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

作者：Shen, Ting; Ni, Ting; Chen, Jiaxuan; Chen, Haitao; Ma, Xiaopin; Cao, Guangwen; Wu, Tianzhi; Xie, Haisheng; Zhou, Bin; Wei, Gang; Saiyin, Hexige; Shen, Suqin; Yu, Peng; Xiao, Qianyi; Liu, Hui; Gao, Yuzheng; Long, Xidai; Yin, Jianhua; Guo, Yanfang; Wu, Jiaxue; Wei, Gong-Hong; Hou, Jinlin; Jiang, De-Ke^*

来源：Nature Communications, 2022, 13(1): 1232.

DOI：10.1038/s41467-022-28861-0

• METHYLTRANSFERASE 7 PRMT7
• GENOME-WIDE ASSOCIATION
• ARGININE METHYLTRANSFERASES
• CHROMATIN
• GENE
• METHYLATION
• METASTASIS
• LOCUS
• H4

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 x 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. @@@ The role of enhancer variants in hepatocellular carcinoma (HCC) predisposition remains unknown. Here, the authors perform a genome-wide survey of HCC-susceptible enhancer variants in 11,958 individuals, identify rs73613962 within the intronic region of PRMT7 and find that PRMT7 upregulation predisposes to HCC.

• 单位
  复旦大学; 中山大学; 广州医学院; 苏州大学; 南方医科大学; 6