West Michelle J, Farrell Paul J
School of Life Sciences, University of Sussex, Falmer, Brighton, BN1 9QG, UK.
Section of Virology, Faculty of Medicine, Imperial College London, Norfolk Place, London, W2 1PG, UK.
Adv Exp Med Biol. 2017;962:283-298. doi: 10.1007/978-981-10-3233-2_18.
RUNX1 and RUNX3 are the main RUNX genes expressed in B lymphocytes. Both are expressed throughout B-cell development and play key roles at certain key developmental transitions. The tumour-associated Epstein-Barr virus (EBV) has potent B-cell transforming ability and manipulates RUNX3 and RUNX1 transcription through novel mechanisms to control B cell growth. In contrast to resting mature B cells where RUNX1 expression is high, in EBV-infected cells RUNX1 levels are low and RUNX3 levels are high. Downregulation of RUNX1 in these cells results from cross-regulation by RUNX3 and serves to relieve RUNX1-mediated growth repression. RUNX3 is upregulated by the EBV transcription factor (TF) EBNA2 and represses RUNX1 transcription through RUNX sites in the RUNX1 P1 promoter. Recent analysis revealed that EBNA2 activates RUNX3 transcription through an 18 kb upstream super-enhancer in a manner dependent on the EBNA2 and Notch DNA-binding partner RBP-J. This super-enhancer also directs RUNX3 activation by two further RBP-J-associated EBV TFs, EBNA3B and 3C. Counter-intuitively, EBNA2 also hijacks RBP-J to target a super-enhancer region upstream of RUNX1 to maintain some RUNX1 expression in certain cell backgrounds, although the dual functioning EBNA3B and 3C proteins limit this activation. Interestingly, the B-cell genome binding sites of EBV TFs overlap extensively with RUNX3 binding sites and show enrichment for RUNX motifs. Therefore in addition to B-cell growth manipulation through the long-range control of RUNX transcription, EBV may also use RUNX proteins as co-factors to deregulate the transcription of many B cell genes during immortalisation.
RUNX1和RUNX3是在B淋巴细胞中表达的主要RUNX基因。二者在整个B细胞发育过程中均有表达，并在某些关键的发育转变中发挥关键作用。肿瘤相关的爱泼斯坦-巴尔病毒（EBV）具有强大的B细胞转化能力，并通过新机制操纵RUNX3和RUNX1转录以控制B细胞生长。与静止成熟B细胞中RUNX1表达较高相反，在EBV感染的细胞中，RUNX1水平较低而RUNX3水平较高。这些细胞中RUNX1的下调是由RUNX3的交叉调节导致的，其作用是解除RUNX1介导的生长抑制。RUNX3由EBV转录因子（TF）EBNA2上调，并通过RUNX1 P1启动子中的RUNX位点抑制RUNX1转录。最近的分析表明，EBNA2通过一个18 kb的上游超级增强子以依赖于EBNA2和Notch DNA结合伙伴RBP-J的方式激活RUNX3转录。这个超级增强子还通过另外两个与RBP-J相关的EBV TF，EBNA3B和3C来指导RUNX3的激活。与直觉相反的是，EBNA2还劫持RBP-J靶向RUNX1上游的一个超级增强子区域，以在某些细胞背景中维持一些RUNX1表达，尽管具有双重功能的EBNA3B和3C蛋白会限制这种激活。有趣的是，EBV TF的B细胞基因组结合位点与RUNX3结合位点广泛重叠，并显示出RUNX基序的富集。因此，除了通过对RUNX转录的远程控制来操纵B细胞生长外，EBV在永生化过程中还可能利用RUNX蛋白作为辅助因子来解除许多B细胞基因的转录调控。
