Project 2. Investigating epigenetic circuitry in multiple myeloma

项目总结(项目2) 这个项目的总体目标是研究多发性骨髓瘤表观遗传回路的关键特征，目的是 提高我们对这种癌症的全球基因调控的理解，并以部署新的 以MM的关键表观基因组回路为依赖关系的治疗学。可以定义单元格和单元格状态 通过它们的基因表达程序，肿瘤细胞通常都有去调控的基因表达程序。 基因表达程序的产生是由细胞的表观遗传学装置完成的。现在是时候了 对于任何正常或癌细胞类型，都有可能确定主要的转录因子，即增强子元件 它们占据，以及它们调控的基因，从而开发出一种可测试的全基因组模型 表观遗传回路。此外，还有可能确定细胞所在的基因调控元件 最依赖的，从而识别癌细胞最依赖的电路部分。 肿瘤细胞倾向于对超级增强子调节元件产生显著的依赖性(3-6)。近期 研究表明，转录辅助因子BRD4、CDK7和CDK12在 肿瘤细胞的表观遗传回路及其与小分子的抑制可导致超级增强子的丢失 驱动在肿瘤发生中具有突出作用的基因的结构域(3-6)。我们建议破译其中的关键特征 MM表观遗传回路的研究，以确定赋予巨大依赖性的特征，并研究 小分子抑制剂可能破坏MM中的这些依赖。为了实现这些目标， 该提案的具体目标是1)通过以下方式发现多发性骨髓瘤的表观基因组回路的关键特征 综合表观基因组分析，2)利用基因确定多发性骨髓瘤的表观遗传相关性 编辑方法，以及3)探索转录辅因子小分子抑制剂的能力 破坏多发性骨髓瘤表观遗传回路中的关键节点。

Project Summary (Project 2) The overarching goal of this project is to study key features of epigenetic circuitry in MM, with the objective of improving our understanding of global gene regulation in this cancer, and with the goal of deploying novel therapeutics that target key epigenomic circuits in MM as dependencies. Cells and cell states can be defined by their gene expression programs, and tumor cells commonly have deregulated gene expression programs. The production of a gene expression program is accomplished by the cell’s epigenetic apparatus. It is now possible, for any normal or cancer cell type, to identify the master transcription factors, the enhancer elements they occupy, and the genes they regulate, and thus to develop a testable model of this genome-wide epigenetic circuitry. Furthermore, it is possible to identify the gene regulatory elements on which the cell is most dependent, and thus identify the portions of the circuitry on which a cancer cell is most dependent. Tumor cells tend to develop striking dependencies on super-enhancer regulatory elements (3-6). Recent studies suggest that the transcriptional cofactors BRD4, CDK7 and CDK12 play especially important roles in tumor cell epigenetic circuitry, and their inhibition with small molecules can cause a loss of super-enhancer domains that drive genes with prominent roles in tumorigenesis (3-6). We propose to decipher the key features of MM epigenetic circuitry, to identify the features that confer great dependency, and to investigate the potential of small molecule inhibitors to disrupt those dependencies in MM. To accomplish these goals, the specific aims of the proposal are 1) To discover key features of epigenomic circuitry in multiple myeloma by integrated epigenomic analysis, 2) to determine epigenetic dependencies in multiple myeloma using gene editing approaches, and 3) to explore the ability of small molecule inhibitors of transcriptional cofactors to disrupt key nodes in multiple myeloma epigenetic circuitry.