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

IF 28.5 1区医学 Q1 ONCOLOGY

Nature cancer Pub Date : 2025-08-25 DOI:10.1038/s43018-025-01031-z

Zequn Lu, Can Chen, Heng Zhang, Bin Li, Yizhuo Liu, Jiayi Guo, Runying Xu, Ke Shi, Qianying Ma, Ming Zhang, Yimin Cai, Jinyu Huang, Hui Geng, Linyun Fan, Caibo Ning, Yanmin Li, Shuoni Chen, Wen Tian, Kexin Hu, Haijie Li, Xiaojun Yang, Chaoqun Huang, Yongchang Wei, Xu Zhu, Xiangpan Li, Zhen Xiong, Ming Cai, Xiaoyang Wang, Shaokai Zhang, Hongda Chen, Min Dai, Kun Chen, Mingjuan Jin, Meng Jin, Ying Zhu, Jianbo Tian, Xiaoping Miao

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引用次数: 0

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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使用表观基因组学和CRISPRi筛选鉴定结直肠癌顺式调控元件和功能变异。

与结直肠癌（CRC）相关的遗传变异主要是非编码的，存在于顺式调控元件（cre）中，但其潜在机制尚不清楚。在这里，我们利用533个从正常到晚期腺瘤到癌症的结直肠组织的多组学数据建立了一个动态表观遗传图谱，确定了7492个与5490个靶基因相关的差异cre。高通量CRISPR干扰筛选发现265个功能性CREs参与结直肠癌细胞增殖。基于功能性CRE变异的多基因风险评分（PRS）有效预测了476770例CRC和癌前病变。值得注意的是，功能变异rs10871066与癌前病变和CRC的风险增加显著相关（优势比= 1.27,P = 1.03 × 10-13）。机制上，rs10871066触发FOXP1和TCF7L2介导的沉默-增强转换，远端上调KLF5激活致癌途径和PIBF1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，并深入了解CRC发展的表观遗传机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature cancer Medicine-Oncology

CiteScore

31.10

自引率

1.80%

发文量

129

期刊介绍： Cancer is a devastating disease responsible for millions of deaths worldwide. However, many of these deaths could be prevented with improved prevention and treatment strategies. To achieve this, it is crucial to focus on accurate diagnosis, effective treatment methods, and understanding the socioeconomic factors that influence cancer rates. Nature Cancer aims to serve as a unique platform for sharing the latest advancements in cancer research across various scientific fields, encompassing life sciences, physical sciences, applied sciences, and social sciences. The journal is particularly interested in fundamental research that enhances our understanding of tumor development and progression, as well as research that translates this knowledge into clinical applications through innovative diagnostic and therapeutic approaches. Additionally, Nature Cancer welcomes clinical studies that inform cancer diagnosis, treatment, and prevention, along with contributions exploring the societal impact of cancer on a global scale. In addition to publishing original research, Nature Cancer will feature Comments, Reviews, News & Views, Features, and Correspondence that hold significant value for the diverse field of cancer research.