University of Oulu

Shen, T., Ni, T., Chen, J. et al. An enhancer variant at 16q22.1 predisposes to hepatocellular carcinoma via regulating PRMT7 expression. Nat Commun 13, 1232 (2022). https://doi.org/10.1038/s41467-022-28861-0

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

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Author: Shen, Ting1,2; Ni, Ting3; Chen, Jiaxuan1;
Organizations: 1State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China
2School of Life Sciences, Central South University, 510006, Changsha, China
3State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, Human Phenome Institute, School of Life Sciences, Fudan University, 200438, Shanghai, China
4School of Public Health (Shenzhen), Sun Yat-sen University, 528406, Shenzhen, China
5Department of Epidemiology, Naval Medical University, 200433, Shanghai, China
6Institute of Bioinformatics, School of Basic Medical Science, Southern Medical University, 510515, Guangzhou, China
7School of Public Health, Fudan University, 200032, Shanghai, China
8School of Basic Medical Sciences; The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People′s hospital, Guangzhou Medical University, 510182, Guangzhou, China
9Department of Forensic Medicine, Medical College of Soochow University, 215123, Suzhou, Jiangsu Province, China
10Department of Pathology, Youjiang Medical College for Nationalities, 533000, Baise, Guangxi Province, China
11Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, 90014, Oulu, Finland
12School of Basic Medical Sciences, Fudan University, 200032, Shanghai, China
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 3.9 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2022051736092
Language: English
Published: Springer Nature, 2022
Publish Date: 2022-05-17
Description:

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.

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Series: Nature communications
ISSN: 2041-1723
ISSN-E: 2041-1723
ISSN-L: 2041-1723
Volume: 13
Article number: 1232
DOI: 10.1038/s41467-022-28861-0
OADOI: https://oadoi.org/10.1038/s41467-022-28861-0
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
3111 Biomedicine
3122 Cancers
Subjects:
Funding: This study was supported by the General Programs from the National Natural Science Foundation of China (No. 81472618 and 81670535 to D.-K.J., 81802828 to T.S. and 81802833 to H.C.), the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (No. 2017BT01S131 to J.H. and D.-K.J.), the National Science and Technology Major Project (No. 2017ZX10202202 and 2018ZX10301202 to J.H. and D.-K.J.), the General Program from the Natural Science Foundation of Guangdong Province (No. 2019A1515011423 to D.-K.J.), the Key-Area Research and Development Program of Guangdong Province (No. 2019B020227004 to D.-K.J.), the Innovative Research Team Project of Guangxi Province (No. 2017GXNSFGA198002 to D.-K.J.), the Dean Fund of Nanfang Hospital, Southern Medical University (No. 2018Z005 to D.-K.J.), the Grant for Recruited Talents to Start Scientific Research from Nanfang Hospital, and the Outstanding Youth Development Scheme of Nanfang Hospital, Southern Medical University (No. 2017J001 to D.-K.J.).
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