Imperial College London
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ProfessorPaulFarrell

Faculty of Medicine, Department of Infectious Disease

Professor of Tumour Virology
 
 
 
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Contact

 

+44 (0)20 7594 2005p.farrell Website

 
 
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Location

 

Section of VirologyNorfolk PlaceSt Mary's Campus

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Summary

 

Publications

Citation

BibTex format

@article{Su:2021:10.1371/journal.ppat.1009834,
author = {Su, C and Lu, F and Soldan, SS and Lamontagne, RJ and Tang, H-Y and Napoletani, G and Farrell, PJ and Tempera, I and Kossenkov, AV and Lieberman, PM},
doi = {10.1371/journal.ppat.1009834},
journal = {PLoS Pathogens},
title = {EBNA2 driven enhancer switching at the CIITA-DEXI locus suppresses HLA class II gene expression during EBV infection of B-lymphocytes},
url = {http://dx.doi.org/10.1371/journal.ppat.1009834},
volume = {17},
year = {2021}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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 naïve 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.
AU  - Su,C
AU  - Lu,F
AU  - Soldan,SS
AU  - Lamontagne,RJ
AU  - Tang,H-Y
AU  - Napoletani,G
AU  - Farrell,PJ
AU  - Tempera,I
AU  - Kossenkov,AV
AU  - Lieberman,PM
DO  - 10.1371/journal.ppat.1009834
PY  - 2021///
SN  - 1553-7366
TI  - EBNA2 driven enhancer switching at the CIITA-DEXI locus suppresses HLA class II gene expression during EBV infection of B-lymphocytes
T2  - PLoS Pathogens
UR  - http://dx.doi.org/10.1371/journal.ppat.1009834
UR  - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000685263100006&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=a2bf6146997ec60c407a63945d4e92bb
UR  - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1009834
UR  - http://hdl.handle.net/10044/1/109208
VL  - 17
ER  -
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