Inhibitors of the histone methyltransferases EZH2/1 induce a potent antiviral state and suppress infection by diverse viral pathogens [RNA-Seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA389770 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5661510_1.fastq.gz | Fastqsanger.gz | |||
| SRR5661510_2.fastq.gz | Fastqsanger.gz | |||
| SRR5661520_1.fastq.gz | Fastqsanger.gz | |||
| SRR5661520_2.fastq.gz | Fastqsanger.gz | |||
| SRR5661530_1.fastq.gz | Fastqsanger.gz |
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Project description:Epigenetic regulation is based upon 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 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 to control infection, persistence, and the resulting recurrent disease. The histone 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 repression of herpesviral gene expression, inhibitors of these enzymes suppressed HSV primary 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 anti-pathogen 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 (hCMV, Adenovirus) and RNA (Zika virus) viruses. Thus, EZH2/1 inhibitors have considerable potential as general antivirals through activation of cellular antiviral and immune responses.
2017-07-17 | GSE99840 | GEO
Project description:Inhibitors of the histone methyltransferases EZH2/1 induce a potent antiviral state and suppress infection by diverse viral pathogens
| PRJNA389769 | ENA
Project description:Epigenetic regulation is based upon 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 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 to control infection, persistence, and the resulting recurrent disease. The histone 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 repression of herpesviral gene expression, inhibitors of these enzymes suppressed HSV primary 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 anti-pathogen 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 (hCMV, Adenovirus) and RNA (Zika virus) viruses. Thus, EZH2/1 inhibitors have considerable potential as general antivirals through activation of cellular antiviral and immune responses.
2017-07-17 | GSE99839 | GEO
Project description: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.
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Project description:This SuperSeries is composed of the SubSeries listed below.
2017-07-17 | GSE99841 | GEO
Project description:The emergence of SARS-CoV-2 variants and drug-resistant mutants underscores the urgent need for novel antiviral therapeutics. SARS-CoV-2 NSP14, an N7-guanosine methyltransferase, plays a critical role in viral RNA capping, enabling viral replication and immune evasion. While NSP14 has emerged as a promising drug target, its role in host-virus crosstalk and the cellular consequences of NSP14 inhibition remain poorly understood. Here, we present the identification and characterization of C10, a highly potent and selective first-in-class non-nucleoside inhibitor of the NSP14 S-adenosylmethionine (SAM)-binding pocket. C10 demonstrates robust antiviral activity against SARS-CoV-2, including its variants, with EC50 values ranging from 64.03 to 301.9 nM, comparable to the FDA-approved drug remdesivir in our cell-based assays. C10 also exhibits broad-spectrum activity against other betacoronaviruses and directly suppresses SARS-CoV-2 genomic replication. C10 specifically reversed NSP14-mediated alterations in host transcriptome and restored host cell cycle progression disrupted by NSP14. The antiviral efficacy of C10 was further validated in a transgenic mouse model of SARS-CoV-2 infection. Our findings highlight C10 as a promising candidate for the development of effective treatments against SARS-CoV-2 and its emerging variants. This study also uncovers a novel mechanism of NSP14 in SARS-CoV-2 pathogenesis and its therapeutic potential, providing insights that may extend to other viral capping methyltransferases.
2025-09-06 | GSE304814 | GEO
Project description:SARS-CoV-2 virus mimics host mRNA by capping its viral RNA to promote replication and evade host immune sensing. SARS-CoV-2 NSP14 is the N7-guanosine methyltransferase (N7-MTase) responsible for RNA cap-0 formation. Targeting NSP14 for antiviral drug development is an under-explored but promising strategy. Here we conducted a high-throughput screening on natural products library derived from Chinese herbal medicine to discover Emodin as a SARS-CoV-2 NSP14 inhibitor. Exploring Emodin derivatives, Questin was identified with potent cellular inhibitory activity (EC50=249 nM) against SARS-CoV-2, which inhibits NSP14 in an RNA cap competitive manner, making it one the most potent anti-coronaviral natural products. Mechanistically, besides catalyzing viral RNA capping, NSP14 by itself could remodel host transcriptome such as enriching CREBBP, a key host factor in cellular cyclic AMP response pathway, to promote viral infection. As a result, targeting NSP14 by Questin significantly impairs viral Replication & Translation step and reverses host transcriptome remodeled by NSP14. We next validated Questin as a promising lead with significantly improved toxicity upon acute exposure in zebrafish larvae. Taken together, our study not only demonstrates Questin as a potent drug lead for clinical antiviral application, but also highlights multiple antiviral potentials of NSP14 as therapeutic target.
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Project description:Viruses target mitochondria, critical for antiviral defense and metabolism, to evade immunity. While mitochondrial antiviral-signaling protein (MAVS) is known for its regulation of type I interferon (IFN) signaling, we discover that its overarching primary role is safeguarding mitochondrial integrity against virus- and toxin-induced mitophagy. This function is critical in enacting a potent, IFN/NF-κB-independent antiviral response. Using SARS-CoV-2 (CoV-2) infection model, where disruption of MAVS aggregation and induction of mitophagy were observed, we demonstrate that functional MAVS prevents CoV-2-induced mitophagy and restricts viral replication without engaging type I or III interferon (IFN), and NF-κB pathways. Employing MAVS-knockout and MAVS:IFNAR1 double-knockout cells, and inhibition studies, our results further establish MAVS as a critical protector against virus- and chemical mitotoxin-induced mitophagy. Loss of MAVS results in increased mitochondrial membrane depolarization, reduced oxidative potential, and increased PINK1-dependent mitophagy leading to elevated viral replication-all reversed by MAVS supplementation. The IFN-independent antiviral immunity generated by MAVS-driven mitochondrial safeguarding conferred robust protection against mitophagy-inducing viruses, such as CoV-2 and JEV, but not DENV, which does not trigger mitophagy. By facilitating the mitochondrial integrity, MAVS governs the overall innate antiviral immunity- integrating IFN-dependent and IFN-independent mechanisms- and energy metabolism in the host cells. Thus, the regulation of these central functions makes MAVS a prime target for subverting host defenses and cellular energy homeostasis. These insights underscoring MAVS’s wider role in sustaining mitochondrial homeostasis positions it as a promising target for antiviral strategies.
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Project description:MAVS Orchestrates a Potent IFN-independent Antiviral Immunity by 2 Preserving Mitochondrial Integrity
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Project description:Detection of viral RNA in the cytosol of infected cells depends on RIG-I-lilke recptors that use MAVS as an adapter protein to activate antiviral gene expression. MAVS is tail-anchored on mitochondria, mitochondria-associated membranes and peroxisomes. As peroxisomal membrane proteins can be mistargeted to mitochondria in the absence of peroxisomes, we hypothesized that MAVS-dependent antiviral gene expression is activated more efficiently in this instance. Pex19 deficient skin firoblasts derived from a Zellweger syndrome patient lack peroxisomes. We introduced wild type Pex19 into these cells to restore peroxisome formation and assessed alterations in the gene expression profile of these cells after reovirus infection. 6 samples: 9 and 16 hrs after reovirus infection at an MOI of 100 total RNA was extracted from Pex19 reconstituted and deficient cell lines. Gene expression data was compared to uninfected cells.
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