Locus-specific proteomics identifies CHD4 and Polycomb PRC1 as novel repressors of Epstein-Barr virus lytic reactivation

ABSTRACT: The Epstein Barr virus (EBV) is a human gammaherpesvirus which infects over 90% of the global population and is associated with lymphoid and epithelioid cancers. After infection, EBV enters a latent state in B-cells where the viral genome persists as a nuclear episome maintained by expression of a small number of latency-associated viral proteins. The lytic viral proteins, required for DNA replication and virion production, are silenced by cellular epigenetic mechanisms. The immediate-early lytic gene BZLF1 is the most important target for transcriptional repression, as its expression triggers the entire lytic cascade. To gain insight into the factors restricting BZLF1 expression, we used the PICh method of locus specific proteomics (Proteomics of Isolated Chromatin segments) to identify proteins which occupy BZLF1 promoter DNA. We show that the nucleosome remodeler CHD4 and components of the Polycomb complex PRC1 are novel repressors of BZLF1 and that both are required to prevent spontaneous lytic reactivation in Burkitt lymphoma cells. We also reveal a marked, cell wide loss of the PRC1 histone mark (H2AK119Ub) during the lytic cycle which is dependent on immediate-early and early lytic gene expression. A proteomic analysis of Burkitt lymphoma cells containing lytic EBV identified upregulation of human de-ubiquitinase USP17 as a candidate for H2AK119Ub removal. Our study demonstrates the power of proteomic approaches to identify repressors of EBV reactivation and provides new insight into how EBV manipulates epigenetic mechanisms during the lytic cycle.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): B Cell

SUBMITTER: James Williamson  

LAB HEAD: Paul Lehner

PROVIDER: PXD068122 | Pride | 2026-02-11

REPOSITORIES: Pride