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Genome-Wide Mapping of E2F1 Transcription Factor Binding Sites Across Human and Epstein-Barr virus (EBV) Chromosomes

ABSTRACT: E2F1, the first member of E2F family transcription factors, plays a central role in cell cycle progression, DNA-damage response and apoptosis. Accumulating evidence indicates that E2F1 regulates replication of several DNA viruses. We and others previously described deregulated E2F1 expression during Epstein-Barr virus (EBV) induced B-cell transformation and its role in survival of transformed B-lymphocytes in response to DNA-damage signals. In addition, global transcriptomic analyses (GSE235941, GSE237484) reveal that E2F1 expression is transcriptionally activated during EBV latent infection in B-lymphocytes but suppressed during lytic-cycle reactivation. However, the precise regulations by which E2F1 sustains EBV latent to lytic switch remains unanswered. Given that E2F activity is often deregulated by infection with DNA viruses, the main objective of our study was to investigate the genome-wide occupancy of E2F1 on both cellular and viral gene promoters, driving EBV pathogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE285456 | GEO | 2025/06/12

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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Genome-Wide Mapping of E2F1 Transcription Factor Binding Sites Across Human and Epstein-Barr virus (EBV) Chromosomes

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