Dynamic modulation of HSV chromatin drives initiation of infection and provides targets for epigenetic therapies

Kristie, Thomas M.

doi:10.1016/j.virol.2015.01.026

Cited by 48 publications

(48 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The assembly and modulation of nucleosomes during infection is dependent on a plethora of viral and host chromatin components (6). Initially, viral genomes have been shown to carry repressive chromatin marks thought to represent a host silencing mechanism (5, 7).…”

Section: Herpes Simplex Virus (Hsv-1)mentioning

confidence: 99%

“…HSV-1 then overcomes this repression through histone H3 acetylation to promote viral gene expression (7). Many chromatin components are involved in the balance between heterochromatic suppression of the viral genome and the euchromatin transition that promotes the expression of viral genes (6). HSV-1 infection also causes extensive reorganization of cellular structures, with nuclear changes including margination of chromatin, enlargement of the nucleus, formation of replication compartments, disruption of the nuclear lamina and nucleoli, and cytoplasmic changes including disruption of the Golgi apparatus and microtubules and genetic damage to mitochondria (4,8,9).…”

Section: Herpes Simplex Virus (Hsv-1)mentioning

confidence: 99%

See 1 more Smart Citation

Time-resolved Global and Chromatin Proteomics during Herpes Simplex Virus Type 1 (HSV-1) Infection

Kulej

Avgousti

Sidoli

et al. 2017

Molecular & Cellular Proteomics

View full text Add to dashboard Cite

Herpes simplex virus (HSV-1) lytic infection results in global changes to the host cell proteome and the proteins associated with host chromatin. We present a system level characterization of proteome dynamics during infection by performing a multi-dimensional analysis during HSV-1 lytic infection of human foreskin fibroblast (HFF) cells. Our study includes identification and quantification of the host and viral proteomes, phosphoproteomes, chromatin bound proteomes and post-translational modifications (PTMs) on cellular histones during infection. We analyzed proteomes across six time points of virus infection (0, 3, 6, 9, 12 and 15 h post-infection) and clustered trends in abundance using fuzzy c-means. Globally, we accurately quantified more than 4000 proteins, 200 differently modified histone peptides and 9000 phosphorylation sites on cellular proteins. In addition, we identified 67 viral proteins and quantified 571 phosphorylation events (465 with high confidence site localization) on viral proteins, which is currently the most comprehensive map of HSV-1 phosphoproteome. We investigated chromatin bound proteins by proteomic analysis of the high-salt chromatin fraction and identified 510 proteins that were significantly different in abundance during infection. We found 53 histone marks significantly regulated during virus infection, including a steady increase of histone H3 acetylation (H3K9ac and H3K14ac). Our data provide a resource of unprecedented depth for human and viral proteome dynamics during infection. Collectively, our results indicate that the proteome composition of the chromatin of HFF cells is highly affected during HSV-1 infection, and that phosphorylation events are abundant on viral proteins. We propose that our epi-proteomics approach will prove to be important in the characterization of other model infectious systems that involve changes to chromatin composition. Molecular & Cellular Proteomics 16: 10.1074/mcp.M116.065987, S92-S107, 2017. Herpes simplex virus (HSV-1)1 leads to a contagious and persistent infection that affects about 95% of the human population. The HSV-1 genome is a double-stranded DNA molecule that replicates in the host cell nucleus (1). HSV-1 initially infects epithelial cells as a lytic infection, and then enters peripheral neurons where it establishes latency (2, 3). Processes such as viral transcription, viral DNA synthesis, virion assembly and DNA packaging take place in discrete virus-induced structures within the nucleus called replication compartments (1, 4). These processes are temporally regulated by the viral cascades of immediate-early (IE), early (E), and late (L) gene expression. The IE proteins are primarily responsible for counteracting intrinsic host defenses and for activating expression of early-phase genes (1). Early viral pro-

show abstract

Section: Herpes Simplex Virus (Hsv-1)mentioning

confidence: 99%

Section: Herpes Simplex Virus (Hsv-1)mentioning

confidence: 99%

Time-resolved Global and Chromatin Proteomics during Herpes Simplex Virus Type 1 (HSV-1) Infection

Kulej

Avgousti

Sidoli

et al. 2017

Molecular & Cellular Proteomics

View full text Add to dashboard Cite

show abstract

“…Synthesis of the IE proteins is necessary for early (E) gene expression, which in turn allows HSV DNA replication and late (L) gene expression. Expression of viral genes at each stage requires both viral and cellular proteins, including histone demethylase enzymes that remove repressive chromatin modifications deposited into the genome immediately following infection (12)(13)(14)(15).…”

Section: Mechanisms Of Hsv Lytic Gene Expression During the First Phamentioning

confidence: 99%

Restarting Lytic Gene Transcription at the Onset of Herpes Simplex Virus Reactivation

Cliffe

Wilson

2017

J Virol

View full text Add to dashboard Cite

Herpes simplex virus (HSV) establishes a latent reservoir in neurons of human peripheral nerves. In this quiescent state, the viral genome persists as a circular, histone-associated episome, and transcription of viral lytic cycle genes is largely suppressed through epigenetic processes. Periodically, latent virus undergoes reactivation whereby lytic genes are activated and viral replication occurs. In this Gem, we review recent evidence that mechanisms governing the initial transcription of lytic genes are distinct from those of de novo infection and directly link reactivation to neuronal stress response pathways. We also discuss evidence that lytic cycle gene expression can be uncoupled from the full reactivation program, arguing for a less sharply bimodal definition of latency.

show abstract

“…Upon infection of permissive cells, the HSV genome is assembled into chromatin structures that initially exhibit both H3K9me3 and H3K27me3 repressive histone methylation signatures (10,18,40,44,45). Initiation of lytic infection requires the recruitment of a cellular transcriptional coactivator complex (HCF-1) that contains histone H3K9 demethylases (LSD1, JMJD2s) and histone H3K4 methyltransferases (SETD1A, MLLs), which limits the accumulation of H3K9me3 and increases the levels of active H3K4me3 to promote the transcription of viral immediate-early (IE) genes (17,18,46).…”

mentioning

confidence: 99%

Inhibitors of the Histone Methyltransferases EZH2/1 Induce a Potent Antiviral State and Suppress Infection by Diverse Viral Pathogens

Arbuckle

Gardina

Gordon

et al. 2017

mBio

Self Cite

View full text Add to dashboard Cite

Epigenetic regulation is based on a network of complexes that modulate the chromatin character and structure of the genome to impact gene expression, cell fate, and development. Thus, epigenetic modulators represent novel therapeutic targets used to treat a range of diseases, including malignancies. Infectious pathogens such as herpesviruses are also regulated by cellular epigenetic machinery, and epigenetic therapeutics represent a novel approach used to control infection, persistence, and the resulting recurrent disease. The histone H3K27 methyltransferases EZH2 and EZH1 (EZH2/1) are epigenetic repressors that suppress gene transcription via propagation of repressive H3K27me3-enriched chromatin domains. However, while EZH2/1 are implicated in the repression of herpesviral gene expression, inhibitors of these enzymes suppressed primary herpes simplex virus (HSV) infection in vitro and in vivo. Furthermore, these compounds blocked lytic viral replication following induction of HSV reactivation in latently infected sensory ganglia. Suppression correlated with the induction of multiple inflammatory, stress, and antipathogen pathways, as well as enhanced recruitment of immune cells to in vivo infection sites. Importantly, EZH2/1 inhibitors induced a cellular antiviral state that also suppressed infection with DNA (human cytomegalovirus, adenovirus) and RNA (Zika virus) viruses. Thus, EZH2/1 inhibitors have considerable potential as general antivirals through the activation of cellular antiviral and immune responses.IMPORTANCE A significant proportion of the world's population is infected with herpes simplex virus. Primary infection and subsequent recurrent reactivation can result in diseases ranging from mild lesions to severe ocular or neurological damage. Herpesviruses are subject to epigenetic regulation that modulates viral gene expression, lytic replication, and latency-reactivation cycles. Thus, epigenetic pharmaceuticals have the potential to alter the course of infection and disease. Here, while the histone methyltransferases EZH2/1 are implicated in the suppression of herpesviruses, inhibitors of these repressors unexpectedly suppress viral infection in vitro and in vivo by induction of key components of cellular innate defense pathways. These inhibitors suppress infection by multiple viral pathogens, indicating their potential as broad-spectrum antivirals.KEYWORDS antiviral, chromatin, epigenetics, herpesvirus, immune mechanisms, innate immunity, Zika virus F ollowing primary infection with herpes simplex virus (HSV), the virus establishes lifelong latency in sensory neurons. However, multiple biological or stress stimuli can induce reactivation of latent genomes and recurrent disease. Ocular HSV infections remain the leading virus-mediated cause of stromal keratitis and corneal scarring, while

show abstract

Dynamic modulation of HSV chromatin drives initiation of infection and provides targets for epigenetic therapies

Cited by 48 publications

References 70 publications

Time-resolved Global and Chromatin Proteomics during Herpes Simplex Virus Type 1 (HSV-1) Infection

Time-resolved Global and Chromatin Proteomics during Herpes Simplex Virus Type 1 (HSV-1) Infection

Restarting Lytic Gene Transcription at the Onset of Herpes Simplex Virus Reactivation

Inhibitors of the Histone Methyltransferases EZH2/1 Induce a Potent Antiviral State and Suppress Infection by Diverse Viral Pathogens

Contact Info

Product

Resources

About