Nat Commun. 2019 Jan 18;10(1):335. doi: 10.1038/s41467-018-08245-z.
Aberrant enhancer hypomethylation contributes to hepatic carcinogenesis through global transcriptional reprogramming.
Xiong L1,2, Wu F1,2, Wu Q2, Xu L2, Cheung OK2, Kang W1, Mok MT2, Szeto LLM2, Lun CY2, Lung RW1, Zhang J1, Yu KH1,3, Lee SD3, Huang G4, Wang CM4, Liu J4, Yu Z5, Yu DY6, Chou JL7, Huang WH7, Feng B2, Cheung YS8, Lai PB8, Tan P9,10, Wong N1, Chan MW7, Huang TH4, Yip KY11, Cheng AS12, To KF13,14.
Author information
1
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
2
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
3
Department of Computer Science and Engineering, The Chinese University of Hong Kong, Hong Kong SAR, China.
4
Department of Molecular Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USA.
5
Department of Liver Disease, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
6
Disease Model Research Laboratory, Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Republic of Korea.
7
Department of Biomedical Sciences, National Chung Cheng University, Chia-Yi 62102, Taiwan, Republic of China.
8
Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, China.
9
Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore 169857, Singapore.
10
Genome Institute of Singapore, Singapore 138672, Singapore.
11
Department of Computer Science and Engineering, The Chinese University of Hong Kong, Hong Kong SAR, China. [email protected].
12
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China. [email protected].
13
Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China. [email protected].
14
State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong SAR, China. [email protected].
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.