Aberrant enhancer hypomethylation contributes to hepatic carcinogenesis through global transcriptional reprogramming
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AbstractHepatocellular 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.
Acceptance Date21/12/2018
All Author(s) ListLei 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 Huang, Bo Feng, Yue-Sun Cheung, Paul B. Lai, Patrick Tan, Nathalie Wong, Michael W. Chan, Tim H. Huang, Kevin Y. Yip, Alfred S. Cheng, Ka-Fai To
Journal nameNature Communications
Year2019
Month1
Day18
Volume Number10
Issue Number1
PublisherNature Publishing Group
Article number335
ISSN2041-1723
LanguagesEnglish-United Kingdom

Last updated on 2020-15-01 at 03:25