Infection phase-dependent dynamics of the viral and host N6-methyladenosine epitranscriptome in the lifecycle of an oncogenic virus in vivo
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ABSTRACT:
ORGANISM(S): Gallus gallus
PROVIDER: GSE208699 | GEO | 2023/07/19
REPOSITORIES: GEO
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Project description:we profiled the transcriptome-wide m6A modification in lncRNAs and circRNA in MDV-infected chicken embryo fibroblast (CEF) cells. Methylated RNA immunoprecipitation sequencing results revealed that the lncRNA m6A modification is highly conserved with MDV infection increasing the expression of lncRNA m6A modified sites compared to uninfected cell controls. m6A modification was highly conserved in circRNAs. Comparing to the uninfected group, the number of peaks, conserved motifs, and abundance of circRNA m6A modification, was not significantly different in cells that were infected with MDV. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) analysis revealed that lncRNA m6A modifications were highly associated with signaling pathways associated with MDV infection. The alterations seen in transcriptome-wide m6A occurring in lncRNAs following MDV-infection suggest this process plays important regulatory roles during MDV replication. And the insulin signaling pathway was associated with the regulation of m6A modified circRNAs in MDV infection. In summary, we report for the first time profiling of the alterations in transcriptome-wide m6A modification in lncRNAs and circRNA of MDV-infected CEF cells.
2021-04-28 | GSE166240 | GEO
Project description:Marek’s disease (MD) is an economically significant disease in chickens caused by the highly oncogenic Marek’s disease virus (MDV). Understanding the genes and biological pathways that confer MD genetic resistance should lead towards the development of more disease resistant commercial poultry flocks or improved MD vaccines. MDV Meq, a bZIP transcription factor, is largely attributed for viral oncogenicity though only a few host target genes have been described, which has impeded our understanding of MDV-induced tumorigenesis. Given the importance of Meq in MDV-induced pathogenesis, we explored the role of Meq in genetic resistance to MDV. Using global transcriptome analysis to compare the host response between birds challenge with either wild type MDV or a recombinant lacking Meq, we identified a number of specific genes and pathways associated with either MD resistance. Integrating prior information from ChIP-seq, microarray analysis, and SNPs exhibiting allele-specific expression (ASE) in response to MDV infection from two inbred layer lines that differ greatly in MD genetic resistance, we were able to provide a evidence for 35 genes that SNPs within transcription factor binding sites can affect transcription factor binding and gene expression in an allele-specific manner.
2016-07-01 | GSE48453 | GEO
Project description:COVID-19 pandemic caused by SARS-CoV-2 is far from getting over because of the emergence of different SARS-CoV-2 variants even though vaccination against SARS-CoV-2 is ongoing. Variant specific mechanistic understanding of host-viral interaction will be required to design novel anti-viral therapeutics. N6-methyladenosine modification (m6A) which is one of the abundant cellular RNA modifications regulates key processes in RNA metabolism during stress response. We observed different SARS-CoV-2 variants during infection causes global loss of m6A in cellular RNA whereas m6A modification was detected abundantly in viral RNA. The loss of m6A in cellular RNAs was more drastic in B.1 and B1.1.7 strains and the main m6A methyltransferase METTL3 shows cytoplasmic localization post-infection. In B1.351 variant effect on METTL3 localization and loss of m6A was less pronounced compared to B.1 and B1.1.7 variants. Gene expression profile suggested changes in RNA catabolism-related pathways including key genes related to m6A readers and erasers during SARS-CoV-2 infection. Genes with m6A peaks were more susceptible to down-regulation during viral infection. Inhibition of export protein XPO1 during infection results in restoration of METTL3 nuclear localization and reduction in viral infection in cell culture suggesting XPO1 inhibition could be an effective therapeutic option for SARS-CoV-2.
2023-02-07 | GSE188477 | GEO
Project description:N6-methyladenosine (m6A), the most abundant mRNA modification, was shown to alter the life cycles of diverse DNA and RNA viruses. These effects were proposed to be mediated in a virus-specific manner, through dysregulated methylation of viral RNA. We use RNA-seq to systematically follow differences in gene expression in cells depleted of m6A machinery, compared to control cells, following human cytomegalovirus (HCMV) infection. We show that following viral infection or stimulation of cells with an inactivated virus, depletion of the m6A 'writer' protein METTL3 or 'reader' protein YTHDF2 leads to a dramatic increase in the induction of hundreds of interferon-stimulated genes (ISGs), which constitutes the first line of antiviral defense. Consequently, propagation of different viruses is markedly suppressed in an interferon (IFN)-signaling dependent manner. Furthermore, we used m6A-immunoprecipitation, followed by RNA-seq, to map m6A sites on human and HCMV transcripts, and found that the mRNA of IFNβ, the central cytokine that drives the type I IFN response, is m6A modified, and is stabilized upon repression of METTL3 and YTHDF2.
2018-11-14 | GSE114019 | GEO
Project description:Background: Marek’s disease (MD) is a highly contagious, lymphomatous disease of chickens induced by a herpesvirus, Marek’s disease virus (MDV) that is the cause of major annual losses to the poultry industry. MD pathogenesis involves multiple stages including an early cytolytic phase and latency, and transitions between these stages are governed by several host and environmental factors. The success of vaccination strategies has led to the increased virulence of MDV and selective breeding of naturally resistant chickens is seen as a viable alternative. While multiple gene expression studies have been performed in resistant and susceptible populations, little is known about the epigenetic effects of infection. Results: In this study, we investigated temporal chromatin signatures induced by MDV by analyzing early cytolytic and latent phases of infection in the bursa of Fabricius of MD-resistant and –susceptible birds. Major global variations in chromatin marks were observed at different stages of MD in the two lines. Differential H3K27me3 marks were associated with immune-related pathways, such as MAP kinase signaling, focal adhesion and neuroactive ligand receptor interaction, and suggested varying degrees of silencing in response to infection. Immune-related microRNAs, e.g. gga-miR-155 and gga-miR-10b, bore chromatin signatures, which suggested their contribution to MD-susceptibility. Finally, several members of the focal adhesion pathway, e.g. THBS4 and ITGA1, showed marked concordance between gene expression and chromatin marks indicating putative epigenetic regulation in response to MDV infection. Conclusions: Our comprehensive analysis of chromatin signatures, therefore, revealed further clues about the epigenetic effects of MDV infection although further studies are necessary to elucidate the functional implications of the observed variations in histone modifications. Total of 32 samples analyzed; 2 histone modifications - H3K4me3 and H3K27me3 x 2 chicken lines with varying resistance to MD - L63 and L72 x 2 time-points of disease progression - 5 and 10 days post infection x 2 conditions - infected and control x 2 biological replicates
2015-04-17 | E-GEOD-65961 | biostudies-arrayexpress
Project description:Background: Marek’s disease (MD) is a highly contagious, lymphomatous disease of chickens induced by a herpesvirus, Marek’s disease virus (MDV) that is the cause of major annual losses to the poultry industry. MD pathogenesis involves multiple stages including an early cytolytic phase and latency, and transitions between these stages are governed by several host and environmental factors. The success of vaccination strategies has led to the increased virulence of MDV and selective breeding of naturally resistant chickens is seen as a viable alternative. While multiple gene expression studies have been performed in resistant and susceptible populations, little is known about the epigenetic effects of infection. Results: In this study, we investigated temporal chromatin signatures induced by MDV by analyzing early cytolytic and latent phases of infection in the bursa of Fabricius of MD-resistant and –susceptible birds. Major global variations in chromatin marks were observed at different stages of MD in the two lines. Differential H3K27me3 marks were associated with immune-related pathways, such as MAP kinase signaling, focal adhesion and neuroactive ligand receptor interaction, and suggested varying degrees of silencing in response to infection. Immune-related microRNAs, e.g. gga-miR-155 and gga-miR-10b, bore chromatin signatures, which suggested their contribution to MD-susceptibility. Finally, several members of the focal adhesion pathway, e.g. THBS4 and ITGA1, showed marked concordance between gene expression and chromatin marks indicating putative epigenetic regulation in response to MDV infection. Conclusions: Our comprehensive analysis of chromatin signatures, therefore, revealed further clues about the epigenetic effects of MDV infection although further studies are necessary to elucidate the functional implications of the observed variations in histone modifications.
2015-04-17 | GSE65961 | GEO
Project description:Marek’s disease (MD) is a viral neoplastic disease in chickens caused by the MD virus (MDV). Successful vaccination strategies against MD have resulted in a progressive increase in the virulence of MDV and therefore, the understanding of genetic resistance to MD is considered crucial to the long-term control of the disease. Here we examine whether MDV infection induces changes in the epigenetic status of genes and whether this response is dependent on the host genotype. We generated genome-wide histone 3 lysine 4 (H3K4) and histone 3 lysine 27 (H3K27) trimethylation maps in thymus tissues from chicken lines with varying resistance to MD. Differential chromatin marks were observed on several genes previously implicated in MD such as MX1, MMP2 and CTLA-4 and also on novel genes such as EAF2, IGF2BP1 and GAL. We also detected bivalent domains on transcriptional regulators such as BCL6, CITED2 and EGR1 that have particular functions in immune response. Moreover, novel putative roles for GAL and CITED2 in the mechanism of MD progression were uncovered. We also found tissue-specific effects of MDV infection with certain genes exhibiting differential marks only in spleen. Our results suggest widespread epigenetic changes are induced by MDV infection extent of which is determined by the level of MD resistance of the host. 8 samples examined: 2 histone modifications X 2 chicken lines with varying resistance to MD X 2 groups - infected and control.
2013-01-01 | E-GEOD-33541 | biostudies-arrayexpress
Project description:Marek’s disease (MD) is a viral neoplastic disease in chickens caused by the MD virus (MDV). Successful vaccination strategies against MD have resulted in a progressive increase in the virulence of MDV and therefore, the understanding of genetic resistance to MD is considered crucial to the long-term control of the disease. Here we examine whether MDV infection induces changes in the epigenetic status of genes and whether this response is dependent on the host genotype. We generated genome-wide histone 3 lysine 4 (H3K4) and histone 3 lysine 27 (H3K27) trimethylation maps in thymus tissues from chicken lines with varying resistance to MD. Differential chromatin marks were observed on several genes previously implicated in MD such as MX1, MMP2 and CTLA-4 and also on novel genes such as EAF2, IGF2BP1 and GAL. We also detected bivalent domains on transcriptional regulators such as BCL6, CITED2 and EGR1 that have particular functions in immune response. Moreover, novel putative roles for GAL and CITED2 in the mechanism of MD progression were uncovered. We also found tissue-specific effects of MDV infection with certain genes exhibiting differential marks only in spleen. Our results suggest widespread epigenetic changes are induced by MDV infection extent of which is determined by the level of MD resistance of the host.
2013-01-01 | GSE33541 | GEO
Project description:N6-methyladenosine (m6A) is the most abundant internal RNA modification catalyzed by host RNA methyltransferases. As obligate intracellular parasites, many viruses acquire m6A methylation in their RNAs. However, the biological functions of viral m6A methylation are poorly understood. Here, we found that viral m6A methylation serves as a molecular marker for host innate immunity to discriminate self from nonself RNA and that this novel biological function of viral m6A methylation is universally conserved in non-segmented negative-sense (NNS) RNA viruses. Using m6A methyltransferase (METTL3)-knockout cells, we produced m6A-deficient virion RNA from the representative members of the families Pneumoviridae, Paramyxoviridae, and Rhabdoviridae and found that these m6A-deficient viral RNAs triggered significantly higher levels of type I interferon compared to the m6A-sufficient viral RNAs, in a RIG-I dependent manner. Reconstitution of the RIG-I pathway revealed that m6A-deficient virion RNA induced higher expression of RIG-I, bound to RIG-I more efficiently, enhanced RIG-I ubiquitination, and facilitated RIG-I conformational rearrangement and oligomerization. Furthermore, the m6A binding protein YTHDF2 sequesters m6A-sufficient virion RNA which suppresses type I interferon signaling pathway. Collectively, our results suggest that NNS RNA viruses acquire m6A in viral RNA as a common strategy to evade host innate immunity.
2021-01-16 | GSE164882 | GEO
Project description:N6-methyladenosine (m6A) is the most abundant internal RNA modification catalyzed by host RNA methyltransferases. As obligate intracellular parasites, many viruses acquire m6A methylation in their RNAs. However, the biological functions of viral m6A methylation are poorly understood. Here, we found that viral m6A methylation serves as a molecular marker for host innate immunity to discriminate self from nonself RNA and that this novel biological function of viral m6A methylation is universally conserved in non-segmented negative-sense (NNS) RNA viruses. Using m6A methyltransferase (METTL3)-knockout cells, we produced m6A-deficient virion RNA from the representative members of the families Pneumoviridae, Paramyxoviridae, and Rhabdoviridae and found that these m6A-deficient viral RNAs triggered significantly higher levels of type I interferon compared to the m6A-sufficient viral RNAs, in a RIG-I dependent manner. Reconstitution of the RIG-I pathway revealed that m6A-deficient virion RNA induced higher expression of RIG-I, bound to RIG-I more efficiently, enhanced RIG-I ubiquitination, and facilitated RIG-I conformational rearrangement and oligomerization. Furthermore, the m6A binding protein YTHDF2 sequesters m6A-sufficient virion RNA which suppresses type I interferon signaling pathway. Collectively, our results suggest that NNS RNA viruses acquire m6A in viral RNA as a common strategy to evade host innate immunity.
2020-12-01 | GSE162339 | GEO