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 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 () and Ka-Fai To ()
Additional contact information
Lei Xiong: The Chinese University of Hong Kong
Feng Wu: The Chinese University of Hong Kong
Qiong Wu: The Chinese University of Hong Kong
Liangliang Xu: The Chinese University of Hong Kong
Otto K. Cheung: The Chinese University of Hong Kong
Wei Kang: The Chinese University of Hong Kong
Myth T. Mok: The Chinese University of Hong Kong
Lemuel L. M. Szeto: The Chinese University of Hong Kong
Cheuk-Yin Lun: The Chinese University of Hong Kong
Raymond W. Lung: The Chinese University of Hong Kong
Jinglin Zhang: The Chinese University of Hong Kong
Ken H. Yu: The Chinese University of Hong Kong
Sau-Dan Lee: The Chinese University of Hong Kong
Guangcun Huang: The University of Texas Health Science Center at San Antonio
Chiou-Miin Wang: The University of Texas Health Science Center at San Antonio
Joseph Liu: The University of Texas Health Science Center at San Antonio
Zhuo Yu: Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine
Dae-Yeul Yu: Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology
Jian-Liang Chou: National Chung Cheng University
Wan-Hong Huang: National Chung Cheng University
Bo Feng: The Chinese University of Hong Kong
Yue-Sun Cheung: The Chinese University of Hong Kong
Paul B. Lai: The Chinese University of Hong Kong
Patrick Tan: Duke-NUS Medical School
Nathalie Wong: The Chinese University of Hong Kong
Michael W. Chan: National Chung Cheng University
Tim H. Huang: The University of Texas Health Science Center at San Antonio
Kevin Y. Yip: The Chinese University of Hong Kong
Alfred S. Cheng: The Chinese University of Hong Kong
Ka-Fai To: The Chinese University of Hong Kong

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-018-08245-z

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