Key questions on the epigenetics of herpes simplex virus latency

Whitford, Abigail L; Cliffe, Anna R.

doi:10.1371/journal.ppat.1010587

Cited by 4 publications

(5 citation statements)

References 30 publications

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“…Hence, using multiple techniques, we set out to determine whether any H3K27me3 could be detectibly deposited on the incoming genome by the host, which the virus removes for lytic replication to take place. This was important to understand, first, to determine how the host cell attempts to silence incoming foreign HSV-1 DNA, and second, because this modification is ultimately enriched on the HSV-1 genome during latent infection of neurons ( 12 , 15 , 19 , 20 , 34 , 35 ). Although we were unable to detect H3K27me3 enrichment on lytic genomes, our data suggest that a subpopulation of genomes is targeted for silencing by H3K27me2.…”

Section: Discussionmentioning

confidence: 99%

“…Polycomb-mediated silencing is a type of facultative heterochromatin, characterized in large part by the enrichment of lysine 27 tri-methylation on histone H3 (H3K27me3) and is associated with multiple latent herpesviruses ( 1 , 2 , 5 , 9 , 10 , 12 , 13 , 15 – 20 ). Facultative heterochromatin is more readily converted to transcriptionally active euchromatin than the more stable constitutive heterochromatin ( 21 ).…”

Section: Introductionmentioning

confidence: 99%

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Single-genome analysis reveals a heterogeneous association of the herpes simplex virus genome with H3K27me2 and the reader PHF20L1 following infection of human fibroblasts

Francois,

Rohani,

Loftus

et al. 2024

mBio

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The fate of herpesvirus genomes following entry into different cell types is thought to regulate the outcome of infection. For the Herpes simplex virus 1 (HSV-1), latent infection of neurons is characterized by association with repressive heterochromatin marked with Polycomb silencing-associated lysine 27 methylation on histone H3 (H3K27me). However, whether H3K27 methylation plays a role in repressing lytic gene expression in non-neuronal cells is unclear. To address this gap in knowledge, and with consideration that the fate of the viral genome and outcome of HSV-1 infection could be heterogeneous, we developed an assay to quantify the abundance of histone modifications within single viral genome foci of infected fibroblasts. Using this approach, combined with bulk epigenetic techniques, we were unable to detect any role for H3K27me3 during HSV-1 lytic infection of fibroblasts. By contrast, we could detect the lesser studied H3K27me2 on a subpopulation of viral genomes, which was consistent with a role for H3K27 demethylases in promoting lytic gene expression. In addition, viral genomes co-localized with the H3K27me2 reader protein PHF20L1, and this association was enhanced by inhibition of the H3K27 demethylases UTX and JMJD3. Notably, targeting of H3K27me2 to viral genomes was enhanced following infection with a transcriptionally defective virus in the absence of Promyelocytic leukemia nuclear bodies. Collectively, these studies implicate a role for H3K27me2 in fibroblast-associated HSV genome silencing in a manner dependent on genome sub-nuclear localization and transcriptional activity. IMPORTANCE Investigating the potential mechanisms of gene silencing for DNA viruses in different cell types is important to understand the differential outcomes of infection, particularly for viruses like herpesviruses that can undergo distinct types of infection in different cell types. In addition, investigating chromatin association with viral genomes informs on the mechanisms of epigenetic regulation of DNA processes. However, there is a growing appreciation for heterogeneity in the outcome of infection at the single cell, and even single viral genome, level. Here we describe a novel assay for quantifying viral genome foci with chromatin proteins and show that a portion of genomes are targeted for silencing by H3K27me2 and associate with the reader protein PHF20L1. This study raises important questions regarding the mechanism of H3K27me2-specific targeting to viral genomes, the contribution of epigenetic heterogeneity to herpesvirus infection, and the role of PHF20L1 in regulating the outcome of DNA virus infection.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Single-genome analysis reveals a heterogeneous association of the herpes simplex virus genome with H3K27me2 and the reader PHF20L1 following infection of human fibroblasts

Francois,

Rohani,

Loftus

et al. 2024

mBio

Self Cite

View full text Add to dashboard Cite

show abstract

“…Hence, using multiple techniques, we set out to determine whether any H3K27me3 could be detectibly deposited on the incoming genome by the host, which the virus removes for lytic replication to take place. This was important to understand, first, to determine how the host cell attempts to silence incoming foreign HSV-1 DNA, and second, because this modification is ultimately enriched on the HSV-1 genome during a latent infection of neurons (12, 15, 19, 20, 34, 35). Although we were unable to detect H3K27me3 enrichment on lytic genomes, are data suggest that a subpopulation of genomes are targeted for silencing by H3K27me2.…”

Section: Discussionmentioning

confidence: 99%

“…Polycomb-mediated silencing is a type of facultative heterochromatin, characterized in large part by the enrichment of lysine 27 tri-methylation on histone H3 (H3K27me3) and is associated with multiple latent herpesviruses (1,2,5,9,10,12,13,(15)(16)(17)(18)(19)(20). Facultative heterochromatin is more readily converted to transcriptionally active euchromatin than the more stable constitutive heterochromatin (21).…”

Section: Introductionmentioning

confidence: 99%

Single-genome analysis reveals heterogeneous association of the Herpes Simplex Virus genome with H3K27me2 and the reader PHF20L1 following infection of human fibroblasts

Francois,

Rohani,

Loftus

et al. 2023

Preprint

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The fate of herpesvirus genomes following entry into different cell types is thought to regulate the outcome of infection. For the Herpes simplex virus 1 (HSV-1), latent infection of neurons is characterized by association with repressive heterochromatin marked with Polycomb silencing-associated lysine 27 methylation on histone H3 (H3K27me). However, whether H3K27 methylation plays a role in repressing lytic gene expression in non-neuronal cells is unclear. To address this gap in knowledge, and with consideration that the fate of the viral genome and outcome of HSV-1 infection could be heterogeneous, we developed an assay to quantify the abundance of histone modifications within single viral genome foci of infected fibroblasts. Using this approach, combined with bulk epigenetic techniques, we were unable to detect any role for H3K27me3 during HSV-1 lytic infection of fibroblasts. In contrast, we could detect the lesser studied H3K27me2 on a subpopulation of viral genomes, which was consistent with a role for H3K27 demethylases in promoting lytic gene expression. This was consistent with a role for H3K27 demethylases in promoting lytic gene expression. In addition, viral genomes co-localized with the H3K27me2 reader protein PHF20L1, and this association was enhanced by inhibition of the H3K27 demethylases UTX and JMJD3. Notably, targeting of H3K27me2 to viral genomes was enhanced following infection with a transcriptionally defective virus in the absence of Promyelocytic leukemia nuclear bodies. Collectively, these studies implicate a role for H3K27me2 in fibroblast-associated HSV genome silencing in a manner dependent on genome sub-nuclear localization and transcriptional activity.ImportanceInvestigating the potential mechanisms of gene silencing for DNA viruses in different cell types is important to understand the differential outcomes of infection, particularly for viruses like herpesviruses that can undergo distinct types of infection in different cell types. In addition, investigating chromatin association with viral genomes informs on the mechanisms of epigenetic regulation of DNA processes. However, there is growing appreciation for heterogeneity in the outcome of infection at the single cell, and even single viral genome, level. Here we describe a novel assay for quantifying viral genome foci with chromatin proteins and show that a portion of genomes are targeted for silencing by H3K27me2 and associate with the reader protein PHF20L1. This study raises important questions regarding the mechanism of H3K27me2-specific targeting to viral genomes, the contribution of epigenetic heterogeneity to herpesvirus infection, and the role of PHF20L1 in regulating the outcome of DNA virus infection.

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“…The reason for the long delay in robust lytic gene expression following a reactivation stimulus is unknown. HSV-1 gene expression initiates from a silenced, heterochromatinized viral genome during reactivation [71][72][73][74][75][76] ; therefore, there are more obstacles to gene expression than de novo infection. However, this does still not perhaps explain the approximate 18hour window from stimulus to lytic gene expression.…”

Section: Studies From Our Lab and Others Mapping The Time Of Lytic Ge...mentioning

confidence: 99%

Co-option of mitochondrial nucleic acid sensing pathways by HSV-1 UL12.5 for reactivation from latent Infection

Cuddy,

Flores,

Krakowiak

et al. 2024

Preprint

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SummaryAlthough viruses subvert innate immune pathways for their replication, there is evidence they can also co-opt anti-viral responses for their benefit. The ubiquitous human pathogen, Herpes Simplex Virus-1 (HSV-1), encodes a protein (UL12.5) that induces the release of mitochondrial nucleic acid into the cytosol, which activates immune sensing pathways and reduces productive replication in non-neuronal cells. HSV-1 establishes latency in neurons and can reactivate to cause disease. We found that UL12.5 is required for HSV-1 reactivation in neurons and acts to directly promote viral lytic gene expression during initial exit from latency. Further, the direct activation of innate immune sensing pathways triggered HSV reactivation and compensated for a lack of UL12.5. Finally, we found that the induction of HSV-1 lytic genes during reactivation required intact RNA and DNA sensing pathways, demonstrating that HSV-1 can both respond to and active antiviral nucleic acid sensing pathways to reactivate from a latent infection.

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Key questions on the epigenetics of herpes simplex virus latency

Cited by 4 publications

References 30 publications

Single-genome analysis reveals a heterogeneous association of the herpes simplex virus genome with H3K27me2 and the reader PHF20L1 following infection of human fibroblasts

Single-genome analysis reveals a heterogeneous association of the herpes simplex virus genome with H3K27me2 and the reader PHF20L1 following infection of human fibroblasts

Single-genome analysis reveals heterogeneous association of the Herpes Simplex Virus genome with H3K27me2 and the reader PHF20L1 following infection of human fibroblasts

Co-option of mitochondrial nucleic acid sensing pathways by HSV-1 UL12.5 for reactivation from latent Infection

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