seq) to support the enhancer-target gene transcription axis. Master transcription factor regulation of NAFLD-HCC super-enhancers was further supported by integrated bioinformatics analysis, including motif enrichment and signature transcription factor discovery. ChIP-seq data for the master transcription factors in HepG2 cells confirmed their occupancies on super enhancers controlling key oncogenic pathways. Results Tumor-enabling super enhancers (averaged 553 and 484 per HCC tumour and non-tumour tissue, respectively) were profiled in primary human NAFLD-HCC tissues, and master transcription factors showed significant binding to NAFLD-HCC oncogenic super enhancers. Interestingly, tumor-enabling super enhancers co-bound by HCC-specific master transcription factors target critical genes involved in hepatic inflammation and NAFLD pathogenesis. Conclusions Integrated analysis of chromatin profiling and transcriptome in primary human tissues provides insights into the trans-regulatory network involving oncogenic super enhancers and master transcription factors during the pathogenic process of metabolic syndrome-associated HCC. Acknowledgement This work is supported by the RGC CRF (C4017–14G).