Characterization of cis-regulatory elements and functional variants in colorectal cancer using epigenomics and CRISPRi screenings

Zequn Lu^#¹, Can Chen^#¹, Heng Zhang^#¹, Bin Li^#¹, Yizhuo Liu¹, Jiayi Guo¹, Runying Xu¹, Ke Shi¹, Qianying Ma¹, Ming Zhang¹, Yimin Cai¹, Jinyu Huang¹, Hui Geng¹, Linyun Fan¹, Caibo Ning¹, Yanmin Li¹, Shuoni Chen¹, Wen Tian¹, Kexin Hu¹, Haijie Li², Xiaojun Yang³, Chaoqun Huang³, Yongchang Wei⁴, Xu Zhu⁵, Xiangpan Li⁶, Zhen Xiong⁷, Ming Cai⁷, Xiaoyang Wang⁸, Shaokai Zhang⁸, Hongda Chen⁹, Min Dai¹⁰, Kun Chen¹¹, Mingjuan Jin¹¹, Meng Jin¹², Ying Zhu¹, Jianbo Tian^{13

14}, Xiaoping Miao^{15

16

17}

Affiliations

¹ Department of Epidemiology and Biostatistics, School of Public Health; State Key Laboratory of Metabolism and Regulation in Complex Organisms, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, China.
² Department of Gastrointestinal Cancer Research Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
³ Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
⁴ Department of Gastrointestinal Oncology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
⁵ Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan, China.
⁶ Department of Radiation Oncology, Renmin Hospital of Wuhan University, Wuhan, China.
⁷ Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁸ Department of Cancer Epidemiology, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Henan Engineering Research Center of Cancer Prevention and Control, Henan International Joint Laboratory of Cancer Prevention, Zhengzhou, China.
⁹ Center for Prevention and Early Intervention, National Infrastructures for Translational Medicine, Institute of Clinical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
¹⁰ Department of Cancer Epidemiology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
¹¹ Department of Public Health, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
¹² Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
¹³ Department of Epidemiology and Biostatistics, School of Public Health; State Key Laboratory of Metabolism and Regulation in Complex Organisms, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, China. tianjb@whu.edu.cn.
¹⁴ Department of Gastrointestinal Oncology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China. tianjb@whu.edu.cn.
¹⁵ Department of Epidemiology and Biostatistics, School of Public Health; State Key Laboratory of Metabolism and Regulation in Complex Organisms, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, China. xpmiao@whu.edu.cn.
¹⁶ Department of Gastrointestinal Oncology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China. xpmiao@whu.edu.cn.
¹⁷ Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China. xpmiao@whu.edu.cn.

^# Contributed equally.

PMID: 40854986
DOI: 10.1038/s43018-025-01031-z

Characterization of cis-regulatory elements and functional variants in colorectal cancer using epigenomics and CRISPRi screenings

Zequn Lu et al. Nat Cancer. 2025.

. 2025 Aug 25.

doi: 10.1038/s43018-025-01031-z. Online ahead of print.

Authors

Affiliations

¹ Department of Epidemiology and Biostatistics, School of Public Health; State Key Laboratory of Metabolism and Regulation in Complex Organisms, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, China.
² Department of Gastrointestinal Cancer Research Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
³ Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
⁴ Department of Gastrointestinal Oncology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
⁵ Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan, China.
⁶ Department of Radiation Oncology, Renmin Hospital of Wuhan University, Wuhan, China.
⁷ Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁸ Department of Cancer Epidemiology, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Henan Engineering Research Center of Cancer Prevention and Control, Henan International Joint Laboratory of Cancer Prevention, Zhengzhou, China.
⁹ Center for Prevention and Early Intervention, National Infrastructures for Translational Medicine, Institute of Clinical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
¹⁰ Department of Cancer Epidemiology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
¹¹ Department of Public Health, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
¹² Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
¹³ Department of Epidemiology and Biostatistics, School of Public Health; State Key Laboratory of Metabolism and Regulation in Complex Organisms, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, China. tianjb@whu.edu.cn.
¹⁴ Department of Gastrointestinal Oncology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China. tianjb@whu.edu.cn.
¹⁵ Department of Epidemiology and Biostatistics, School of Public Health; State Key Laboratory of Metabolism and Regulation in Complex Organisms, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, China. xpmiao@whu.edu.cn.
¹⁶ Department of Gastrointestinal Oncology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China. xpmiao@whu.edu.cn.
¹⁷ Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China. xpmiao@whu.edu.cn.

^# Contributed equally.

PMID: 40854986
DOI: 10.1038/s43018-025-01031-z

Abstract

Genetic variants associated with colorectal cancer (CRC) are primarily noncoding and reside in cis-regulatory elements (CREs), yet their underlying mechanisms remain elusive. Here we established a dynamic epigenetic atlas using multiomics data from 533 colorectal tissues spanning normal to advanced adenoma to cancer, identifying 7,492 differential CREs linked to 5,490 target genes. High-throughput CRISPR interference screening revealed 265 functional CREs involved in CRC cell proliferation. A polygenic risk score (PRS) based on functional CRE variants effectively predicted CRC and precancerous lesions among 476,770 individuals. Notably, the functional variant rs10871066 was significantly associated with increased risk of precancerous lesions and CRC (odds ratio = 1.27, P = 1.03 × 10^-13). Mechanistically, rs10871066 triggers silencer-to-enhancer switching mediated by FOXP1 and TCF7L2, distally upregulating KLF5 to activate oncogenic pathways and PIBF1 to suppress natural killer cell cytotoxicity. Our study provides a comprehensive resource of dynamic epigenomic atlas, a functionally informed PRS for risk prediction and insights into epigenetic mechanisms underlying CRC development.

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Conflict of interest statement

Competing interests: The authors declare no competing interests.

References

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NSFC-82130098/National Science Foundation of China | Key Programme

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Characterization of cis-regulatory elements and functional variants in colorectal cancer using epigenomics and CRISPRi screenings

Affiliations

Characterization of cis-regulatory elements and functional variants in colorectal cancer using epigenomics and CRISPRi screenings

Authors

Affiliations

Abstract

Conflict of interest statement

References

Grants and funding

LinkOut - more resources

Full Text Sources