PDF(Pubmed)
Abstract：
Sequencing-based mapping of ensemble pairwise interactions among regulatory elements support the existence of topological assemblies known as promoter-enhancer hubs or cliques in cancer. Yet, prevalence, regulators, and functions of promoter-enhancer hubs in individual cancer cells remain unclear. Here, we systematically integrated functional genomics, transcription factor screening, and optical mapping of promoter-enhancer interactions to identify key promoter-enhancer hubs, examine heterogeneity of their assembly, determine their regulators, and elucidate their role in gene expression control in individual triple negative breast cancer (TNBC) cells. Optical mapping of individual SOX9 and MYC alleles revealed the existence of frequent multiway interactions among promoters and enhancers within spatial hubs. Our single-allele studies further demonstrated that lineage-determining SOX9 and signaling-dependent NOTCH1 transcription factors compact MYC and SOX9 hubs. Together, our findings suggest that promoter-enhancer hubs are dynamic and heterogeneous topological assemblies, which are controlled by oncogenic transcription factors and facilitate subtype-restricted gene expression in cancer.
摘要：
调控元件之间的集合成对相互作用的基于测序的作图支持在癌症中存在称为启动子-增强子中心或集团的拓扑组装。然而，患病率,监管者,和启动子-增强子集线器在单个癌细胞中的功能仍不清楚。这里,我们系统地整合了功能基因组学，转录因子筛选，和启动子-增强子相互作用的光学作图，以确定关键的启动子-增强子中心，检查它们组装的异质性，确定他们的监管者，并阐明它们在单个三阴性乳腺癌（TNBC）细胞中基因表达控制中的作用。单个SOX9和MYC等位基因的光学图谱显示，空间中心内启动子和增强子之间存在频繁的多路相互作用。我们的单等位基因研究进一步证明，谱系决定SOX9和依赖信号传导的NOTCH1转录因子使MYC和SOX9中心紧密相连。一起,我们的发现表明，启动子-增强子中心是动态的和异质的拓扑组装，它们受致癌转录因子控制，并促进癌症中亚型限制的基因表达。
