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

The gastrointestinal adenocarcinoma is a major cancer type for the digestive system, ranking as the top cause of cancer-related deaths worldwide. In contrast to the large body of studies on the mutations of protein-coding gene, the knowledge about the landscape of its non-coding regulatory elements is still insufficient. Combining the analysis of enhancer profiling and genomic structural variation, we discovered and validated a lineage-specific super-enhancer for MYB in gastrointestinal adenocarcinoma. This super-enhancer is constituted by a predominant enhancer e4 and multiple facilitator enhancers, whose transcriptional activity is controlled by the direct binding of HNF4A and MYB itself. Suppression of the super-enhancer downregulated the expression of MYB, inhibited the downstream Notch signaling and prevented the development of gastrointestinal adenocarcinoma in vitro and in vivo. Our study revealed a novel regulatory mechanism activating MYB expression in a lineage-specific manner, which provided an inspiring insight into the carcinogenic mechanism and therapeutic strategies for gastrointestinal adenocarcinoma.