Alternative polyadenylation quantitative trait methylation mapping in human cancers provides clues into the molecular mechanisms of APA

Yige Li; Jingwen Gong; Qingrong Sun; Eu Gene Vong; Xiaoqing Cheng; Binghong Wang; Ying Yuan; Li Jin; Eric R Gamazon; Dan Zhou; Maode Lai; Dandan Zhang

doi:10.1016/j.ajhg.2024.01.010

Alternative polyadenylation quantitative trait methylation mapping in human cancers provides clues into the molecular mechanisms of APA

Am J Hum Genet. 2024 Mar 7;111(3):562-583. doi: 10.1016/j.ajhg.2024.01.010. Epub 2024 Feb 16.

Authors

Yige Li¹, Jingwen Gong², Qingrong Sun³, Eu Gene Vong⁴, Xiaoqing Cheng⁵, Binghong Wang⁶, Ying Yuan⁷, Li Jin⁸, Eric R Gamazon⁹, Dan Zhou¹⁰, Maode Lai¹¹, Dandan Zhang¹²

Affiliations

¹ Department of Pathology, and Department of Medical Oncology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China; Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China; Department of Pathology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.
² Department of Pathology, and Department of Medical Oncology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China; Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China; Alibaba-Zhejiang University Joint Research Center of Future Digital Healthcare, Hangzhou, Zhejiang Province, China.
³ Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China; Alibaba-Zhejiang University Joint Research Center of Future Digital Healthcare, Hangzhou, Zhejiang Province, China; Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, Zhejiang Province, China; College of Information Science and Technology, ZheJiang Shuren University, Hangzhou 310015, ZheJiang, China.
⁴ Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China; Department of Biochemistry and Genetics, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China; The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.
⁵ Department of Pathology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.
⁶ Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.
⁷ Department of Medical Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China; Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, Chinese National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.
⁸ State Key Laboratory of Genetic Engineering, School of Life Sciences, Human Phenome Institute, Zhangjiang Fudan International Innovation Center, Fudan University, Shanghai, China; Research Unit of Dissecting the Population Genetics and Developing New Technologies for Treatment and Prevention of Skin Phenotypes and Dermatological Diseases (2019RU058), Chinese Academy of Medical Sciences, Shanghai, China.
⁹ Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Data Science Institute, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁰ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA; School of Public Health and the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
¹¹ Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China; Alibaba-Zhejiang University Joint Research Center of Future Digital Healthcare, Hangzhou, Zhejiang Province, China; Department of Pathology, Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences (2019RU042), Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China. Electronic address: lmd@zju.edu.cn.
¹² Department of Pathology, and Department of Medical Oncology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China; Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China; Alibaba-Zhejiang University Joint Research Center of Future Digital Healthcare, Hangzhou, Zhejiang Province, China; Department of Pathology, Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences (2019RU042), Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China. Electronic address: dandanz@zju.edu.cn.

PMID: 38367620
PMCID: PMC10940021 (available on 2024-09-07)
DOI: 10.1016/j.ajhg.2024.01.010

Abstract

Genetic variants are involved in the orchestration of alternative polyadenylation (APA) events, while the role of DNA methylation in regulating APA remains unclear. We generated a comprehensive atlas of APA quantitative trait methylation sites (apaQTMs) across 21 different types of cancer (1,612 to 60,219 acting in cis and 4,448 to 142,349 in trans). Potential causal apaQTMs in non-cancer samples were also identified. Mechanistically, we observed a strong enrichment of cis-apaQTMs near polyadenylation sites (PASs) and both cis- and trans-apaQTMs in proximity to transcription factor (TF) binding regions. Through the integration of ChIP-signals and RNA-seq data from cell lines, we have identified several regulators of APA events, acting either directly or indirectly, implicating novel functions of some important genes, such as TCF7L2, which is known for its involvement in type 2 diabetes and cancers. Furthermore, we have identified a vast number of QTMs that share the same putative causal CpG sites with five different cancer types, underscoring the roles of QTMs, including apaQTMs, in the process of tumorigenesis. DNA methylation is extensively involved in the regulation of APA events in human cancers. In an attempt to elucidate the potential underlying molecular mechanisms of APA by DNA methylation, our study paves the way for subsequent experimental validations into the intricate biological functions of DNA methylation in APA regulation and the pathogenesis of human cancers. To present a comprehensive catalog of apaQTM patterns, we introduce the Pancan-apaQTM database, available at https://pancan-apaqtm-zju.shinyapps.io/pancanaQTM/.

Keywords: DNA methylation; Mendelian randomization analysis; alternative polyadenylation; and colocalization; cis-regulation; human cancer; pan-cancer analysis; post-transcription; quantitative trait methylation sites; trans-regulation.

MeSH terms

3' Untranslated Regions
DNA Methylation / genetics
Diabetes Mellitus, Type 2* / genetics
Gene Expression Regulation
Humans
Neoplasms* / genetics
Neoplasms* / pathology
Polyadenylation / genetics

Substances

3' Untranslated Regions