Abstract
Hepatocellular carcinomas (HCC) exhibit distinct promoter hypermethylation patterns, but the epigenetic regulation and function of transcriptional enhancers remain unclear. Here, our affinity- and bisulfite-based whole-genome sequencing analyses reveal global enhancer hypomethylation in human HCCs. Integrative epigenomic characterization further pinpoints a recurrent hypomethylated enhancer of CCAAT/enhancer-binding protein-beta (C/EBPβ) which correlates with C/EBPβ over-expression and poorer prognosis of patients. Demethylation of C/EBPβ enhancer reactivates a self-reinforcing enhancer-target loop via direct transcriptional up-regulation of enhancer RNA. Conversely, deletion of this enhancer via CRISPR/Cas9 reduces C/EBPβ expression and its genome-wide co-occupancy with BRD4 at H3K27ac-marked enhancers and super-enhancers, leading to drastic suppression of driver oncogenes and HCC tumorigenicity. Hepatitis B X protein transgenic mouse model of HCC recapitulates this paradigm, as C/ebpβ enhancer hypomethylation associates with oncogenic activation in early tumorigenesis. These results support a causal link between aberrant enhancer hypomethylation and C/EBPβ over-expression, thereby contributing to hepatocarcinogenesis through global transcriptional reprogramming.
Highlights
Hepatocellular carcinomas (HCC) exhibit distinct promoter hypermethylation patterns, but the epigenetic regulation and function of transcriptional enhancers remain unclear
We have recently developed a new method for inferring enhancer-target interactions by integrating epigenomic and transcriptomic data from hundreds of primary cells and tissues, which enabled the identification of target genes that are controlled by differentially methylated enhancers (DMEs) in HCC cells[17]
We found a significantly negative correlation between C/EBPβ enhancer methylation and enhancer RNA (eRNA) expression (P < 0.005; Fig. 2b), while the C/EBPβ promoter methylation levels were invariably low (~10%; Supplementary Fig. 1b), similar to those observed in the primary HCC tissues
Summary
Hepatocellular carcinomas (HCC) exhibit distinct promoter hypermethylation patterns, but the epigenetic regulation and function of transcriptional enhancers remain unclear. Hepatitis B X protein transgenic mouse model of HCC recapitulates this paradigm, as C/ebpβ enhancer hypomethylation associates with oncogenic activation in early tumorigenesis These results support a causal link between aberrant enhancer hypomethylation and C/EBPβ over-expression, thereby contributing to hepatocarcinogenesis through global transcriptional reprogramming. Genome-scale DNA methylation profiles of nearly two-hundred HCC cases via an array-based platform further revealed distinct cancer-specific DNA hypermethylation clusters[9] Most of these studies, focused on altered methylation at gene promoters and CpG islands/shores. Utilizing affinity- and bisulfite-based whole-genome sequencing, here we show a genome-wide enhancer hypomethylation pattern in primary human HCCs. Our integrative epigenomic analysis highlights a recurrent hypomethylated enhancer of CCAAT/enhancer-binding protein-beta (C/EBPβ), which exhibits clinical and biological significance in promoting HCC tumorigenicity through global transcriptional reprogramming
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