Highlights d CRISPR/Cas9 screen highlights host epigenetic suppressors of the EBV lytic cycle d EBV senses MYC abundance to maintain B cell latency d MYC depletion alters three-dimensional EBV genomic architecture d FACT is a druggable target for Burkitt B cell EBV latency reversal
To accomplish the remarkable task of lifelong infection, Epstein-Barr
virus (EBV) switches between four viral genome latency and lytic programs to
navigate the B-cell compartment and evade immune responses. The transforming
program, comprised of highly immunogenic EBV nuclear antigen (EBNA) and Latent
Membrane Proteins (LMP), is expressed in newly infected B-lymphocytes and in
post-transplant lymphomas. Upon memory cell differentiation and in most
EBV-associated Burkitt lymphomas (BL), all but one viral antigen are repressed
for immunoevasion. To gain insights into epigenetic mechanisms that restrict
immunogenic oncoprotein expression, a genome-scale CRISPR/Cas9 screen was
performed in EBV+ BL cells. Here we show that the ubiquitin ligase UHRF1 and its
DNA methyltransferase partner DNMT1 were critical for restriction of EBNA and
LMP expression. All UHRF1 reader and writer domains were necessary for
silencing, and DNMT3B was identified as an upstream viral genome CpG methylation
initiator. Polycomb repressive complex I exerted a further layer of control over
LMP expression, suggesting a second mechanism for latency program switching.
UHRF1, DNMT1 and DNMT3B are upregulated in germinal center B-cells, the BL cell
of origin, providing a molecular link between B-cell state and EBV latency
program. These results suggest rational therapeutic targets to manipulate EBV
oncoprotein expression.
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