Characterization of cis-regulatory elements and functional variants in colorectal cancer using epigenomics and CRISPRi screenings
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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scTraitReg: a single-cell multi-omic database of trait-relevant transcription factor eRegulons
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- Authors
- Lu, Z., Chen, C., Zhang, H., Li, B., Liu, Y., Guo, J., Xu, R., Shi, K., Ma, Q., Zhang, M., Cai, Y., Huang, J., Geng, H., Fan, L., Ning, C., Li, Y., Chen, S., Tian, W., Hu, K., Li, H., Yang, X., Huang, C., Wei, Y., Zhu, X., Li, X., Xiong, Z., Cai, M., Wang, X., Zhang, S., Chen, H., Dai, M., Chen, K., Jin, M., Jin, M., Zhu, Y., Tian, J., & Miao, X.
- Affiliations
- Wuhan University (CN)
- Tongji Hospital (CN)
- Renmin Hospital of Wuhan University (CN)
- Wuhan Union Hospital (CN)
- Zhengzhou University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Second Affiliated Hospital of Zhejiang University (CN)
- Corresponding author
- Tian, Jianbo
- Miao, Xiaoping
- ORCID
- Lu, Zequn
- Chen, Can
- Zhang, Heng
- Liu, Yizhuo
- Guo, Jiayi
- Shi, Ke
- Zhang, Ming
- Cai, Yimin
- Huang, Jinyu
- Geng, Hui
- Fan, Linyun
- Ning, Caibo
- Chen, Shuoni
- Hu, Kexin
- Li, Haijie
- Yang, Xiaojun
- Huang, Chaoqun
- Wei, Yongchang
- Li, Xiangpan
- Cai, Ming
- Wang, Xiaoyang
- Zhang, Shaokai
- Chen, Hongda
- Dai, Min
- Chen, Kun
- Jin, Mingjuan
- Jin, Meng
- Zhu, Ying
- Tian, Jianbo
- Miao, Xiaoping
- Venue
- Nature Cancer
- Published
- 2025-08-25
- Volume
- 6
- Issue
- 11
- Pages
- 1777-1799
- ISSN
- 2662-1347 (ISSN-L)
- OpenAlex
- W4413495074
- Semantic Scholar
- f396f45a05f69851b7610dc8198d4d5a27e35207
- Cited by
- 4
- References
- 75
- Citations by year
- 2026: 4
- FWCI
- 0.99
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Nature Cancer (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China ((NSFC-82130098)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- colorectal cancer, cis-regulatory elements, non-coding variants, polygenic risk score, colorectal adenoma, FOXP1, TCF7L2, KLF5, NK cell cytotoxicity, transcription factor binding, tumor progression
- MeSH terms
- Humans, Regulatory Sequences, Nucleic Acid, Repressor Proteins, Colorectal Neoplasms, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Epigenesis, Genetic, Cell Line, Tumor, Cell Proliferation, Epigenomics, Transcription Factor 7-Like 2 Protein, CRISPR-Cas Systems
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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