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

## TL;DR

The study identifies a specific super-enhancer for the MYB gene in gastrointestinal adenocarcinoma, which could lead to new cancer treatments.

## Contribution

The discovery of a lineage-specific super-enhancer for MYB regulated by HNF4A and MYB binding in gastrointestinal adenocarcinoma.

## Key findings

- A super-enhancer composed of enhancer e4 and others regulates MYB in gastrointestinal adenocarcinoma.
- Suppression of the super-enhancer reduces MYB expression and inhibits cancer development in vitro and in vivo.
- MYB activation makes gastrointestinal adenocarcinoma cells dependent on MYB.

## 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.

By combining the analysis of active enhancer profiles and genomic structural variation, a lineage-specific super enhancer for MYB in gastrointestinal adenocarcinoma was discovered and validated.

MYB-high/-dependent gastrointestinal adenocarcinoma cells harbor a MYB super-enhancer.HNF4A and MYB bind to the enhancer e4 within MYB super-enhancer.MYB activation confers a dependency of gastrointestinal adenocarcinoma cell on MYB.

MYB-high/-dependent gastrointestinal adenocarcinoma cells harbor a MYB super-enhancer.

HNF4A and MYB bind to the enhancer e4 within MYB super-enhancer.

MYB activation confers a dependency of gastrointestinal adenocarcinoma cell on MYB.

By combining the analysis of active enhancer profiles and genomic structural variation, a lineage-specific super enhancer for MYB in gastrointestinal adenocarcinoma was discovered and validated.