Abstract
Epstein-Barr virus (EBV) infection converts resting human B cells into permanently proliferating lymphoblastoid cell lines (LCLs). The Epstein-Barr virus nuclear antigen 2 (EBNA2) plays a key role in this process. It preferentially binds to B cell enhancers and establishes a specific viral and cellular gene expression program in LCLs. The cellular DNA binding factor CBF1/CSL serves as a sequence specific chromatin anchor for EBNA2. The ubiquitous expression of this highly conserved protein raises the question whether additional cellular factors might determine EBNA2 chromatin binding selectively in B cells. Here we used CBF1 deficient B cells to identify cellular genes up or downregulated by EBNA2 as well as CBF1 independent EBNA2 chromatin binding sites. Apparently, CBF1 independent EBNA2 target genes and chromatin binding sites can be identified but are less frequent than CBF1 dependent EBNA2 functions. CBF1 independent EBNA2 binding sites are highly enriched for EBF1 binding motifs. We show that EBNA2 binds to EBF1 via its N-terminal domain. CBF1 proficient and deficient B cells require EBF1 to bind to CBF1 independent binding sites. Our results identify EBF1 as a co-factor of EBNA2 which conveys B cell specificity to EBNA2.
Highlights
CBF1/CSL (C promoter binding factor, Suppressor of Hairless, and lag1 called RBPJ or RBPJκ) is a cellular DNA binding protein, ubiquitously expressed in all mammalian tissues
We show that Epstein-Barr virus nuclear antigen 2 (EBNA2) can form complexes with early B cell factor 1 (EBF1), a B cell specific DNA binding transcription factor, and EBF1 stabilizes EBNA2 chromatin binding
This EBNA2/EBF1 complex might serve as a novel target to develop future small molecule strategies that act as antivirals in latent B cell infection
Summary
CBF1/CSL (C promoter binding factor, Suppressor of Hairless, and lag called RBPJ or RBPJκ) is a cellular DNA binding protein, ubiquitously expressed in all mammalian tissues. CBF1 serves as a DNA adaptor molecule that recruits either repressors or activators to transcriptional control elements like enhancers and transcription start sites of genes and is described as the major downstream effector of the cellular Notch signal transduction pathway [1]. Despite the ubiquitous expression of its chromatin anchor CBF1, target gene control by Notch is context dependent and requires tissue and lineage specific cooperating transcription factors [2]. In B cells, latently infected with Epstein-Barr virus (EBV), CBF1 anchors the viral transactivator protein EBV nuclear antigen 2 (EBNA2) to chromatin and thereby initiates a cascade of signaling events that coordinate B cell activation and proliferation of infected cells [3,4,5,6]. In contrast to the universal expression and pleiotropic activities of Notch, the expression and the biological activity of EBNA2 is strictly confined to EBV infected B cells, characterized by a transcription program that phenocopies antigen activated B cell blasts [8, 9]
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