Targeting the JMJD2 Histone Demethylases to Epigenetically Control Herpesvirus Infection and Reactivation from Latency

Liang, Yu; Vogel, Joseph P.; Arbuckle, Jesse H.; Rai, Ganesha; Jadhav, Ajit; Simeonov, Anton; Maloney, David J.; Kristie, Thomas M.

doi:10.1126/scitranslmed.3005145

Cited by 98 publications

(152 citation statements)

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“…Variations in transcription levels are associated with variations in mutation rates (55,56) and thus could be a confounding factor in the analysis, as could alterations of transcriptional kinetics. Relatedly, differences in histone association (57) and epigenetic silencing (58) alter transcriptional activity and may be associated with protein function. Changes in DNA biophysical properties that alter mutation potential, such as secondary structure (59), also cannot be excluded as possible contributors to the observed pattern.…”

Section: Discussionmentioning

confidence: 99%

Limits and patterns of cytomegalovirus genomic diversity in humans

Renzette

Pokalyuk

Gibson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

112

129

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Human cytomegalovirus (HCMV) exhibits surprisingly high genomic diversity during natural infection although little is known about the limits or patterns of HCMV diversity among humans. To address this deficiency, we analyzed genomic diversity among congenitally infected infants. We show that there is an upper limit to HCMV genomic diversity in these patient samples, with ∼25% of the genome being devoid of polymorphisms. These low diversity regions were distributed across 26 loci that were preferentially located in DNA-processing genes. Furthermore, by developing, to our knowledge, the first genome-wide mutation and recombination rate maps for HCMV, we show that genomic diversity is positively correlated with these two rates. In contrast, median levels of viral genomic diversity did not vary between putatively single or mixed strain infections. We also provide evidence that HCMV populations isolated from vascular compartments of hosts from different continents are genetically similar and that polymorphisms in glycoproteins and regulatory proteins are enriched in these viral populations. This analysis provides the most highly detailed map of HCMV genomic diversity in human hosts to date and informs our understanding of the distribution of HCMV genomic diversity within human hosts.human cytomegalovirus | HCMV | congenital CMV | virology | evolution

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Section: Discussionmentioning

confidence: 99%

Limits and patterns of cytomegalovirus genomic diversity in humans

Renzette

Pokalyuk

Gibson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

112

129

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“…Thus, components of the cellular epigenetic machinery represent a plethora of novel therapeutic targets that can be used to modulate the expression of specific gene sets and alter the course of disease. Inhibitors of LSD1 and members of the JMJD2 family of histone H3K9 demethylases have been shown to suppress HSV infection and reactivation from latency (15)(16)(17)(18). In a contrasting approach, histone deacetylase inhibitors have been components of some strategies to induce HIV reactivation and deplete latent viral reservoirs (19)(20)(21).…”

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confidence: 99%

“…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). Similarly, the levels of H3K27me3 associated with the viral genome decrease over the course of productive infection in a manner dependent on IE protein ICP0 and viral DNA replication (40).…”

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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

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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

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“…It has been demonstrated that H3K9me2/3 demethylases (JMJD2s) and H3K9me1/2 demethylase LSDI reduce HSV-1 reactivation both in vitro and in vivo (20)(21)(22). It is difficult to state why inhibitors of the H3K9me2/me3 demethylases did not completely inhibit reactivation fully given issues with penetrance in the tissue and the experimental half-life of the drug.…”

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confidence: 99%

Inhibition of H3K27me3-Specific Histone Demethylases JMJD3 and UTX Blocks Reactivation of Herpes Simplex Virus 1 in Trigeminal Ganglion Neurons

Messer

Jacobs

Dhummakupt

et al. 2015

J Virol

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Herpes simplex virus 1 (HSV-1) genomes are associated with the repressive heterochromatic marks H3K9me2/me3 and H3K27me3 during latency. Previous studies have demonstrated that inhibitors of H3K9me2/me3 histone demethylases reduce the ability of HSV-1 to reactivate from latency. Here we demonstrate that GSK-J4, a specific inhibitor of the H3K27me3 histone demethylases UTX and JMJD3, inhibits HSV-1 reactivation from sensory neurons in vitro. These results indicate that removal of the H3K27me3 mark plays a key role in HSV-1 reactivation. Histone posttranslational modifications, both euchromatic and heterochromatic, are found in association with herpes simplex virus 1 (HSV-1) genes as the genome associates with nucleosomes during latency. The presence of permissive euchromatic marks (H3KAc, H9KAc, and H18K18Ac) in association with the latency-associated transcript (LAT) promoter and 5= exon during latency is consistent with its transcriptional activity during latency (1-4). Intrinsic to the latent state, however, are several repressive epigenetic marks that are also found in association with lytic genes of the latent HSV-1 genomes, notably, H3K9me2/me3 and H3K27me3, enriched along lytic genes. These marks have been implicated in helping to maintain lytic genes in a repressed state (3,5,6).Presumably, to reactivate from latency, the H3K9me2/me3 and H3K27me3 repressive marks need to be removed by chromatin remodeling enzymes. H3K27me3 is reversibly removed through the action of specific histone demethylases KDM6B/JMJD3 and KDM6A/ UTX (7). H3K9me3 can be removed by all members of the JMJD2 family (8), while H3K9me2/me3/1 can be removed by LSD1, KIAA1718, JHDM1F, and JMJD1A (9-12). In this study, we sought to determine whether blocking the removal of H3K27me3 would also block HSV-1 reactivation. This issue was addressed using GSK-J4, a specific inhibitor of both JMJD3 and UTX (13).Inhibition of JMJD3 and UTX blocks reactivation-induced H3K27me3 demethylation of HSV genomes. To understand the roles of UTX and JMJD3 in viral reactivation, we used an in vitro model of HSV-1 latency in primary adult murine trigeminal ganglion (TG) neurons (14), where reactivation is stimulated by nerve growth factor (NGF) depletion (15). TGs from 6-week-old outbred Swiss Webster mice were incubated in papain (Worthington, Lakewood, NJ) reconstituted with neurobasal A medium (Gibco; catalog no. 10888-022) followed by Hanks balanced salt solution containing dispase (4 mg/ml) and collagenase (4.7 mg/ml) (Sigma). Mechanically dissociated TGs were purified on an iodixinol gradient (OptiPrep; Sigma). Neuronal cells were counted and plated onto plates precoated with poly-D-lysine and laminin. Cells were maintained in neuralbasal media containing NGF, glial cell line-derived neurotrophic factor, neutrinin, L-glutamine, 2% (vol/vol) B-27 supplement minus AO (Gibco; catalog no. 10889-038), and 1% (vol/vol) penicillin-streptomycin. To suppress actively dividing nonneuronal cells, the media were supplemented with fluorodeoxyuridine for 72 h prior to i...

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Targeting the JMJD2 Histone Demethylases to Epigenetically Control Herpesvirus Infection and Reactivation from Latency

Cited by 98 publications

References 50 publications

Limits and patterns of cytomegalovirus genomic diversity in humans

Limits and patterns of cytomegalovirus genomic diversity in humans

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

Inhibition of H3K27me3-Specific Histone Demethylases JMJD3 and UTX Blocks Reactivation of Herpes Simplex Virus 1 in Trigeminal Ganglion Neurons

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