De Novo Polycomb Recruitment: Lessons from Latent Herpesviruses

Abstract

The Human Herpesviruses persist in the form of a latent infection in specialized cell types. During latency, the herpesvirus genomes associate with cellular histone proteins and the viral lytic genes assemble into transcriptionally repressive heterochromatin. Although there is divergence in the nature of heterochromatin on latent herpesvirus genomes, in general the genomes assemble into forms of heterochromatin that can convert to euchromatin to permit gene expression and therefore reactivation. This reversible form of heterochromatin is known as facultative heterochromatin and is most commonly characterized by polycomb silencing. Polycomb silencing is prevalent on the cellular genome and plays a role in developmentally regulated and imprinted genes, as well as X chromosome inactivation. As herpesviruses initially enter the cell in an un-chromatinized state, they provide an optimal system to study how de novo facultative heterochromatin is targeted to regions of DNA and how it contributes to silencing. Here, we describe how polycomb-mediated silencing potentially assembles onto herpesvirus genomes, synergizing what is known about herpesvirus latency with facultative heterochromatin targeting to the cellular genome. A greater understanding of polycomb silencing of herpesviruses will inform on the mechanism of persistence and reactivation of these pathogenic human viruses and provide clues regarding how de novo facultative heterochromatin forms on the cellular genome.

DLK-Dependent Biphasic Reactivation of Herpes Simplex Virus Latency Established in the Absence of Antivirals

“…Viral genome synthesis is a pre-requisite for true-late (TL) mRNA transcription, likely due to a shift in genome accessibility and increased binding of host transcriptional machinery (44). In contrast to productive infection, during HSV-1 latency, viral lytic mRNAs are largely transcriptionally repressed and promoters assemble into silent heterochromatin marked by the tri-methylation of histone H3 lysine 27 (H3K27me3) and di/tri-methylation of histone H3 on lysine 9 (H3K9me2/3) (45)(46)(47)(48)(49)(50). The initiation of viral gene expression during reactivation is induced from a heterochromatinassociated viral genome and occurs in the absence of viral activators like VP16.…”

DLK-dependent biphasic reactivation of herpes simplex virus latency established in the absence of antivirals

“…The kinetics of H3K27me3 deposition remain to be investigated in vitro , but if they are mirrored this could suggest that active chromatinization and reinforcement of silencing continues even after initial shut-down of viral gene expression. In the cellular context, H3K27me3 is linked with the recruitment of canonical Polycomb repressor complex 1 (cPRC1), which may reinforce silencing through long-range chromosomal interactions or 3D compaction (54, 108, 109). It is therefore possible that even following H3K27me3 formation on the genome, there are additional layers of protein recruitment that build up over time.…”

“…Viral genome synthesis is a pre-requisite for true-late (TL) mRNA transcription, likely due to a shift in genome accessibility and increased binding of host transcriptional machinery (44). In contrast to productive infection, during HSV-1 latency, viral lytic mRNAs are largely transcriptionally repressed and promoters assemble into silent heterochromatin marked by the tri-methylation of histone H3 lysine 27 (H3K27me3) and di/tri-methylation of histone H3 on lysine 9 (H3K9me2/3) (45)(46)(47)(48)(49)(50). The initiation of viral gene expression during reactivation is induced from a heterochromatinassociated viral genome and occurs in the absence of viral activators like VP16.…”

“…During HSV-1 latency, viral transcription is largely limited to a family of non-coding RNAs known as the latency-associated transcripts (LATs) (46)(47)(48) . Viral lytic mRNAs are largely transcriptionally repressed and promoters assemble into silent heterochromatin marked by the tri-methylation of histone H3 lysine 27 (H3K27me3) and di/tri-methylation of histone H3 on lysine 9 (H3K9me2/3) (49)(50)(51)(52)(53)(54). The initiation of viral gene expression during reactivation is induced from a heterochromatin-associated viral genome and occurs in the absence of viral activators like VP16.…”

Ex Vivo Herpes Simplex Virus Reactivation Involves a DLK-Dependent Wave of Lytic Gene Expression that is Independent of Histone Demethylase Activity and Viral Genome Synthesis

“…During a latent infection of neurons, the HSV genome is assembled into repressive heterochromatin. This has been characterized by the enrichment of post-translational modifications on histone H3; namely di-and tri-methyl lysine 9 (H3K9me2/3) and tri-methyl lysine 27 (H3K27me3) on lytic promoters (11)(12)(13)(14)(15)(16)(17). By assembling into heterochromatin, viral lytic transcripts are maintained in a silent state.…”