Aberrant enhancer hypomethylation contributes to hepatic carcinogenesis through global transcriptional reprogramming

Lei Xiong, Feng Wu, Qiong Wu, Liangliang Xu, Otto K. Cheung, Wei Kang, Myth T. Mok, Lemuel L.M. Szeto, Cheuk Yin Lun, Raymond W. Lung, Jinglin Zhang, Ken H. Yu, Sau Dan Lee, Guangcun Huang, Chiou Miin Wang, Joseph Liu, Zhuo Yu, Dae Yeul Yu, Jian Liang Chou, Wan Hong HuangBo Feng, Yue Sun Cheung, Paul B. Lai, Patrick Tan, Nathalie Wong, Michael W. Chan, Hui-ming Huang, Kevin Y. Yip, Alfred S. Cheng, Ka Fai To

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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.

Original languageEnglish (US)
Article number335
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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