DOI：10.1038/nature14904 作者：Matthew D. Shair
摘要 : 超级增强子是被转录因子、Mediator复合物和染色质调控因子紧密连接在一起的大增强子，它们驱动在细胞身份和疾病中所涉及基因的高度表达。
超级增强子是被转录因子、Mediator复合物和染色质调控因子紧密连接在一起的大增强子，它们驱动在细胞身份和疾病中所涉及基因的高度表达。Matthew Shair及同事发现，与Mediator相关的激酶CDK8的一种小分子抑制剂抑制 “急性骨髓性白血病”(AML)细胞的生长，诱导与肿瘤抑制因子和世系控制功能关联的“超级增强子相关基因”的上调。 这种增强子上调是出乎意料的，因为一种“bromodomain BRD4”抑制剂抑制AML细胞生长、但却下调“超级增强子相关基因”。因此，AML细胞似乎取决于“超级增强子相关基因”表达和CDK8抑制的精确剂量。
Super-enhancers (SEs), which are composed of large clusters of enhancers densely loaded with the Mediator complex, transcription factors and chromatin regulators, drive high expression of genes implicated in cell identity and disease, such as lineage-controlling transcription factors and oncogenes. BRD4 and CDK7 are positive regulators of SE-mediated transcription. By contrast, negative regulators of SE-associated genes have not been well described. Here we show that the Mediator-associated kinases cyclin-dependent kinase 8 (CDK8) and CDK19 restrain increased activation of key SE-associated genes in acute myeloid leukaemia (AML) cells. We report that the natural product cortistatin A (CA) selectively inhibits Mediator kinases, has anti-leukaemic activity in vitro and in vivo, and disproportionately induces upregulation of SE-associated genes in CA-sensitive AML cell lines but not in CA-insensitive cell lines. In AML cells, CA upregulated SE-associated genes with tumour suppressor and lineage-controlling functions, including the transcription factors CEBPA, IRF8, IRF1 and ETV6. The BRD4 inhibitor I-BET151 downregulated these SE-associated genes, yet also has anti-leukaemic activity. Individually increasing or decreasing the expression of these transcription factors suppressed AML cell growth, providing evidence that leukaemia cells are sensitive to the dosage of SE-associated genes. Our results demonstrate that Mediator kinases can negatively regulate SE-associated gene expression in specific cell types, and can be pharmacologically targeted as a therapeutic approach to AML.
来源： Nature 浏览次数：0