Inhibitors of the Histone Methyltransferases EZH2/1 Induce a Potent Antiviral State and Suppress Infection by Diverse Viral Pathogens
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....
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| Published in | mBio Vol. 8; no. 4 |
|---|---|
| Main Authors | , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
American Society for Microbiology
15.08.2017
|
| Subjects | |
| Online Access | Get full text |
| ISSN | 2161-2129 2150-7511 2150-7511 |
| DOI | 10.1128/mBio.01141-17 |
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| Abstract | 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.
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. |
|---|---|
| AbstractList | ABSTRACT 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. 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. 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. 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. 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. 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.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. 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 and 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 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. 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 and 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. |
| Author | Pierson, Theodore C. Arbuckle, Jesse H. Gordon, David N. Hickman, Heather D. Gardina, Paul J. Myers, Timothy G. Yewdell, Jonathan W. Kristie, Thomas M. |
| Author_xml | – sequence: 1 givenname: Jesse H. surname: Arbuckle fullname: Arbuckle, Jesse H. organization: Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA – sequence: 2 givenname: Paul J. surname: Gardina fullname: Gardina, Paul J. organization: Genomic Technologies Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA – sequence: 3 givenname: David N. surname: Gordon fullname: Gordon, David N. organization: Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA – sequence: 4 givenname: Heather D. surname: Hickman fullname: Hickman, Heather D. organization: Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA – sequence: 5 givenname: Jonathan W. surname: Yewdell fullname: Yewdell, Jonathan W. organization: Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA – sequence: 6 givenname: Theodore C. surname: Pierson fullname: Pierson, Theodore C. organization: Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA – sequence: 7 givenname: Timothy G. surname: Myers fullname: Myers, Timothy G. organization: Genomic Technologies Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA – sequence: 8 givenname: Thomas M. surname: Kristie fullname: Kristie, Thomas M. organization: Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/28811345$$D View this record in MEDLINE/PubMed |
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| Keywords | innate immunity herpesvirus immune mechanisms antiviral Zika virus chromatin epigenetics |
| Language | English |
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| Snippet | Epigenetic regulation is based on a network of complexes that modulate the chromatin character and structure of the genome to impact gene expression, cell... ABSTRACT Epigenetic regulation is based on a network of complexes that modulate the chromatin character and structure of the genome to impact gene expression,... |
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| SubjectTerms | antiviral Antiviral Agents - pharmacology chromatin DNA Replication Enhancer of Zeste Homolog 2 Protein - antagonists & inhibitors Enzyme Inhibitors - pharmacology Epigenetic Repression epigenetics Herpes Simplex - drug therapy Herpes Simplex - immunology Herpes Simplex - virology herpesvirus Herpesvirus 1, Human - drug effects Herpesvirus 1, Human - genetics Herpesvirus 1, Human - pathogenicity Herpesvirus 1, Human - physiology Humans immune mechanisms Immunity, Innate innate immunity Polycomb Repressive Complex 2 - antagonists & inhibitors Virus Latency Virus Replication - drug effects Zika Virus - drug effects Zika Virus - genetics Zika Virus - pathogenicity Zika Virus - physiology Zika Virus Infection - immunology Zika Virus Infection - virology |
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| Title | Inhibitors of the Histone Methyltransferases EZH2/1 Induce a Potent Antiviral State and Suppress Infection by Diverse Viral Pathogens |
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