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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
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| Publish Date: | 2022-05-17 |
| Description: |
AbstractMost 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. see all
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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.). |
| Copyright information: |
© The Author(s) 2022. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
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https://creativecommons.org/licenses/by/4.0/ |