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RNA-sequencing analysis identifies BRLF1-dependent viral and cellular transcriptome during EBV primary infection in B lymphoma cells

ABSTRACT: Purpose: Immediate-early protein BRLF1 plays an important role in lytic infection of Epstein-Barr virus (EBV), it activates lytic viral transcription and viral DNA replication, affects cell cycle and suppresses inflammatory responses. However, the understanding of BRLF1 influence on cellular gene expression during early lytic cycle remains limited. Methods:RNA-sequencing analysis identified the differentially expressed genes (DEGs) in B lymphoma cells undergoing wild type and BRLF1-deficient EBV primary infection. The libraries were sequenced on an Illumina HiSeq-Xten platform and 150 bp paired‐end reads were generated. An average read depth of 12G reads per sample was collected and analyzed. Data analysis was performed with Molecule Annotation System 3.0. Results: A total of 159 unigenes were annotated and the major differentially enriched pathways were related to DNA replication and transcription, immune and inflammatory response, cytokine-receptor interaction and chemokine signaling, ECM-receptor interaction and focal adhesion. Further the mass spectrometry identified the BRLF1-binding proteins and showed that BRLF1 employed different strategies to influence RNA polymerase II-dependent viral and cellular transcription, by binding to a particular RREs motif and binding to unique transcription factors which binding to specific motifs. Conclusions: Our study characterized the BRLF1-dependent cellular and viral transcriptional profile during primary infection and then revealed the important virus-cell interaction and alterations of cell activity for EBV primary infection and lytic replication.

ORGANISM(S): Homo sapiens

PROVIDER: GSE154786 | GEO | 2020/08/30

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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RNA-sequencing analysis identifies BRLF1-dependent viral and cellular transcriptome during EBV primary infection in B lymphoma cells

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