超级增强子在肿瘤恶病质肌肉和脂肪消耗中的调控作用机制研究

Cancer cachexia is a devastating metabolic syndrome characterized by atrophy of muscle and adipose tissue, occurring in up to 80% of cancer patients, resulting in the death of nearly 1/3 of tumor patients. However, the underlying mechanism is still unclear and there is no effective treatment plan. Super-enhancer with strong transcriptional activity may regulate the abnormally active expression of genes involved in muscle and fat consumption in cancer cachexia. From the public data, we found that: 1. Cancer cachexia has a large number of super enhancers related to muscle development, such as Trim68 and Fbxo32, which are related to muscle atrophy; 2. Long-range regulation may be involved in muscle development related regulation; 3. Different models show significant overlapped differential expressed genes; 4, Integrated analysis obtained 63 muscle development and FoxO signal-related super enhancers and muscle development and transcription factors such as AP2a, Mef2a, Mef2c, Myf6 and Pax7 are enriched on these super enhancers. In summary, it suggested that super enhancers may play role in caner cachexia. In this project, we first propose the role of super enhancer in cancer cachexia and integrates three-dimensional genome and bioinformatics analysis methods, molecular cells, animal functions and other experiments to explore the mechanism of super-enhancer in the muscle and fat consumption of cancer cachexia. It will provide important data support for the treatment and drug development of cancer cachexia.

肿瘤恶病质是以肌肉和脂肪组织萎缩为主要特征的毁灭性代谢综合征，发生于高达80%的肿瘤病人，导致近1/3肿瘤患者死亡。其作用机制尚不明确，缺乏有效治疗方案。具有强转录活性的超级增强子，可能调控肿瘤恶病质中肌肉和脂肪消耗相关基因异常活跃表达。从公共数据中发现：1、肿瘤恶病质的肌肉存在与肌肉发育相关大量超级增强子，如Trim68和Fbxo32与肌肉萎缩相关；2、远程调控可能参与肌肉发育相关调控；3、不同模型差异表达高度重合；4、整合分析获得63个与肌肉发育和FoxO信号相关超级增强子,且富集出AP2a、Mef2a、Mef2c、Myf6和Pax7等肌肉发育相关转录因子。综上超级增强子在肿瘤恶病质中可能发挥重要作用。本项目首次从超级增强子角度，整合三维基因组和生物信息学分析方法、分子细胞、动物功能等实验挖掘其在肿瘤恶病质的肌肉和脂肪消耗中作用机制。为肿瘤恶病质的治疗和药物开发提供重要数据支持。

肿瘤恶病质是肿瘤患者伴发的以脂肪萎缩和骨骼肌萎缩为主要特征的消耗性代谢综合征。前期研究发现肿瘤恶病质状态下，BRD4是参与表观调控的重要蛋白，其在肌肉组织中基因组上的结合发生了显著变化，提示肿瘤恶病质引起了肌肉组织的表观重塑。以组蛋白H3K27ac为代表的增强子的标记也可能发生着变化。已知Fbxo32和Trim63作为泛素连接酶形成的泛素蛋白酶体降解系统和自噬系统导致肌肉萎缩。有意思的是通过公共数据鉴定得到Fbxo32和Trim63上游有一类重要的超级增强子，提示超级增强子在肿瘤恶病质中可能存在重要作用。因此，我们开展了肿瘤恶病质的细胞模型和动物模型的构建，并进一步进行肌肉和脂肪组织的H3K27ac的Cut&Tag的测定。通过系统分析超级增强子，我们鉴定出其在各个模型中的异同靶基因，提示肿瘤恶病质模型下对肌肉和脂肪的差异化调控。再者通过对公共表达数据探究了肿瘤恶病质模型下炎性环境下免疫微环境，细胞的组成发生了显著的变化，提示后续可利用单细胞测序技术解析肿瘤恶病质对靶组织/器官的微环境的调控。