Pluto Bioinformatics

GSE123098: Aberrant enhancer reprogramming drives hepatic carcinogenesis through global transcriptional reprogramming [RNA-seq]

Bulk RNA sequencing

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/EBP) which correlates with C/EBP over-expression and poorer prognosis of patients. Demethylation of C/EBP 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/EBP expression and its genome-wide co-occupancy with BRD4 at H3K27ac-marked enhancers and super-enhancers, leading to drastic suppression of driver oncogenes and abrogation of HCC tumorigenicity. Hepatitis B X protein transgenic mouse model of HCC recapitulates this paradigm, as C/ebp enhancer hypomethylation associates with oncogenic activation in early tumorigenesis. These results support a causal link between aberrant enhancer hypomethylation and C/EBP over-expression, thereby driving hepatocarcinogenesis through global transcriptional reprogramming. SOURCE: Alfred Sze-Lok Cheng (alfredcheng@cuhk.edu.hk) - The Chinese University of Hong Kong