Herpesviruses mimic zygotic genome activation to promote viral replication
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1134630 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29777400_1.fastq.gz | Fastqsanger.gz | |||
| SRR29777400_2.fastq.gz | Fastqsanger.gz | |||
| SRR29777401_1.fastq.gz | Fastqsanger.gz | |||
| SRR29777401_2.fastq.gz | Fastqsanger.gz | |||
| SRR29777402_1.fastq.gz | Fastqsanger.gz |
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Project description:Herpesviruses mimic zygotic genome activation to promote viral replication
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Project description:DUX4 is a germline transcription factor and a master regulator of zygotic genome activation. During early embryogenesis, DUX4 is crucial for maternal to zygotic transition at the 8-cell stage in order to overcome silencing of genes and enable transcription from the zygotic genome. In adult somatic cells, DUX4 expression is silenced and its activation in adult muscle cells causes the genetic disorder Facioscapulohumeral Muscular Dystrophy (FSHD). Here we show that herpesviruses actively induce DUX4 expression to promote viral transcription and replication. We demonstrate that HSV-1 immediate early proteins directly induce expression of DUX4 and its target genes including endogenous retroelements, which mimics zygotic genome activation. DUX4 directly binds to the viral genome, promotes viral transcription and genetic depletion of DUX4 by CRISPR/Cas9 abrogates viral replication. Our results show that viruses from alpha-, beta- and gamma-herpesvirus subfamilies induce DUX4 expression and downstream germline-specific genes and retroelements. Herpesviruses activate DUX4 expression in order to induce an early embryonic-like transcriptional program that prevents epigenetic silencing of the viral genome and facilitates herpesviral gene expression.
2024-12-12 | GSE272015 | GEO
Project description:DUX4 is a germline transcription factor and a master regulator of zygotic genome activation. During early embryogenesis, DUX4 is crucial for maternal to zygotic transition at the 8-cell stage in order to overcome silencing of genes and enable transcription from the zygotic genome. In adult somatic cells, DUX4 expression is silenced and its activation in adult muscle cells causes the genetic disorder Facioscapulohumeral Muscular Dystrophy (FSHD). Here we show that herpesviruses actively induce DUX4 expression to promote viral transcription and replication. We demonstrate that HSV-1 immediate early proteins directly induce expression of DUX4 and its target genes including endogenous retroelements, which mimics zygotic genome activation. DUX4 directly binds to the viral genome, promotes viral transcription and genetic depletion of DUX4 by CRISPR/Cas9 abrogates viral replication. Our results show that viruses from alpha-, beta- and gamma-herpesvirus subfamilies induce DUX4 expression and downstream germline-specific genes and retroelements. Herpesviruses activate DUX4 expression in order to induce an early embryonic-like transcriptional program that prevents epigenetic silencing of the viral genome and facilitates herpesviral gene expression.
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Project description:The adenovirus (Ad) serotype 5 genome encodes two non-coding small RNAs (virus-associated RNAs: VA-RNAI and II), which are approximately 160nt-long RNAs transcribed by RNA polymerase III. Recent studies revealed that VA-RNAs are processed into VA-RNA-derived microRNAs (miRNAs) (mivaRNAI, II); however, we and another group recently demonstrated that mivaRNAI does not promote Ad replication. On the other hand, roles of VA-RNAII and VA-RNAII-derived miRNA (mivaRNAII) in Ad replication have remained to be clarified. In this study, we showed mivaRNAII-mediated promotion of Ad replication. Transfection with chemically synthesized 3'-mivaRNAII-138, one of the most abundant mivaRNAII, significantly enhanced Ad replication, while the other species of mivaRNAII did not. We used microarrays to detail gene expression profiles in HeLa cells transfected with 3'-miaRNAII-138 mimic and demonstarted that expression levels of various genes were down- or up-regulated following transfection with 3'-mivaRNAII-138 mimic.
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Project description:Hepatitis B virus deregulates cell cycle to promote viral replication and a premalignant phenotype
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Project description:Regulation of DNA replication and copy number are necessary to promote genome stability and maintain cell and tissue function. DNA replication is regulated temporally in a process known as replication timing (RT). Rif1 is key regulator of RT and has a critical function in copy number control in polyploid cells. In a previous study (Munden et al., 2018), we demonstrated that Rif1 functions with SUUR to inhibit replication fork progression and promote underreplication of specific genomic regions. How Rif1-dependent control of RT factors into its ability to promote underreplication is unknown. By applying a computational approach to measure RT in Drosophila polyploid cells, we show that SUUR and Rif1 have differential roles in controlling underreplication and RT. Our findings reveal that Rif1 functions both upstream and downstream of SUUR to promote underreplication. Our work provides new mechanistic insight into the process of underreplication and its links to RT.
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Project description:SARS-CoV-2 emerged in China at the end of 2019 and caused the global pandemic of COVID-19, a disease with high morbidity and mortality. While our understanding of this new virus is rapidly increasing, gaps remain in our understanding of how SARS-CoV-2 can effectively suppress host cell antiviral responses. Recent work on other viruses has demonstrated a novel mechanism through which viral proteins can mimic critical regions of human histone proteins. Histone proteins are responsible for governing genome accessibility and their precise regulation is critical for a cell’s ability to control transcription and respond to viral threats. Here, we show that the protein encoded by ORF8 (Orf8) in SARS-CoV-2 functions as a histone mimic of the ARKS motif in histone 3. Orf8 is associated with chromatin, binds to numerous histone-associated proteins, and is itself acetylated within the histone mimic site. Orf8 expression in cells disrupts multiple critical histone post-translational modifications (PTMs) including H3K9ac, H3K9me3, and H3K27me3 and promotes chromatin compaction while Orf8 lacking the histone mimic motif does not. Further, SARS-CoV-2 infection in human cell lines and postmortem patient lung tissue cause these same disruptions to chromatin. However, deletion of the Orf8 gene from SARS-CoV-2 largely blocks its ability to disrupt host-cell chromatin indicating that Orf8 is responsible for these effects. Finally, deletion of the ORF8 gene affects the host-cell transcriptional response to SARS-CoV-2 infection in multiple cell types and decreases the replication of SARS-CoV-2 in human induced pluripotent stem cell-derived lung alveolar type 2 (iAT2) pulmonary cells. These findings demonstrate a novel function for the poorly understood ORF8-encoded protein and a mechanism through which SARS-CoV-2 disrupts host cell epigenetic regulation. Finally, this work provides a molecular basis for the finding that SARS-CoV-2 lacking ORF8 is associated with decreased severity of COVID-19.
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