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BRD7 is a candidate tumour suppressor gene required for p53 function

ABSTRACT: Oncogene-induced senescence (OIS) is a p53-dependent defence mechanism against uncontrolled proliferation. Consequently, many human tumours harbour p53 mutations while others show a dysfunctional p53 pathway, frequently by unknown mechanisms. We identified BRD7, a bromodomain-containing protein whose inhibition allows full neoplastic transformation in the presence of wild-type p53. Intriguingly, in human breast tumours harbouring wild-type, but not mutant p53, the BRD7 gene locus was frequently deleted and low BRD7 expression was found in a subgroup of tumours. Functionally, BRD7 is required for efficient p53-mediated transcription of a subset of target genes. BRD7 interacts with p53 and p300, and is recruited to target gene promoters, affecting histone acetylation, p53 acetylation, and promoter activity. Thus, BRD7 suppresses tumourigenicity by serving as a p53 cofactor required for efficient induction of p53-dependent OIS.

ORGANISM(S): Homo sapiens

PROVIDER: GSE20076 | GEO | 2010/03/14

SECONDARY ACCESSION(S): PRJNA124195

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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BRD7 is a candidate tumour suppressor gene required for p53 function

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