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Gene expression patterns of EBV negative BJAB B-lymphoma lines stably and conditionally expressing EBNA-1

ABSTRACT: EBNA-1 is expressed in all EBV-associated malignancies and may play a role in transcription regulation through its DNA binding ability. This is our attempt to examine the effect of EBNA-1 on the expression of cellular genes. We have compared the transcription profiles of conditional and stable EBNA-1 transfected sublines of the EBV negative B-cell lymphoma BJAB where EBNA-1 was expressed for few days, few months or years. The non-specific effects were accounted by comparing the gene expression profiles of untransfected cells or cells transfected with the empty vector or cultured in the presence or absence of doxycycline.

ORGANISM(S): Homo sapiens

PROVIDER: GSE22964 | GEO | 2010/07/17

SECONDARY ACCESSION(S): PRJNA127853

REPOSITORIES: GEO

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Project description:Epstein-Barr virus (EBV) epigenetically reprogrammes B-lymphocytes to drive immortalization and facilitate viral persistence. Host-cell transcription is perturbed principally through the actions of EBV EBNA 2, 3A, 3B and 3C, with cellular genes deregulated by specific combinations of these EBNAs through unknown mechanisms. Comparing human genome binding by these viral transcription factors we discovered that 25% of binding sites were shared by EBNA 2 and the EBNA 3s and were located predominantly in enhancers. Moreover, 80% of potential EBNA 3A, 3B or 3C target genes were also targeted by EBNA 2, implicating extensive interplay between EBNA 2 and 3 proteins in cellular reprogramming. Investigating shared enhancer sites neighbouring two new targets (WEE1 and CTBP2) we discovered that EBNA 3 proteins repress transcription by modulating enhancer-promoter loop formation to establish repressive chromatin hubs or prevent assembly of active hubs. Re-ChIP analysis revealed that EBNA 2 and 3 proteins do not bind simultaneously at shared sites but compete for binding thereby modulating enhancer-promoter interactions. At an EBNA 3-only intergenic enhancer site between ADAM28 and ADAMDEC1 EBNA 3C was also able to independently direct epigenetic repression of both genes through enhancer-promoter looping. Significantly, studying shared or unique EBNA 3 binding sites at WEE1, CTBP2, ITGAL (LFA-1 alpha chain), BCL2L11 (Bim) and the ADAMs, we also discovered that different sets of EBNA 3 proteins bind regulatory elements in a gene and cell-type specific manner. Binding profiles correlated with the effects of individual EBNA 3 proteins on the expression of these genes, providing a molecular mechanism for the targeting of different sets of cellular genes by the EBNA 3s. Our results therefore highlight the influence of the genomic and cellular context in determining the specificity of gene deregulation by EBV and provide a paradigm for host-cell reprogramming through modulation of enhancer-promoter interactions by viral transcription factors. Examination of EBNA 3 protein binding (EBNA 3A, 3B and 3C) using a pan-specific antibody and EBNA 2 binding in single ChIP-seq experiments carried out in the Mutu III Burkitt's lymphoma cell-line.

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Gene expression patterns of EBV negative BJAB B-lymphoma lines stably and conditionally expressing EBNA-1

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