Group_3亚型髓母细胞瘤是发病率高且预后差的恶性儿童脑瘤类型。申请人前期发现表观转录调控因子BRD4和CDK7参与其关键转录因子MYC和OTX2的表达调控，且它们的靶向药物均在肿瘤预临床模型中展现良好治疗效果。鉴于这两个蛋白均为顺式表观调控元件超级增强子的功能复合物中的重要组分，本项目拟通过表观遗传组学分析结合CRISPR-Cas9功能基因组筛选，深入剖析Group_3亚型髓母细胞瘤中超级增强子驱动的核心转录调控环路的组成、功能及其对上述表观转录靶向药物的反应；挖掘其中新的关键转录因子、靶基因及相关机制；并进一步探索治疗新靶标和新策略。由于BRD4和CDK7的靶向药物均已进入早期临床试验，这些研究不仅将为它们治疗Group_3亚型髓母细胞瘤的临床试验提供理论基础，还将通过深入了解肿瘤基因表达调控网络促进揭示新的致癌分子机制和靶向治疗策略，因此对于基础研究和临床开发均具有重大意义。

Group 3 subtype medulloblastoma (G3-MB) is a high-incidence and poor-prognosis type of malignant pediatric brain tumor. The applicant has recently demonstrated that epigenetic/transcriptional modulators BRD4 and CDK7 play important roles in regulating the transcription of MYC and OTX2, two master transcription factors of G3-MB, and their targeted drugs are effective in treating preclinical models of G3-MB. BRD4 and CDK7 are both important components of the functional complex of super-enhancer (SE), a recently defined critical epigenetic cis-element in tumor. Based on these findings, we propose in this project to utilize epigenomic analysis and functional genomics screening approaches, to comprehensively investigate the composition and function of SE-driven core transcriptional regulatory circuit of G3-MB, as well as its response to treatment of the two types of SE-targeted epigenetic/transcriptional drugs. We plan to dissect out novel key transcription factors, functional target genes and related molecular mechanisms from analyzing SE-driven core transcriptional regulatory circuit of G3-MB, which will then lead to the identification of novel therapeutic targets and strategies. Since both BRD4 inhibitor and CDK7 inhibitor drugs have entered early-phase clinical trials, our study will not only provide theoretical support for initiating their future trials of treating G3-MB, but also help reveal novel oncogenic mechanisms and therapeutic strategies. Therefore, our project will contribute significantly to both understanding tumor biology and developing clinical applications.