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Aberrant enhancer hypomethylation contributes to hepatic carcinogenesis through global transcriptional reprogramming

Author

Listed:
  • Lei Xiong

    (The Chinese University of Hong Kong
    The Chinese University of Hong Kong)

  • Feng Wu

    (The Chinese University of Hong Kong
    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
    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
    Genome Institute of Singapore)

  • 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
    The Chinese University of Hong Kong)

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.

Suggested Citation

  • 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 Hua, 2019. "Aberrant enhancer hypomethylation contributes to hepatic carcinogenesis through global transcriptional reprogramming," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-018-08245-z
    DOI: 10.1038/s41467-018-08245-z
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