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
  • 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. [email protected].
  • 3. Fudan University Taizhou Institute of Health Sciences, Taizhou, China. [email protected].
  • 4. Yiwu Research Institute of Fudan University, Yiwu, Zhejiang, China. [email protected].
  • 5. National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, China. [email protected].
  • 6. State Key Laboratory of Genetics and Development of Complex Phenotype, School of Life Sciences, Human Phenome Institute, Fudan University, Shanghai, 200438, China. [email protected].
  • # 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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