Lu Zequn, Chen Can, Zhang Heng, Li Bin, Liu Yizhuo, Guo Jiayi, Xu Runying, Shi Ke, Ma Qianying, Zhang Ming, Cai Yimin, Huang Jinyu, Geng Hui, Fan Linyun, Ning Caibo, Li Yanmin, Chen Shuoni, Tian Wen, Hu Kexin, Li Haijie, Yang Xiaojun, Huang Chaoqun, Wei Yongchang, Zhu Xu, Li Xiangpan, Xiong Zhen, Cai Ming, Wang Xiaoyang, Zhang Shaokai, Chen Hongda, Dai Min, Chen Kun, Jin Mingjuan, Jin Meng, Zhu Ying, Tian Jianbo, Miao Xiaoping
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.
Department of Gastrointestinal Cancer Research Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Nat Cancer. 2025 Aug 25. doi: 10.1038/s43018-025-01031-z.
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). 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.
与结直肠癌（CRC）相关的基因变异主要是非编码的，且存在于顺式调控元件（CREs）中，但其潜在机制仍不清楚。在这里，我们利用来自533个结直肠组织的多组学数据建立了一个动态表观基因组图谱，这些组织涵盖了从正常组织到高级腺瘤再到癌症的各个阶段，鉴定出7492个与5490个靶基因相关的差异CREs。高通量CRISPR干扰筛选揭示了265个参与CRC细胞增殖的功能性CREs。基于功能性CRE变异的多基因风险评分（PRS）有效地预测了476770名个体中的CRC和癌前病变。值得注意的是，功能性变异rs10871066与癌前病变和CRC风险增加显著相关（优势比 = 1.27，P = 1.03×10）。从机制上讲，rs10871066触发由FOXP1和TCF7L2介导的沉默子到增强子的转换，在远端上调KLF5以激活致癌途径，上调PIBF1以抑制自然杀伤细胞的细胞毒性。我们的研究提供了一个全面的动态表观基因组图谱资源、一个用于风险预测的功能知情PRS，以及对CRC发生背后的表观遗传机制的深入了解。
