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Transcriptomic analysis of early HSV-1 transcription in the absence of the immediate early protein, ICP4 [PROSeq]

ABSTRACT: Herpes simplex virus 1 (HSV-1) transcription is tightly regulated in a temporal cascade, utilizing cellular RNA polymerase (Pol). We previously observed that infection with HSV-1 mutants lacking immediate early (IE) genes a0, a4 and a22 exhibited unusually high levels of aberrant transcription across the viral genome at just 1.5 hpi. The strongest effect occurred in the absence of a4, which is both an essential transcriptional activator and repressor. The goal of the current study was to define the mechanism of ICP4-mediated early transcriptional repression on the viral genome. Using the transcriptomic tools PRO-Cap, PRO-Seq, GRO-Seq and Nanopore direct RNA sequencing we found that initiation was elevated at viral promoters of all temporal classes in the absence of ICP4. Despite higher levels of initiation, transcription of non-IE genes was stalled within gene bodies and did not lead to production of mature mRNA. We therefore posit that HSV-1 retains additional ICP4-independent mechanisms to limit expression of viral genes that initiate prematurely. The data also indicated rapid release from promoter proximal pausing and progression along HSV IE genes and revealed termination as an important rate -limiting regulatory step. These findings highlight multiple mechanisms that HSV-1 employs to regulate early transcription and identify ICP4’s repressive role is to restrict initiation on non IE genes, thereby ensuring correct progression of the temporal cascade.

ORGANISM(S): Homo sapiens

PROVIDER: GSE235227 | GEO | 2023/09/05

REPOSITORIES: GEO

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Transcriptomic analysis of early HSV-1 transcription in the absence of the immediate early protein, ICP4 [PROCap]

Project description:Herpes simplex virus 1 (HSV-1) transcription is tightly regulated in a temporal cascade, utilizing cellular RNA polymerase (Pol). We previously observed that infection with HSV-1 mutants lacking immediate early (IE) genes a0, a4 and a22 exhibited unusually high levels of aberrant transcription across the viral genome at just 1.5 hpi. The strongest effect occurred in the absence of a4, which is both an essential transcriptional activator and repressor. The goal of the current study was to define the mechanism of ICP4-mediated early transcriptional repression on the viral genome. Using the transcriptomic tools PRO-Cap, PRO-Seq, GRO-Seq and Nanopore direct RNA sequencing we found that initiation was elevated at viral promoters of all temporal classes in the absence of ICP4. Despite higher levels of initiation, transcription of non-IE genes was stalled within gene bodies and did not lead to production of mature mRNA. We therefore posit that HSV-1 retains additional ICP4-independent mechanisms to limit expression of viral genes that initiate prematurely. The data also indicated rapid release from promoter proximal pausing and progression along HSV IE genes and revealed termination as an important rate -limiting regulatory step. These findings highlight multiple mechanisms that HSV-1 employs to regulate early transcription and identify ICP4’s repressive role is to restrict initiation on non IE genes, thereby ensuring correct progression of the temporal cascade.

2023-09-05 | GSE235226 | GEO

Transcriptomic analysis of early HSV-1 transcription in the absence of the immediate early protein, ICP4 [GRO-seq]

2023-09-05 | GSE235224 | GEO

Transcriptomic analysis of early HSV-1 transcription in the absence of the immediate early protein, ICP4 [Nanopore]

2023-09-05 | GSE235872 | GEO

Immediate early proteins of herpes simplex virus transiently repress viral transcription before subsequent activation.

Project description:This study was undertaken to further clarify the roles of HSV-1 immediately early (IE) genes ICP4, ICP0, and ICP22 in early viral transcription. Precision nuclear Run On followed by deep Sequencing (PRO-Seq) was used to identify sites of Pol activity to high resolution on the genomes of HSV-1 viruses bearing mutations in a0, a4 or a22/US1, and corresponding viruses in which these loci were genetically restored. The results indicated that prior to initiating activation of transcription, IE genes first mediate transcriptional repression.

2022-10-18 | GSE202363 | GEO

Parallel G-quadruplexes recruit the HSV-1 transcription factor ICP4 to promote viral transcription in herpes virus-infected human cells

Project description:G-quadruplexes (G4s) are four-stranded nucleic acid structures abundant at gene promoters. They can adopt several distinctive conformations. G4s have been shown to form in the herpes simplex virus-1 (HSV-1) genome during its viral cycle. Here by cross-linking/pull-down assay we identified ICP4, the major HSV-1 transcription factor, as the protein that most efficiently interacts with viral G4s during infection. ICP4 specific and direct binding and unfolding of parallel G4s, including those present in HSV-1 immediate early gene promoters, induced transcription in vitro and in infected cells. This mechanism was also exploited by ICP4 to promote its own transcription. Proximity ligation assay allowed visualization of G4-protein interaction at the single selected G4 in cells. G4 ligands inhibited ICP4 binding to G4s. Our results indicate the existence of a well-defined G4-viral protein network that regulates the productive HSV-1 cycle. They also point to G4s as elements that recruit transcription factors to activate transcription in cells.

2021-09-10 | PXD024743 | Pride

Genome-wide analysis of RNA polymerase II occupancy during HSV-1 infection in the presence and absence of ICP4.

Project description:The goal of this study was to identify how the occupancy of RNA polymerase II (Pol II) on the host genome changes during HSV-1 infection and is impacted by the viral immediate early protein ICP4. Pol II ChIP-seq experiments after infection with the wild-type (WT) virus and mutant ICP4 (n12) virus, compared to mock infection, revealed global increases and decreases in Pol II occupancy on the host genome that depended upon ICP4.

2021-07-07 | GSE171600 | GEO

Effect of Cyclohexidmide treatment on early transcription of HSV-1 ΔICP22 and repaired virus

Project description:Study was performed to assess the requirement for HSV-1 IE protein, ICP22, to be expressed to regulate early HSV-1 transcription

2022-10-18 | GSE213098 | GEO

Nucleosome maps of the human cytomegalovirus genome reveal a temporal switch in chromatin organization linked to a major IE protein

Project description:Human CMV (hCMV) establishes lifelong infections in most of us, causing developmental defects in human embryos and life-threatening disease in immunocompromised individuals. During productive infection, the viral >230,000-bp dsDNA genome is expressed widely and in a temporal cascade. The hCMV genome does not carry histones when encapsidated but has been proposed to form nucleosomes after release into the host cell nucleus. Here, we present hCMV genome-wide nucleosome occupancy and nascent transcript maps during infection of permissive human primary cells. We show that nucleosomes occupy nuclear viral DNA in a nonrandom and highly predictable fashion. At early times of infection, nucleosomes associate with the hCMV genome largely according to their intrinsic DNA sequence preferences, indicating that initial nucleosome formation is genetically encoded in the virus. However, as infection proceeds to the late phase, nucleosomes redistribute extensively to establish patterns mostly determined by nongenetic factors. We propose that these factors include key regulators of viral gene expression encoded at the hCMV major immediate-early (IE) locus. Indeed, mutant virus genomes defcient for IE1 expression exhibit globally increased nucleosome loads and reduced nucleosome dynamics compared with WT genomes. The temporal nucleosome occupancy differences between IE1-defcient and WT viruses correlate inversely with changes in the pattern of viral nascent and total transcript accumulation. These results provide a framework of spatial and temporal nucleosome organization across the genome of a major human pathogen and suggest that an hCMV major IE protein governs overall viral chromatin structure and function.

2013-07-17 | GSE48875 | GEO

Temporal Dynamics of HCMV Gene Expression in Lytic and Latent Infections

Project description:Primary infection with Human cytomegalovirus (HCMV) results in a persistent lifelong infection due to its ability to establish latent infection. During productive HCMV infection, viral genes are expressed in a coordinated cascade that is characteristic of all herpesviruses and traditionally relies on the dependencies of viral genes on protein synthesis and viral DNA replication. In contrast, the transcriptional landscape associated with HCMV latency is still disputed and poorly understood. Here, we examine viral transcriptomic dynamics during the establishment of both productive and latent HCMV infections. These temporal measurements reveal that viral gene expression dynamics along productive infection and their dependencies on protein synthesis and viral DNA replication, do not fully align. This illustrates that the regulation of herpesvirus genes does not represent a simple sequential transcriptional cascade and surprisingly many viral genes are regulated by multiple independent modules. Using our improved classification of viral gene expression kinetics in conjunction with transcriptome-wide measurements of the effects of a wide array of chromatin modifiers, we unbiasedly show that a defining characteristic of latent cells is the unique repression of immediate early (IE) genes. In particular, we demonstrate that IE1 (a central IE protein) expression is the principal barrier for achieving a full productive cycle. Altogether, our findings provide an unbiased and elaborate definition of HCMV gene expression in lytic and latent infection states.

2022-03-29 | GSE193467 | GEO

Classification of three temporal kinetic transcripts of SGIV

Project description:Singapore grouper iridovirus (SGIV) is the major agent that causes severe iridovirus diseases in grouper maricluture. Based on the genomic information, a DNA microarray, containing probes corresponding to 162 putative SGIV open reading frames (ORFs) was constucted. The viral microarrays wereused to classify the majority of SGIV transcripts into three temporal kinetic classes (immediate-early, IE; early, E; late, L) during an in vitro infection by their dependence on de novo protein synthesis inhibitor and viral DNA replication. Keywords: drug response

2008-01-28 | GSE7154 | GEO

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