RUNX super-enhancer control through the Notch pathway by Epstein-Barr virus transcription factors regulates B cell growth.
RUNX super-enhancer control through the Notch pathway by Epstein-Barr virus transcription factors regulates B cell growth.
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DOI：
10.1093/nar/gkw085
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发表时间：
2016-06-02
影响因子：
14.9
通讯作者：
West MJ
中科院分区：
文献类型：
--
作者：
Gunnell A;Webb HM;Wood CD;McClellan MJ;Wichaidit B;Kempkes B;Jenner RG;Osborne C;Farrell PJ;West MJ
在被癌症相关的eb病毒（EBV）感染的B细胞中，RUNX3和RUNX1转录被操纵来控制细胞生长。ebv编码的EBNA2转录因子（TF）激活RUNX3转录，导致RUNX3介导的RUNX1启动子抑制和RUNX1导向的生长抑制得到缓解。我们发现EBNA2通过−97 kb超增强子中的特定元件激活RUNX3，其方式依赖于Notch dna结合伙伴RBP-J的表达。我们还发现EBV TFs EBNA3B和EBNA3C通过靶向相同的元件参与EBV感染细胞中的RUNX3激活。我们揭示了一个反调控前瞻步骤，证明EBNA2激活RUNX1超增强子（- 139至- 250 kb），导致RUNX1在对RUNX1介导的生长抑制难以耐受的细胞中低水平表达。RUNX1超级增强子的EBNA2激活也依赖于RBP-J。与EBNA3B和EBNA3C作为激活或抑制因子的上下文依赖作用一致，我们发现这些蛋白负调控RUNX1超增强子，抑制EBNA2的激活。综上所述，我们的研究结果揭示了多种EBV tf通过Notch通路对RUNX基因超增强子的细胞类型特异性利用，以微调RUNX3和RUNX1的表达并操纵b细胞的生长。
In B cells infected by the cancer-associated Epstein-Barr virus (EBV), RUNX3 and RUNX1 transcription is manipulated to control cell growth. The EBV-encoded EBNA2 transcription factor (TF) activates RUNX3 transcription leading to RUNX3-mediated repression of the RUNX1 promoter and the relief of RUNX1-directed growth repression. We show that EBNA2 activates RUNX3 through a specific element within a −97 kb super-enhancer in a manner dependent on the expression of the Notch DNA-binding partner RBP-J. We also reveal that the EBV TFs EBNA3B and EBNA3C contribute to RUNX3 activation in EBV-infected cells by targeting the same element. Uncovering a counter-regulatory feed-forward step, we demonstrate EBNA2 activation of a RUNX1 super-enhancer (−139 to −250 kb) that results in low-level RUNX1 expression in cells refractory to RUNX1-mediated growth inhibition. EBNA2 activation of the RUNX1 super-enhancer is also dependent on RBP-J. Consistent with the context-dependent roles of EBNA3B and EBNA3C as activators or repressors, we find that these proteins negatively regulate the RUNX1 super-enhancer, curbing EBNA2 activation. Taken together our results reveal cell-type-specific exploitation of RUNX gene super-enhancers by multiple EBV TFs via the Notch pathway to fine tune RUNX3 and RUNX1 expression and manipulate B-cell growth.