2. Academic Validation
  3. Systemic genome-epigenome analysis captures a lineage-specific super-enhancer for MYB in gastrointestinal adenocarcinoma

Systemic genome-epigenome analysis captures a lineage-specific super-enhancer for MYB in gastrointestinal adenocarcinoma

  • Mol Syst Biol. 2025 Jun;21(6):696-719. doi: 10.1038/s44320-025-00098-1.
Fuyuan Li # 1,  Shangzi Wang # 1,  Lian Chen 1,  Ning Jiang 1,  Xingdong Chen 2 3 4 5,  Jin Li 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Genetics and Development of Complex Phenotype, School of Life Sciences, Human Phenome Institute, Fudan University, Shanghai, 200438, China.
  • 2 State Key Laboratory of Genetics and Development of Complex Phenotype, School of Life Sciences, Human Phenome Institute, Fudan University, Shanghai, 200438, China. xingdongchen@fudan.edu.cn.
  • 3 Fudan University Taizhou Institute of Health Sciences, Taizhou, China. xingdongchen@fudan.edu.cn.
  • 4 Yiwu Research Institute of Fudan University, Yiwu, Zhejiang, China. xingdongchen@fudan.edu.cn.
  • 5 National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, China. xingdongchen@fudan.edu.cn.
  • 6 State Key Laboratory of Genetics and Development of Complex Phenotype, School of Life Sciences, Human Phenome Institute, Fudan University, Shanghai, 200438, China. li_jin_lifescience@fudan.edu.cn.
  • # Contributed equally.
PMID: 40234694 DOI: 10.1038/s44320-025-00098-1
Abstract

Gastrointestinal adenocarcinoma is a major Cancer type for the digestive system, ranking as the top cause of cancer-related deaths worldwide. While there has been extensive research on mutations in protein-coding regions, the knowledge of the landscape of its non-coding regulatory elements is still insufficient. Combining the analysis of active enhancer profiles and genomic structural variation, we discovered and validated a lineage-specific super-enhancer for MYB in gastrointestinal adenocarcinoma. This super-enhancer is composed of a predominant enhancer e4 and several additional enhancers, whose transcriptional activity is regulated by the direct binding of HNF4A and MYB itself. Suppression of the super-enhancer downregulated the expression of MYB, inhibited downstream Notch signaling and prevented the development of gastrointestinal adenocarcinoma both in vitro and in vivo. Our study uncovers a mechanism driven by non-coding variations that regulate MYB expression in a lineage-specific manner, offering new insights into the carcinogenic mechanism and potential therapeutic strategies for gastrointestinal adenocarcinoma.

Keywords

Epigenetics; Gastrointestinal Adenocarcinoma; Lineage-specific; MYB; Super-enhancer.

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