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 & 10 others Bo 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 journalArticle

3 Citations (Scopus)

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

Fingerprint

CCAAT-Enhancer-Binding Protein-beta
Carcinogenesis
proteins
Liver
Hepatocellular Carcinoma
Epigenomics
genome
cancer
Clustered Regularly Interspaced Short Palindromic Repeats
Genes
Genome
oncogenes
hepatitis
deletion
Hepatitis B
sequencing
Oncogenes
prognosis
Transgenic Mice
Up-Regulation

ASJC Scopus subject areas

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

Cite this

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

In: Nature communications, Vol. 10, No. 1, 335, 01.12.2019.

Research output: Contribution to journalArticle

Xiong, L, Wu, F, Wu, Q, Xu, L, Cheung, OK, Kang, W, Mok, MT, Szeto, LLM, Lun, CY, Lung, RW, Zhang, J, Yu, KH, Lee, SD, Huang, G, Wang, CM, Liu, J, Yu, Z, Yu, DY, Chou, JL, Huang, WH, Feng, B, Cheung, YS, Lai, PB, Tan, P, Wong, N, Chan, MW, Huang, H, Yip, KY, Cheng, AS & To, KF 2019, 'Aberrant enhancer hypomethylation contributes to hepatic carcinogenesis through global transcriptional reprogramming', Nature communications, vol. 10, no. 1, 335. https://doi.org/10.1038/s41467-018-08245-z
Xiong, Lei ; Wu, Feng ; Wu, Qiong ; Xu, Liangliang ; Cheung, Otto K. ; Kang, Wei ; Mok, Myth T. ; Szeto, Lemuel L.M. ; Lun, Cheuk Yin ; Lung, Raymond W. ; Zhang, Jinglin ; Yu, Ken H. ; Lee, Sau Dan ; Huang, Guangcun ; Wang, Chiou Miin ; Liu, Joseph ; Yu, Zhuo ; Yu, Dae Yeul ; Chou, Jian Liang ; Huang, Wan Hong ; Feng, Bo ; Cheung, Yue Sun ; Lai, Paul B. ; Tan, Patrick ; Wong, Nathalie ; Chan, Michael W. ; Huang, Hui-ming ; Yip, Kevin Y. ; Cheng, Alfred S. ; To, Ka Fai. / Aberrant enhancer hypomethylation contributes to hepatic carcinogenesis through global transcriptional reprogramming. In: Nature communications. 2019 ; Vol. 10, No. 1.
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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.",
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AU - Xiong, Lei

AU - Wu, Feng

AU - Wu, Qiong

AU - Xu, Liangliang

AU - Cheung, Otto K.

AU - Kang, Wei

AU - Mok, Myth T.

AU - Szeto, Lemuel L.M.

AU - Lun, Cheuk Yin

AU - Lung, Raymond W.

AU - Zhang, Jinglin

AU - Yu, Ken H.

AU - Lee, Sau Dan

AU - Huang, Guangcun

AU - Wang, Chiou Miin

AU - Liu, Joseph

AU - Yu, Zhuo

AU - Yu, Dae Yeul

AU - Chou, Jian Liang

AU - Huang, Wan Hong

AU - Feng, Bo

AU - Cheung, Yue Sun

AU - Lai, Paul B.

AU - Tan, Patrick

AU - Wong, Nathalie

AU - Chan, Michael W.

AU - Huang, Hui-ming

AU - Yip, Kevin Y.

AU - Cheng, Alfred S.

AU - To, Ka Fai

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

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