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.

De Novo Polycomb Recruitment and Repressive Domain Formation

“…This evidence suggests that the sites where H3K27M and Ezhip stall the PRC2 complex may coincide with the de novo recruitment sites, although this is an unproven hypothesis. Hence, an example of how Polycomb dysregulation, particularly de novo recruitment, renders the development of certain disorders such as cancer [ 189 , 190 , 191 , 192 , 193 ]. Similarly, the Eed mutant protein found in the Weaver syndrome is deficient in spreading H3K27me3 [ 142 ], potentially explaining the genetic deregulation in the disease.…”

Key questions on the epigenetics of herpes simplex virus latency

“…The complex that adds the H3K27me3 mark, and also has H3K27me3 reading function (PRC2), is known to associate with the HSV genome following the resolution of acute infection in mice [ 9 ]. A second complex, known as PRC1, exists in multiple forms and can bind H3K27me3 to mediate gene silencing via genome compaction, three-dimensional interactions, and/or formation of phase separated domains [ 10 ]. A component of PRC1, Bmi1, has only limited association with the latent HSV genome [ 6 , 9 ].…”

“…In addition, the relative levels of PRC1 proteins also changes with neuronal maturation [ 17 ]. Polycomb group complexes display considerable heterogeneity in their protein composition, which can result in different consequences on chromatin structure [ 10 ]. Therefore, it is probable that are multiple unexplored differences in the epigenetic environment of neurons compared to nonneuronal cells and likely also between different neuronal subtypes, which could influence epigenetics on the HSV genome.…”

Epigenetic Regulation by Polycomb Complexes from Drosophila to Human and Its Relation to Communicable Disease Pathogenesis

“…They are the Herpes Simplex Virus 1 (HSV1), HSV 2, Varicella-Zoster Virus (VZV/HHV3), Epstein–Barr Virus (EBV/HHV4), Cytomegalovirus (HHV5), Human Herpes Virus-6 (HHV6), HHV7, and Kaposi’s Sarcoma Herpes Virus (KSHV/HHV8). Herpes viruses can remain dormant in the host and create recurrent infections [ 123 ]. While in latency, Herpes virus genomes associate with cellular histones to create a chromatinized structure.…”

“…While in latency, Herpes virus genomes associate with cellular histones to create a chromatinized structure. This enables Herpes virus genomes to suppress their lytic genes, avoid being identified as foreign DNA particles, and remain undetected [ 123 , 124 ]. In order to better understand the natural latency of Herpes viruses, the epigenetic structure of viral genomes has been examined in cells and tissues separated from human individuals [ 43 , 46 , 47 , 125 , 126 ].…”