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Histone H3 lysine 9 di-methylation as an epigenetic signature of the interferon response (WT and G9a deficient MEFs)

ABSTRACT: Effective anti-viral immunity depends on the ability of infected cells or cells triggered with virus-derived nucleic acids to produce type I interferon (IFN), which activates transcription of numerous antiviral genes. However, disproportionately strong or chronic IFN expression is a common cause of inflammatory and autoimmune diseases. Here we describe an epigenetic mechanism that determines cell-type specific differences in IFN and IFN-stimulated gene expression in response to exogenous signals. We identify di-methylation of histone H3 at lysine 9 (H3K9me2) as a suppressor of IFN and IFN-inducible antiviral gene expression. We show that levels of H3K9me2 at IFN and IFN stimulated genes (ISG) correlate inversely with the scope and amplitude of IFN and ISG expression in fibroblasts and dendritic cells. Accordingly, genetic ablation or pharmacological inactivation of lysine methyltransferase G9a, which is essential for the generation of H3K9me2, resulted in phenotypic conversion of fibroblasts into highly potent IFN-producing cells and rendered these cells resistant to pathogenic RNA viruses. In summary, our studies implicate H3K9me2 and enzymes controlling its abundance as key regulators of innate antiviral immunity. Examination of gene expression in response to PolyI:C in WT and G9a deficient MEFs

ORGANISM(S): Mus musculus

SUBMITTER: Terry Fang

PROVIDER: E-GEOD-24776 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Histone H3 lysine 9 di-methylation as an epigenetic signature of the interferon response (sequencing)

Project description:Effective anti-viral immunity depends on the ability of infected cells or cells triggered with virus-derived nucleic acids to produce type I interferon (IFN), which activates transcription of numerous antiviral genes. However, disproportionately strong or chronic IFN expression is a common cause of inflammatory and autoimmune diseases. Here we describe an epigenetic mechanism that determines cell-type specific differences in IFN and IFN-stimulated gene expression in response to exogenous signals. We identify di-methylation of histone H3 at lysine 9 (H3K9me2) as a suppressor of IFN and IFN-inducible antiviral gene expression. We show that levels of H3K9me2 at IFN and IFN stimulated genes (ISG) correlate inversely with the scope and amplitude of IFN and ISG expression in fibroblasts and dendritic cells. Accordingly, genetic ablation or pharmacological inactivation of lysine methyltransferase G9a, which is essential for the generation of H3K9me2, resulted in phenotypic conversion of fibroblasts into highly potent IFN-producing cells and rendered these cells resistant to pathogenic RNA viruses. In summary, our studies implicate H3K9me2 and enzymes controlling its abundance as key regulators of innate antiviral immunity. Examination of epigenetic modifications in WT and G9a deficient MEFs and splenic DCs

2012-03-02 | E-GEOD-22102 | biostudies-arrayexpress

Histone H3 lysine 9 di-methylation as an epigenetic signature of the interferon response (WT and G9a deficient DCs)

Project description:Effective anti-viral immunity depends on the ability of infected cells or cells triggered with virus-derived nucleic acids to produce type I interferon (IFN), which activates transcription of numerous antiviral genes. However, disproportionately strong or chronic IFN expression is a common cause of inflammatory and autoimmune diseases. Here we describe an epigenetic mechanism that determines cell-type specific differences in IFN and IFN-stimulated gene expression in response to exogenous signals. We identify di-methylation of histone H3 at lysine 9 (H3K9me2) as a suppressor of IFN and IFN-inducible antiviral gene expression. We show that levels of H3K9me2 at IFN and IFN stimulated genes (ISG) correlate inversely with the scope and amplitude of IFN and ISG expression in fibroblasts and dendritic cells. Accordingly, genetic ablation or pharmacological inactivation of lysine methyltransferase G9a, which is essential for the generation of H3K9me2, resulted in phenotypic conversion of fibroblasts into highly potent IFN-producing cells and rendered these cells resistant to pathogenic RNA viruses. In summary, our studies implicate H3K9me2 and enzymes controlling its abundance as key regulators of innate antiviral immunity. Examination of gene expression in response to PolyI:C in WT and G9a deficient DCs

2012-03-02 | E-GEOD-24774 | biostudies-arrayexpress

Histone H3 lysine 9 di-methylation as an epigenetic signature of the interferon response (sequencing)

2012-03-02 | GSE22102 | GEO

Histone H3 lysine 9 di-methylation as an epigenetic signature of the interferon response (WT and G9a deficient DCs)

2012-03-02 | GSE24774 | GEO

Histone H3 lysine 9 di-methylation as an epigenetic signature of the interferon response (WT and G9a deficient MEFs)

2012-03-02 | GSE24776 | GEO

Histone H3 lysine 9 di-methylation as an epigenetic signature of the interferon response

Project description:This SuperSeries is composed of the following subset Series: GSE22102: Histone H3 lysine 9 di-methylation as an epigenetic signature of the interferon response (sequencing) GSE24774: Histone H3 lysine 9 di-methylation as an epigenetic signature of the interferon response (WT and G9a deficient DCs) GSE24776: Histone H3 lysine 9 di-methylation as an epigenetic signature of the interferon response (WT and G9a deficient MEFs) Refer to individual Series

2012-03-02 | E-GEOD-24826 | biostudies-arrayexpress

A role for Widely Interspaced Zinc finger (WIZ) in retention of the G9a methyltransferase on chromatin

Project description:G9a and GLP lysine methyltransferases form a heterodimeric complex that is responsible for the bulk of cellular mono- and di-methylation on histone H3 lysine 9 (H3K9me1/me2). Widely Interspaced Zinc finger (WIZ) associates with the G9a/GLP protein complex, but its role in lysine methylation is poorly defined. Here, we show that WIZ regulates global H3K9me2 levels through a mechanism that involves retention of G9a on chromatin. We also show that WIZ-mediated chromatin loss of G9a/GLP results in altered gene expression and protein-protein interactions that are distinguishable from that of using a molecule-induced enzymatic inhibitor towards G9a/GLP – thus providing evidence that the G9a/GLP/WIZ complex has unique functions when bound to chromatin that are independent of the H3K9me2 mark DMSO, UNC0638, NS, and siWIZ treatments to HEK293T cells, assessing G9a and H3K9me2 localization, each performed in duplicate, plus one input control for each cell condition. 30 samples total.

2015-09-03 | E-GEOD-67317 | biostudies-arrayexpress

Regulation of mammalian 3D genome organization and histone H3K9 dimethylation by H3K9 methyltransferases

Project description:Histone H3 lysine 9 dimethylation (H3K9me2) is a highly conserved silencing epigenetic mark. Chromatin marked with H3K9me2 forms large domains in mammalian cells and overlaps well with lamina-associated domains and the B compartment defined by Hi-C. However, the role of H3K9me2 in 3-dimensional (3D) genome organization remains unclear. We investigated genome-wide H3K9me2 distribution, transcriptome, and 3D genome organization in mouse embryonic stem cells following the inhibition or depletion of five H3K9 methyltransferases (MTases): G9a, GLP, SETDB1, SUV39H1, and SUV39H2. H3K9me2 was regulated by all five MTases; however, H3K9me2 and transcription in the A and B compartments were regulated by different MTases. H3K9me2 in A compartments was primarily regulated by G9a/GLP and SETDB1, while H3K9me2 in the B compartments was regulated by all five MTases. Furthermore, decreased H3K9me2 correlated with changes to the more active compartmental state that accompanied transcriptional activation.

2021-08-05 | PXD024756 | Pride

IFN-alpha Stimulated Gene Expression in Sensitive and Resistant Renal Cell Carcinoma Cell Lines

Project description:The antiproliferative, antiviral, and immunomodulatory properties of interferons (IFNs) have led to its therapeutic implementation. IFNs effects are mediated by a complex network of signal transducers, culminating in IFN-stimulated gene (ISG) induction. This complexity leads to diverse clinical responses to IFN, from no response to complete regression of disease. Elucidation of ISG induction patterns is, therefore, essential to understand and maximize its therapeutic potential. To correlate ISG expression profiles with IFN responsiveness, two renal cell carcinoma (RCC) cell lines differing in antiviral and apoptotic response to IFN were treated with IFN-alpha for different times, and expression profiles were analyzed using a customized microarray containing 850 unique putative ISGs. Genes with similar kinetics of induction in both cell lines were clustered and analyzed for gene function. Seven sets of coordinately regulated genes were identified by k-means cluster analysis, and significant functional similarities were identified for five of the seven sets. Strikingly, expression of genes associated with transcription temporally preceded expression of those involved in signal transduction. Enhanced antiviral sensitivity to IFN was coincident with sustained expression of ISGs involved in transcriptional regulation. However, no difference in Stat1 activation was observed between the cell lines. Analysis of ISG expression patterns suggests that subtle differences in transcription profiles contribute to differences in IFN responsiveness. Two human renal cell carcinoma cell lines (ACHN and RCC1) were treated with IFN-alpha for 3, 6, 9, 12, 16, and 24 hours. Total RNA from treated cells (Cy5) is hybridized with total RNA from untreated control cells (Cy3) to the custom ISG 1.3.1 cDNA array.

2010-05-18 | E-GEOD-15193 | biostudies-arrayexpress

Primary human hepatocytes treated with IFNalpha and IL28B

Project description:Recent identification of IL28B gene polymorphisms associated with hepatitis C virus (HCV) clearance suggests a role for type III interferons (IFNs) in hepatitis C infection. The function of type III IFNs in intrinsic antiviral immunity is poorly understood. Here we show that HCV infection of primary human hepatocytes results in a robust induction of type III but not type I IFNs, leading to IFN- stimulated gene (ISG) expression. In addition, HCV infection elicits a much broader range of gene expression alterations in addition to ISG induction. The induction of type III IFNs is mediated by IRF3 and NFkB- dependent pathways. Type III IFN, aside from upregulating ISGs with a different kinetic profile, induces a distinct set of genes from type I IFN, potentially explaining the functional difference between the two types of IFNs. Chimpanzees undergoing experimental HCV infection demonstrated a prompt hepatic induction of IL28, associating with ISG upregulation, but minimal type I IFN induction. Analysis of liver biopsies from HCV-infected patients supported a close correlation among hepatic expression of IL28 and ISGs, but not with type I IFNs. Our study demonstrates that HCV infection results predominantly in type III IFN induction in the liver and the level of induction correlates with hepatic ISG levels, thus providing a mechanistic explanation for the association between IL28, ISG levels and recovery from HCV infection as well as a potential therapeutic strategy for the treatment of non-responders. Samples were treated with IFN, IL28b and T-PolyC after 6 or 24 hours respectively

2012-03-09 | E-GEOD-31264 | biostudies-arrayexpress

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