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Epstein-Barr virus reactivation induces divergent abortive, reprogrammed, and host shutoff states by lytic progression

ABSTRACT: Viral infection leads to heterogeneous cellular outcomes ranging from resistance to virion amplification and cell death. In this study, we apply single-cell techniques to analyze diverse fate trajectories during Epstein-Barr virus (EBV) lytic reactivation in three B cell models. We expand upon the previous finding that c-Myc regulates lytic reactivation and determine that MYC downregulation during the lytic phase is correlated with a loss of germinal center (GC) B cell expression signatures. Consistent with prior work, lytic induction yields both abortive and complete reactivation. Abortive lytic cells, which express high STAT3 and initiate but do not complete the lytic cycle, also upregulate NF-kB and IRF3 pathway target genes. Cells that proceeded through the full lytic cycle exhibited unexpected and striking expression of genes associated with cellular reprogramming, developmental progenitor phenotypes, and cytokine upregulation. Distinct subpopulations of lytic cells further displayed variable profiles for transcripts known to escape virus-mediated host shutoff. These data reveal previously unknown and promiscuous outcomes of lytic reactivation with broad implications for viral replication and EBV-associated oncogenesis.

ORGANISM(S): Homo sapiens Saguinus oedipus

PROVIDER: GSE272763 | GEO | 2024/10/31

REPOSITORIES: GEO

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Project description:The Epstein-Barr virus (EBV) switches between latent and lytic phases in hosts that are important in developing related diseases. However, the underlying mechanism of how the viral latent-lytic switch is controlled and how EBV itself mediates this regulation remains largely unknown. This study identified the upregulated histone acetyl reader bromodomain-containing protein 7 (BRD7) during EBV latent infection. Based on the ChIP-sequencing of endogenous BRD7 in Burkitt lymphoma cells, we found that EBV drove BRD7 to regulate cellular and viral genomic loci, including the transcriptional activation of c-Myc, a recently reported regulator of EBV latency. Additionally, EBV-mediated BRD7 signals enriched around the FUSE site in chromosome 8, and the enhancer LOC108348026 in the lgH locus, which might activate the c-Myc alleles. Mechanically, EBV-encoded nuclear antigen 1 (EBNA1) bound and recruited BRD7 to colocalize at promotor regions of the related genes, thus serving as cofactors for the maintenance of viral latency. Moreover, the disruption of BRD7 decreased the c-Myc expression, induced the BZLF1 expression, and reactivated the lytic cycle. Our findings reveal the unique role of BRD7 hijacked by EBV in maintaining the viral latency state via chromatin remodeling. The study paved the way for understanding the new molecular mechanism of EBV-induced chromatin remodeling and latent-lytic switch regulation, providing novel therapeutic candidate targets for EBV persistent infection. With establishing persistent infection in most human hosts, EBV is usually at a latent infection state. How the viral latency is maintained in cells remains largely unknown. c-Myc was recently reported to act as a controller of the lytic switch, while whether and how EBV regulates it remains to be explored. Here, we identified that BRD7 is involved in controlling EBV latency. We found that EBV-mediated BRD7 was enriched in both the normal promoter regions and the translocation alleles of c-Myc, and the disruption of BRD7 decreased c-Myc expression to reactivate the lytic cycle. We also demonstrated that EBV-encoded EBNA1 bound to and regulated BRD7. Therefore, we reveal a novel mechanism by which EBV can regulate its infection state by hijacking host BRD7 to target c-Myc. Our findings will help future therapeutic intervention strategies of EBV infection and pathogenesis.

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Epstein-Barr virus reactivation induces divergent abortive, reprogrammed, and host shutoff states by lytic progression

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