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; Ka Fai To

doi:10.1038/s41467-018-08245-z

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, Ka Fai To

Department of Molecular Medicine

Research output: Contribution to journal › Article › peer-review

77 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 language	English (US)
Article number	335
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-08245-z
State	Published - Dec 1 2019

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Xiong, L., Wu, F., Wu, Q., Xu, L., Cheung, O. K., Kang, W., Mok, M. T., Szeto, L. L. M., Lun, C. Y., Lung, R. W., Zhang, J., Yu, K. H., Lee, S. D., Huang, G., Wang, C. M., Liu, J., Yu, Z., Yu, D. Y., Chou, J. L., ... To, K. F. (2019). Aberrant enhancer hypomethylation contributes to hepatic carcinogenesis through global transcriptional reprogramming. Nature communications, 10(1), Article 335. https://doi.org/10.1038/s41467-018-08245-z

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, TH, 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

@article{e6ac8f8acbc14341aae9ccd922d674de,

title = "Aberrant enhancer hypomethylation contributes to hepatic carcinogenesis through global transcriptional reprogramming",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

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day = "1",

doi = "10.1038/s41467-018-08245-z",

language = "English (US)",

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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, Tim H.

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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UR - https://www.scopus.com/pages/publications/85060185000#tab=citedBy

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SN - 2041-1723

VL - 10

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 335

ER -

Aberrant enhancer hypomethylation contributes to hepatic carcinogenesis through global transcriptional reprogramming

Abstract

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