Journal
PLOS PATHOGENS
Volume 17, Issue 8, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.ppat.1009834
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Funding
- NIH [R01 CA093606, R01 DE017336, R01 AI153508, R01AI130209, R50CA221838, R50 CA211199]
- MRC [MR/S0022597/1]
- Imperial NIHR BRC
- [P30 CA010815]
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The study reveals a new transcriptional mechanism by which EBV encoded EBNA2 down-regulates HLA class II gene expression, impacting T-cell recognition of infected cells. EBNA2 competes with CIITA binding, leading to CIITA transcriptional down-regulation and subsequent HLA-II gene expression attenuation. This indirect regulation is proposed to be due to enhancer competition at neighboring chromosome domains.
Author summary We describe a novel transcriptional mechanism through which EBV encoded EBNA2 down-regulates HLA class II gene expression. EBNA2 is known to be a potent transcriptional activator and strengthens enhancer formation at many sites in B-lymphocytes. We show that EBNA2 binds to an enhancer element at the DEXI gene that competes with CIITA gene promoter, leading to the down regulation of CIITA transcription. As CIITA is the master regulator of HLA class II gene expression, these findings reveal a novel, highly indirect mechanism for EBNA2 down-regulation of HLA II gene transcription. Down regulation of HLA class II gene expression by EBNA2 is functionally important for the attenuation of T-cell recognition of EBV infected cells, and likely to contribute to EBV persistence and lymphomagenesis in vivo. Viruses suppress immune recognition through diverse mechanisms. Epstein-Barr Virus (EBV) establishes latent infection in memory B-lymphocytes and B-cell malignancies where it impacts B-cell immune function. We show here that EBV primary infection of naive B-cells results in a robust down-regulation of HLA genes. We found that the viral encoded transcriptional regulatory factor EBNA2 bound to multiple regulatory regions in the HLA locus. Conditional expression of EBNA2 correlated with the down regulation of HLA class II transcription. EBNA2 down-regulation of HLA transcription was found to be dependent on CIITA, the major transcriptional activator of HLA class II gene transcription. We identified a major EBNA2 binding site downstream of the CIITA gene and upstream of DEXI, a dexamethasone inducible gene that is oriented head-to-head with CIITA gene transcripts. CRISPR/Cas9 deletion of the EBNA2 site upstream of DEXI attenuated CIITA transcriptional repression. EBNA2 caused an increase in DEXI transcription and a graded change in histone modifications with activation mark H3K27ac near the DEXI locus, and a loss of activation marks at the CIITA locus. A prominent CTCF binding site between CIITA and DEXI enhancers was mutated and further diminished the effects of EBNA2 on CIITA. Analysis of HiC data indicate that DEXI and CIITA enhancers are situated in different chromosome topological associated domains (TADs). These findings suggest that EBNA2 down regulates HLA-II genes through the down regulation of CIITA, and that this down regulation is an indirect consequence of EBNA2 enhancer formation at a neighboring TAD. We propose that enhancer competition between these neighboring chromosome domains represents a novel mechanism for gene regulation demonstrated by EBNA2.
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