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

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.