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An enhancer variant at 16q22.1 predisposes to hepatocellular carcinoma via regulating PRMT7 expression

Author

Listed:
  • Ting Shen

    (Nanfang Hospital, Southern Medical University
    Central South University)

  • Ting Ni

    (Fudan University)

  • Jiaxuan Chen

    (Nanfang Hospital, Southern Medical University)

  • Haitao Chen

    (Nanfang Hospital, Southern Medical University
    Sun Yat-sen University)

  • Xiaopin Ma

    (Fudan University)

  • Guangwen Cao

    (Naval Medical University)

  • Tianzhi Wu

    (Southern Medical University)

  • Haisheng Xie

    (Nanfang Hospital, Southern Medical University)

  • Bin Zhou

    (Nanfang Hospital, Southern Medical University)

  • Gang Wei

    (Fudan University)

  • Hexige Saiyin

    (Fudan University)

  • Suqin Shen

    (Fudan University)

  • Peng Yu

    (Fudan University)

  • Qianyi Xiao

    (Fudan University)

  • Hui Liu

    (Guangzhou Medical University)

  • Yuzheng Gao

    (Medical College of Soochow University)

  • Xidai Long

    (Youjiang Medical College for Nationalities)

  • Jianhua Yin

    (Naval Medical University)

  • Yanfang Guo

    (Southern Medical University)

  • Jiaxue Wu

    (Fudan University)

  • Gong-Hong Wei

    (University of Oulu
    Fudan University)

  • Jinlin Hou

    (Nanfang Hospital, Southern Medical University)

  • De-Ke Jiang

    (Nanfang Hospital, Southern Medical University)

Abstract

Most cancer causal variants are found in gene regulatory elements, e.g., enhancers. However, enhancer variants predisposing to hepatocellular carcinoma (HCC) remain unreported. Here we conduct a genome-wide survey of HCC-susceptible enhancer variants through a three-stage association study in 11,958 individuals and identify rs73613962 (T > G) within the intronic region of PRMT7 at 16q22.1 as a susceptibility locus of HCC (OR = 1.41, P = 6.02 × 10−10). An enhancer dual-luciferase assay indicates that the rs73613962-harboring region has allele-specific enhancer activity. CRISPR-Cas9/dCas9 experiments further support the enhancer activity of this region to regulate PRMT7 expression. Mechanistically, transcription factor HNF4A binds to this enhancer region, with preference to the risk allele G, to promote PRMT7 expression. PRMT7 upregulation contributes to in vitro, in vivo, and clinical HCC-associated phenotypes, possibly by affecting the p53 signaling pathway. This concept of HCC pathogenesis may open a promising window for HCC prevention/treatment.

Suggested Citation

  • Ting Shen & Ting Ni & Jiaxuan Chen & Haitao Chen & Xiaopin Ma & Guangwen Cao & Tianzhi Wu & Haisheng Xie & Bin Zhou & Gang Wei & Hexige Saiyin & Suqin Shen & Peng Yu & Qianyi Xiao & Hui Liu & Yuzheng , 2022. "An enhancer variant at 16q22.1 predisposes to hepatocellular carcinoma via regulating PRMT7 expression," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28861-0
    DOI: 10.1038/s41467-022-28861-0
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