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Title 

Aberrant enhancer hypomethylation contributes to hepatic carcinogenesis through global transcriptional reprogramming

Authors 

L XiongF WuQ WuL XuO K CheungW KangM T MokL L M SzetoC Y LunR W LungJ ZhangK H YuS D LeeG HuangC M WangJ LiuZ YuDae Yeul YuJ L ChouW H HuangB FengY S CheungK Y YipA S ChengK F To

Publisher 

Nature Publishing Group

Issue Date 

2019

Citation 

Nature Communications

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

URI 

https://doi.org/10.1038/s41467-018-08245-z

ISSN 

2041-1723

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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