Abstract
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.
Highlights
The mammalian runt-related family of transcription factors (TF) (RUNX) is encoded by three separate genes (RUNX1, RUNX2 and RUNX3) located on different chromosomes that play crucial roles in the control of a range of developmental and differentiation processes [1]
We reveal that the EpsteinBarr virus (EBV) TFs EBNA3B and EBNA3C contribute to RUNX3 activation in EBV-infected cells by targeting the same element
To elucidate the mechanism of EBNA2 activation of RUNX3 in EBV infected cells we examined EBNA2 binding data obtained by ChIP-sequencing from two EBV-infected cell lines, one a Burkitt’s lymphoma cell line expressing the full panel of EBV latent genes (Mutu III [16]), and the other the Tier 1 ENCODE EBV-immortalized lymphoblastoid cell line GM12878
Summary
The mammalian runt-related family of transcription factors (TF) (RUNX) is encoded by three separate genes (RUNX1, RUNX2 and RUNX3) located on different chromosomes that play crucial roles in the control of a range of developmental and differentiation processes [1]. RUNX genes have distinct patterns of tissue-specific expression, but all bind the same DNA consensus site, through heterodimerization with the non-DNA binding CBF protein, to activate or repress transcription [2,3]. Disruption or misregulation of RUNX expression is associated with a wide range of human tumours [1]. For all RUNX genes transcription initiates from one of two promoters located distal (P1) or proximal (P2) to the translation start site that give rise
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