cis-Regulatory Circuits Regulating NEK6 Kinase Overexpression in Transformed B Cells Are Super-Enhancer Independent.
cis-Regulatory Circuits Regulating NEK6 Kinase Overexpression in Transformed B Cells Are Super-Enhancer Independent.
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DOI：
10.1016/j.celrep.2017.02.067
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发表时间：
2017-03-21
期刊：
影响因子：
8.8
通讯作者：
Oltz EM
中科院分区：
文献类型：
--
作者：
Huang Y;Koues OI;Zhao JY;Liu R;Pyfrom SC;Payton JE;Oltz EM
控制基因表达的远端调控元件的改变是许多疾病（包括癌症）的基础。对正常和病变细胞的表观基因组学分析已经产生了对参与发病机制的失调增强子和靶基因之间的连接的相关预测。然而，除了少数例外，这些预测的顺式调节电路仍然未经测试。在这里，我们解剖顺式调节电路，导致过度表达NEK6，有丝分裂相关激酶，在人类B细胞淋巴瘤。我们发现，只有一小部分预测的增强子需要NEK6的表达。事实上，注释的超级增强子是用于NEK 6过表达和用于维持B细胞特异性调控中心的结构的增强子。CTCF簇充当染色质和结构边界以阻断NEK6调控中心与邻近基因的通信。我们的研究结果强调，预测的顺式调节电路和超级增强子的验证是必要的优先转录控制元件作为治疗目标。Huang等从功能上剖析了与NEK 6（一种在B细胞淋巴瘤中过表达的有丝分裂激酶）相关的顺式调节回路。只有一个子集的预测增强子和CTCF网站合作建设的调节枢纽NEK6。超级增强子被完全抑制以维持转化的B细胞中的NEK 6表达和结构。
Alterations in distal regulatory elements that control gene expression underlie many diseases, including cancer. Epigenomic analyses of normal and diseased cells have produced correlative predictions for connections between dysregulated enhancers and target genes involved in pathogenesis. However, with few exceptions, these predicted cis-regulatory circuits remain untested. Here, we dissect cis-regulatory circuits that lead to overexpression of NEK6, a mitosis-associated kinase, in human B cell lymphoma. We find that only a minor subset of predicted enhancers is required for NEK6 expression. Indeed, an annotated super-enhancer is dispensable for NEK6 overexpression and for maintaining the architecture of a B cell-specific regulatory hub. A CTCF cluster serves as a chromatin and architectural boundary to block communication of the NEK6 regulatory hub with neighboring genes. Our findings emphasize that validation of predicted cis-regulatory circuits and super-enhancers is needed to prioritize transcriptional control elements as therapeutic targets. Huang et al. functionally dissect cis-regulatory circuits associated with NEK6, a mitotic kinase overexpressed in B cell lymphoma. Only a subset of predicted enhancers and CTCF sites cooperatively construct the regulatory hub of NEK6. A super-enhancer is completely dispensable for maintaining NEK6 expression and architecture in transformed B cells.