Genome-wide chromatin loop landscape in HCC

We investigated the genomic enhancer landscape of Hepatocellular Carcinoma (HCC) using H3K27ac ChIP-seq and HiC/HiChIP data from resected tumour samples of 30 patients, whose genome, transcriptome, and clinical trajectory data were available. Differential enhancer analysis revealed dysregulated enhancer loci, but without strong enrichment of underlying DNA mutation hotspots. As many of the gain-in-tumour enhancer associated genes were fetal liver hepatoblast genes, we investigated the stochastic expression pattern of the overlapping genes (epigenetic oncofetal genes) using previously published single cell RNA-seq data, in which the patients partially overlapped. The proportion of cells expressing epigenetic oncofetal genes clustered liver tissue samples into two groups - adjacent normal liver-like, or oncofetal-like. Notably, gain-in-tumour enhancer associated genes showed prognostic value, with patient clusters revealed by co-clustering the differential gene expression pattern. Altogether, we report the genomic enhancer signature that associates with differential prognosis in HCC. Findings that cohere with oncofetal reprogramming in HCC is underpinned by genome-wide enhancer rewiring. Our results present the epigenetic changes in HCC that offer the rational selection of epigenetic-driven gene targets for therapeutic intervention or disease prognostication in HCC. Overall design: HiC and H3K27ac HiChIP data of 2 adjacent normal and 8 tumour samples obtained from resected HCC tissues. 7 HiC libraries and 3 H3K27ac HiChIP libraries are included