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<p>Genetic variants associated with colorectal cancer (CRC) are primarily noncoding and reside in <i>cis</i>-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 <a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs10871066">rs10871066</a> was significantly associated with increased risk of precancerous lesions and CRC (odds ratio = 1.27, <i>P</i> = 1.03 × 10<sup>−13</sup>). Mechanistically, <a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs10871066">rs10871066</a> triggers silencer-to-enhancer switching mediated by FOXP1 and TCF7L2, distally upregulating <i>KLF5</i> to activate oncogenic pathways and <i>PIBF1</i> 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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年8月25日

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  • 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

摘要

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.