Changes to Euchromatin on LAT and ICP4 Following Reactivation Are More Prevalent in an Efficiently Reactivating Strain of HSV-1

Creech, Clinton C.; Neumann, Donna M.

doi:10.1371/journal.pone.0015416

Cited by 16 publications

(20 citation statements)

References 53 publications

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“…We and others have previously reported that transcriptionally permissive histone marks, specifically acetyl H3 K9, K14, and dimethyl H3 K4, accumulate on the repressed IE regions of HSV-1 by 2 to 4 h following the application of reactivation stimuli (1,13,31). This provides evidence that the distinct chromatin domains observed during latency are no longer intact at early times following reactivation stressors.…”

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confidence: 52%

“…These key findings provide evidence that HSV-1 latency is established and maintained, at least in part, by complex epigenetic mechanisms that further poise the virus for reactivation. To support this, recent data show that the enrichments of euchromatic histone marks on the HSV-1 LAT and IE promoters change in response to reactivation stimuli in both rabbit and mouse models latently infected with wild-type HSV-1 (1,13,26,31,36). Specifically, histone marks on ICP0 and ICP4 rapidly and transiently become more euchromatic in nature, while the LAT region loses enrichment of euchromatic histone marks as LAT is degraded at early times in reactivation in the two different in vivo models (1,13,31).…”

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confidence: 98%

“…To support this, recent data show that the enrichments of euchromatic histone marks on the HSV-1 LAT and IE promoters change in response to reactivation stimuli in both rabbit and mouse models latently infected with wild-type HSV-1 (1, 13, 26, 31, 36). Specifically, histone marks on ICP0 and ICP4 rapidly and transiently become more euchromatic in nature, while the LAT region loses enrichment of euchromatic histone marks as LAT is degraded at early times in reactivation in the two different in vivo models (1,13,31). Considering the reversibility of latency reactivation in vivo, it is logical that epigenetic mechanisms play a critical role in this transition in the neuron at very early times following a reactivation stressor.…”

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confidence: 99%

“…Recent studies have shown that there are epigenetic components involved in HSV-1 latency and in reactivation (1,13,21,31,36,39). For example, during latency, the LAT regions of the LAT reactivation-critical promoter and LAT 5= exon (containing the LAT enhancer) (8) are enriched in euchromatic histone markers compared to the promoters of the immediateearly (IE) ICP0, ICP4, and ICP27 genes (1,13,21,24,31). Further, these permissive marks established on the LAT are independent of LAT transcription (24).…”

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confidence: 99%

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CTCF Occupation of the Herpes Simplex Virus 1 Genome Is Disrupted at Early Times Postreactivation in a Transcription-Dependent Manner

Ertel

Cammarata

Hron

et al. 2012

J Virol

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cIn herpes simplex virus 1 (HSV-1), binding clusters enriched in CTCF during latency have been previously identified. We hypothesized that CTCF binding to CTCF clusters in HSV-1 would be disrupted in a reactivation event. To investigate, CTCF occupation of three CTCF binding clusters in HSV-1 was analyzed following sodium butyrate (NaB)-and explant-induced reactivation in the mouse. Our data show that the CTCF domains positioned within the HSV-1 genome, specifically around the latency-associated transcript (LAT) and ICP0 and ICP4 regions of the genome, lose CTCF occupancy following the application of reactivation stimuli in wild-type virus. We also found that CTCF binding clusters upstream of the ICP0 and ICP4 promoters both function as classical insulators capable of acting as enhancer blockers of the LAT enhancer. Finally, our results suggest that CTCF occupation of domains in HSV-1 may be differentially regulated both during latency and at early times following reactivation by the presence of lytic transcripts and further implicate epigenetic regulation of HSV-1 as a critical component of the latency-reactivation transition.T he human alphaherpesvirus herpes simplex virus 1 (HSV-1), infects sensory neurons, where it establishes a lifelong latent infection as a circular episome associated with histones (6,16,38,40,44). During HSV-1 latency, the latency-associated transcript (LAT) is abundantly transcribed, and lytic regions are, in essence, silent (6,38,40). Recent studies have shown that there are epigenetic components involved in HSV-1 latency and in reactivation (1,13,21,31,36,39). For example, during latency, the LAT regions of the LAT reactivation-critical promoter and LAT 5= exon (containing the LAT enhancer) (8) are enriched in euchromatic histone markers compared to the promoters of the immediateearly (IE) ICP0, ICP4, and ICP27 genes (1,13,21,24,31). Further, these permissive marks established on the LAT are independent of LAT transcription (24). Additional reports indicated that the LAT region of HSV-1 also contains facultative heterochromatin (12, 25), a form of repressed chromatin that can convert to euchromatin via posttranslational histone tail modifications. Consequently, the nearby IE regions are also enriched with repressive histone marks that have been characterized predominantly as facultative heterochromatin (12,25,26,45). These key findings provide evidence that HSV-1 latency is established and maintained, at least in part, by complex epigenetic mechanisms that further poise the virus for reactivation. To support this, recent data show that the enrichments of euchromatic histone marks on the HSV-1 LAT and IE promoters change in response to reactivation stimuli in both rabbit and mouse models latently infected with wild-type HSV-1 (1, 13, 26, 31, 36). Specifically, histone marks on ICP0 and ICP4 rapidly and transiently become more euchromatic in nature, while the LAT region loses enrichment of euchromatic histone marks as LAT is degraded at early times in reactivation in the two different in...

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confidence: 52%

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confidence: 98%

mentioning

confidence: 99%

mentioning

confidence: 99%

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CTCF Occupation of the Herpes Simplex Virus 1 Genome Is Disrupted at Early Times Postreactivation in a Transcription-Dependent Manner

Ertel

Cammarata

Hron

et al. 2012

J Virol

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“…Although the role and target of HSV-2 miR-H6 is unknown, and abrogation of its expression by insertion of a polyadenylation site directly upstream of the miRNA had no influence on acute viral infection or recurrence (26), it is possible that miR-H6 promoter sequences in exon 1 could be important for viral latency and recurrence phenotypes. During latency, these sequences (in HSV-1) are enriched for euchromatin marks (56)(57)(58)(59), likely playing a role in the expression of miR-H6 during latency and thus possibly also playing a role in the activity of the nearby LAT promoter.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Herpes Simplex Virus 2 Primary MicroRNA Transcript Regulation

Tang

Bosch–Marcé

Patel

et al. 2015

J Virol

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In order to understand factors that may influence latency-associated transcription and latency-associated transcript (LAT) phenotypes, we studied the expression of the herpes simplex virus 2 (HSV-2) LAT-associated microRNAs (miRNAs). We mapped the transcription initiation sites of all three primary miRNA transcripts and identified the ICP4-binding sequences at the transcription initiation sites of both HSV-2 LAT (pri-miRNA for miR-I and miR-II, which target ICP34.5, and miR-III, which targets ICP0) and L/ST (a pri-miRNA for miR-I and miR-II) but not at that of the primary miR-H6 (for which the target is unknown). We confirmed activity of the putative HSV-2 L/ST promoter and found that ICP4 trans-activates the L/ST promoter when the ICP4-binding site at its transcription initiation site is mutated, suggesting that ICP4 may play a dual role in regulating transcription of L/ST and, consequently, of miR-I and miR-II. LAT exon 1 (containing LAT enhancer sequences), together with the LAT promoter region, comprises a bidirectional promoter required for the expression of both LAT-encoded miRNAs and miR-H6 in latently infected mouse ganglia. The ability of ICP4 to suppress ICP34.5-targeting miRNAs and to activate lytic viral genes suggests that ICP4 could play a key role in the switch between latency and reactivation. IMPORTANCEThe HSV-2 LAT and viral miRNAs expressed in the LAT region are the most abundant viral transcripts during HSV latency. The balance between the expression of LAT and LAT-associated miRNAs and the expression of lytic viral transcripts from the opposite strand appears to influence whether individual HSV-infected neurons will be latently or productively infected. The outcome of neuronal infection may thus depend on regulation of gene expression of the corresponding primary miRNAs. In the present study, we characterize promoter sequences responsible for miRNA expression, including identification of the primary miRNA 5= ends and evaluation of ICP4 response. These findings provide further insight into the virus' strategy to tightly control expression of lytic cycle genes (especially the neurovirulence factor, ICP34.5) and suggest a mechanism (via ICP4) for the transition from latency to reactivated productive infection. Herpes simplex virus 1 (HSV-1) and HSV-2 are closely related herpesviruses. HSV-1 typically infects the facial region and establishes a lifelong latent infection in sensory neurons of the trigeminal ganglia (TG), while HSV-2 typically infects the genital region and establishes a lifelong latent infection in sensory neurons of the sacral dorsal root ganglia. Periodically, either virus may reactivate to cause symptomatic or asymptomatic recurrences in the area served by these sensory neurons.Both HSV-2 and HSV-1 acutely and latently express miRNAs, which are proposed to play an important role in regulating whether an infection will be productive or latent. These miRNAs, which are conserved more in location than in sequence (1, 2, 9, 10), reduce expression of viral genes transcribed ...

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Chromatin-mediated epigenetic regulation of HSV-1 transcription as a potential target in antiviral therapy

Schang

Cortes

et al. 2021

Antiviral Research

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The ability to establish, and reactivate from, latent infections is central to the biology and pathogenesis of HSV-1. It also poses a strong challenge to antiviral therapy, as latent HSV-1 genomes do not replicate or express any protein to be targeted. Although the processes regulating the establishment and maintenance of, and reactivation from, latency are not fully elucidated, the current general consensus is that epigenetics play a major role. A unifying model postulates that whereas HSV-1 avoids or counteracts chromatin silencing in lytic infections, it becomes silenced during latency, silencing which is somewhat disrupted during reactivation. Many years of work by different groups using a variety of approaches have also shown that the lytic HSV-1 chromatin is distinct and has unique biophysical properties not shared with most cellular chromatin. Nonetheless, the lytic and latent viral chromatins are typically enriched in post translational modifications or histone variants characteristic of active or repressed transcription, respectively. Moreover, a variety of small molecule epigenetic modulators inhibit viral replication and reactivation from latency. Despite these successes in culture and animal models, it is not obvious how epigenetic modulation would be used in antiviral therapy if the same epigenetic mechanisms governed viral and cellular gene expression. Recent work has highlighted several important differences between the viral and cellular chromatins, which appear to be of consequence to their respective epigenetic regulations. In this review, we will discuss the distinctiveness of the viral chromatin, and explore whether it is regulated by mechanisms unique enough to be exploited in antiviral therapy.

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Changes to Euchromatin on LAT and ICP4 Following Reactivation Are More Prevalent in an Efficiently Reactivating Strain of HSV-1

Cited by 16 publications

References 53 publications

CTCF Occupation of the Herpes Simplex Virus 1 Genome Is Disrupted at Early Times Postreactivation in a Transcription-Dependent Manner

CTCF Occupation of the Herpes Simplex Virus 1 Genome Is Disrupted at Early Times Postreactivation in a Transcription-Dependent Manner

Characterization of Herpes Simplex Virus 2 Primary MicroRNA Transcript Regulation

Chromatin-mediated epigenetic regulation of HSV-1 transcription as a potential target in antiviral therapy

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