Epigenetic inhibitors of BAF chromatin remodeling complexes activate herpes simplex virus 1 transcription in epithelial and fibroblast cells BAF chromatin remodeling complexes during HSV-1 lytic infection
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Herpes simplex virus 1 (HSV-1) is a prevalent DNA virus with a major impact on human health. The HSV-1 genome is assembled into silenced stable chromatin and minimally transcribed during latent infection in neurons or assembled into permissive highly dynamic chromatin and highly transcribed during lytic infection in non-neuronal cells. It is unclear how HSV-1 genomes transition from static to highly dynamic chromatin during reactivation, but epigenetics and chromatin dynamics have been proposed to play an important role. Chromatin remodeling complexes regulate cellular chromatin dynamics and contribute to DNA transcription, replication, and repair. The BAF family of chromatin remodeling complexes includes three ubiquitously expressed complexes (cBAF, PBAF, and GBAF) and cell type-specific complexes, including a neuronal BAF (nBAF). Three subunits shared by all BAF complexes and a unique subunit each from cBAF, PBAF, and GBAF were enriched in herpes nuclear domains (HND), which are the novel nuclear domains formed during lytic infection in which HSV-1 genomes are transcribed, replicated, and packaged, and the ATPase SMARCA4, which is shared by all BAF complexes, bound HSV-1 genomes. Four structurally unrelated small molecule bromodomain inhibitors of BAF complexes modulated the abundance of a subset of HSV-1 transcripts, but not genome copy numbers. The inhibitors did not inhibit the recruitment of BAF subunits to HND, and four commonly acetylated histone residues were depleted from HND. We propose that BAF complexes are recruited to the HND by their known interactions with viral proteins and independently of their bromodomains and act early during HSV-1 infection to inhibit viral transcription. These findings also have major implications to the potential of anticancer therapy targeting epigenetic modifiers inducing reactivation of latent herpes simplex viruses.
Author Summary
Herpes simplex virus 1 (HSV-1) infects over two-thirds of the world population. HSV-1 establishes latency in neurons, resulting in life-long infection. Although most infections are asymptomatic, reactivation can produce a wide range of clinical manifestations, including cold sores, stromal keratitis, and encephalitis. Available treatments do not prevent reactivation or eliminate latent viral reservoirs, as no viral proteins are expressed during latency. Epigenetic regulation plays a role during the lytic and latent cycles. Lytic HSV-1 chromatin is highly dynamic whereas latent chromatin is stable. Chromatin dynamics are regulated by multiple factors, including the chromatin remodeling complexes. Here we show that the BAF chromatin remodeling complexes regulate HSV-1 transcription during lytic infection in primary fibroblast and transformed epithelial human cells. These complexes that are known to be recruited to the viral genomes by viral proteins counterintuitively downregulate viral transcription before the onset of DNA replication but have no effect on viral DNA replication or later gene transcription. We propose that these factors contribute to the orchestrated cascade of viral gene expression.
