超级增强子是具有转录活性增强子的一个大簇，能驱动细胞和组织特异性基因表达，同时能促肿瘤发生发展。申请人前期发现肝癌细胞系中MAX、NR2F2、ZEB1和CREB1四个转录因子的表达本身受超级增强子驱动，同时这些转录因子又能调控数目庞大的超级增强子，与核心转录调控环(CRC)数学模型的特征相吻合。该模型是指CRC成员基因与其超级增强子相互调控，形成一个相互联通的闭合调控环路。申请人的确发现这四个转录因子之间存在相互作用。因此，我们提出科学假说：MAX-NR2F2-ZEB1-CREB1与超级增强子相互调控构成核心转录调控环，从而调控肝细胞癌的核心转录网络。预实验表明这四个转录因子确实能促进肝癌细胞恶性表型。本项目拟从细胞、动物和临床水平三个层次研究核心转录调控环MAX-NR2F2-ZEB1-CREB1的异常活化机理并探究其在肝细胞癌中的作用，这将为寻找肝细胞癌的治疗靶点和预后标志物提供新思路。

Super-enhancer are large clusters of transcriptionally active enhancers. Functionally, they are capable of driving the expression of key genes that control cell identity, which are also particularly important for tumor biology. Our preliminary experiments showed that the expression of four transcription factors MAX, NR2F2, ZEB1 and CREB1 is driven by super-enhancers in hepatocellular carcinoma cells. Notably, these four transcription factors also regulate large number of super-enhancers, whose characteristics fit the mathematical model of the core transcriptional regulatory circuitry (CRC). CRC model refers to the mutual regulation between the CRC members and their super-enhancers to form an interconnected auto-regulatory loop. Our further analysis revealed that indeed these four transcription factors co-regulate each other’s transcription. Therefore, we propose a scientific hypothesis: MAX-NR2F2-ZEB1-CREB1 regulate super-enhancers and form a core transcriptional regulatory circuitry, thereby orchestrating the transcriptional network in hepatocellular carcinoma. This project is aimed at probing the mechanisms of the hyper-activation of the core transcriptional regulatory circuitry constituted by MAX-NR2F2-ZEB1-CREB1, then exploring its biological function in hepatocellular carcinoma from cell, animal and clinical three levels, which are potential therapeutic targets for hepatocellular carcinoma and prognostic biomarkers.