Chromatin Dynamics during Lytic Infection with Herpes Simplex Virus 1

Abstract

Latent HSV-1 genomes are chromatinized with silencing marks. Since 2004, however, there has been an apparent inconsistency in the studies of the chromatinization of the HSV-1 genomes in lytically infected cells. Nuclease protection and chromatin immunoprecipitation assays suggested that the genomes were not regularly chromatinized, having only low histone occupancy. However, the chromatin modifications associated with transcribed and non-transcribed HSV-1 genes were those associated with active or repressed transcription, respectively. Moreover, the three critical HSV-1 transcriptional activators all had the capability to induce chromatin remodelling, and interacted with critical chromatin modifying enzymes. Depletion or overexpression of some, but not all, chromatin modifying proteins affected HSV-1 transcription, but often in unexpected manners. Since 2010, it has become clear that both cellular and HSV-1 chromatins are highly dynamic in infected cells. These dynamics reconcile the weak interactions between HSV-1 genomes and chromatin proteins, detected by nuclease protection and chromatin immunoprecipitation, with the proposed regulation of HSV-1 gene expression by chromatin, supported by the marks in the chromatin in the viral genomes and the abilities of the HSV-1 transcription activators to modulate chromatin. It also explains the sometimes unexpected results of interventions to modulate chromatin remodelling activities in infected cells.

The Differential Mobilization of Histones H3.1 and H3.3 by Herpes Simplex Virus 1 Relates Histone Dynamics to the Assembly of Viral Chromatin

“…The dynamics of viral chromatin are proving important in the regulation of HSV-1 gene expression (reviewed in [50]). Whilst cellular mechanisms promote the establishment of repressive viral chromatin to silence viral gene expression, viral mechanisms counteract silencing and promote the establishment of transcriptionally active viral chromatin.…”

Spatiotemporal dynamics of HSV genome nuclear entry and compaction state transitions using bioorthogonal chemistry and super-resolution microscopy

“…Previous work has helped elucidate many aspects of the key processes of capsid transport within the cytoplasm, engagement with the nuclear pore, uncoating and genome transport into the nucleus [1,[4][5][6][7][8][9][41][42][43][44]. Moreover for some viruses including HSV, the nature of the infecting genome has been extensively pursued by biochemical analyses, e.g., micrococcal nuclease (MCN) digestion [45][46][47][48][49][50][51] or by chromatin immunoprecipitation (ChiP) with antibodies to specific host cell histones or histone isoforms [52][53][54][55], Nevertheless altogether these studies give an incomplete understanding of infecting genome dynamics, at times difficult to reconcile [56] and with little insight into spatial aspects of transport, uncoating and organisation of the genome itself during the progressive stages or early infection. Thus many fundamental aspects of early genome dynamics remain poorly understood.…”

“…On the other hand ChiP analyses, which usually address a minor fraction of the total DNA, suggests that histones in some form are associated with at least a population of genomes [52,53,55,70,71]. One model attempting to integrate results from different approaches proposes that infecting genomes associate with some form of nucleoprotein complex that includes histones but in a non-conventional highly distributive, rapidly associating/dissociating organisation [56,69]. We show that after capsid exit and nuclear import, genomes expand but in a constrained and distinct state and then further decondenses in a discernible fashion prior to replication, and that replication and potentially associated transcription result in further extensive dissipation within the nucleus.…”

Characterization of Elements Regulating the Nuclear-to-Cytoplasmic Translocation of ICP0 in Late Herpes Simplex Virus 1 Infection

“…As a counteraction, HSV-1 deploys ICP0 to target PML and Sp100 for proteosomal degradation, which leads to the dispersal of ND10 bodies and the derepression of viral genes (2,8). Another example is the formation of the naked incoming HSV-1 genome into the nucleosome-like structure by associating it with host histones and chromatin remodelers (14,15). ICP0 is also known to interact with host factors such as CoREST and CLOCK to modulate chromatin-associated gene regulation (16,17).…”