Imperial College London
Alternate

Dr Rob White

Faculty of Medicine, Department of Infectious Disease

Senior Lecturer
 
 
 
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Contact

 

+44 (0)20 7594 1124robert.e.white Website

 
 
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Location

 

308Norfolk PlaceSt Mary's Campus

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Summary

 

Publications

Citation

BibTex format

@article{Styles:2017:10.1371/journal.pbio.2001992,
author = {Styles, CT and Bazot, Q and Parker, GA and White, RE and Paschos, K and Allday, MJ},
doi = {10.1371/journal.pbio.2001992},
journal = {PLoS Biology},
pages = {1--30},
title = {EBV epigenetically suppresses the B cell-to-plasma cell differentiation pathway while establishing long-term latency},
url = {http://dx.doi.org/10.1371/journal.pbio.2001992},
volume = {15},
year = {2017}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Mature human B cells infected by Epstein-Barr virus (EBV) become activated, grow, andproliferate. If the cells are infected ex vivo, they are transformed into continuously proliferatinglymphoblastoid cell lines (LCLs) that carry EBV DNA as extra-chromosomal episomes,express 9 latency-associated EBV proteins, and phenotypically resemble antigen-activatedB-blasts. In vivo similar B-blasts can differentiate to become memory B cells (MBC), inwhich EBV persistence is established. Three related latency-associated viral proteinsEBNA3A, EBNA3B, and EBNA3C are transcription factors that regulate a multitude of cellulargenes. EBNA3B is not necessary to establish LCLs, but EBNA3A and EBNA3C arerequired to sustain proliferation, in part, by repressing the expression of tumour suppressorgenes. Here we show, using EBV-recombinants in which both EBNA3A and EBNA3C canbe conditionally inactivated or using virus completely lacking the EBNA3 gene locus, that—after a phase of rapid proliferation—infected primary B cells express elevated levels of factorsassociated with plasma cell (PC) differentiation. These include the cyclin-dependentkinase inhibitor (CDKI) p18INK4c, the master transcriptional regulator of PC differentiation Blymphocyte-induced maturation protein-1 (BLIMP-1), and the cell surface antigens CD38and CD138/Syndecan-1. Chromatin immunoprecipitation sequencing (ChIP-seq) and chromatinimmunoprecipitation quantitative PCR (ChIP-qPCR) indicate that in LCLs inhibition ofCDKN2C (p18INK4c) and PRDM1 (BLIMP-1) transcription results from direct binding ofEBNA3A and EBNA3C to regulatory elements at these loci, producing stable reprogramming.Consistent with the binding of EBNA3A and/or EBNA3C leading to irreversible epigeneticchanges, cells become committed to a B-blast fate <12 days post-infection and areunable to de-repress p18INK4c or BLIMP-1—in either newly infected cells or conditionalLCLs—by inactivating EBNA3A and EBNA3C. In vitro, about 20 days aft
AU  - Styles,CT
AU  - Bazot,Q
AU  - Parker,GA
AU  - White,RE
AU  - Paschos,K
AU  - Allday,MJ
DO  - 10.1371/journal.pbio.2001992
EP  - 30
PY  - 2017///
SN  - 1544-9173
SP  - 1
TI  - EBV epigenetically suppresses the B cell-to-plasma cell differentiation pathway while establishing long-term latency
T2  - PLoS Biology
UR  - http://dx.doi.org/10.1371/journal.pbio.2001992
UR  - https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.2001992
UR  - http://hdl.handle.net/10044/1/52043
VL  - 15
ER  -
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