Global reprogramming of the cellular translational landscape facilitates cytomegalovirus replication
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE50938 | GEO | 2013/11/01
SECONDARY ACCESSION(S): PRJNA219395
REPOSITORIES: GEO
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Project description:Genome-wide profiling establishes that human cytomegalovirus (HCMV) exerts an extensive, unforeseen level of specific control over which cellular mRNAs are recruited to or excluded from polyribosomes. The landscape of translationally-regulated host mRNAs regulates HCMV replication. The HCMV imposed translational signature shares similarities with cancer cells Two biological replicate experiments were performed profiling total and polysomal mRNAs from i) HCMV-infected vs mock-infected cells and ii) uninfected cells transduced with a lentivirus expressing doxycyclin (dox)-inducible HCMV UL38 +/- dox. Analysis of translationally-controlled host genes in HCMV-infected cell and cells expressing the HCMV UL38 gene product
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Project description:The human cytomegalovirus (HCMV) genome was sequenced 20 years ago. However, like other complex viruses, our understanding of its protein coding potential is far from complete. Here, we use ribosome profiling and transcript analysis to experimentally define the HCMV translation products and follow their temporal expression. We identified several hundred previously unidentified open reading frames and confirmed a fraction by mass spectrometry. We found that regulated use of alternative transcript start sites plays a broad role in enabling tight temporal control of HCMV protein expression and allowing multiple distinct polypeptides to be generated from a single genomic locus. Our results reveal an unanticipated complexity to the HCMV coding capacity and illustrate the role of regulated changes in transcript start sites in generating this complexity. Ribosome profiling and mRNA-seq from 3 time points (5hr, 24hr, 72hr) along HCMV infection. The supplementary file 'GSE41605_merlin_final_orfs.bed.gz' includes the 751 ORFs of HCMV that were identified in this study.
2012-10-17 | E-GEOD-41605 | biostudies-arrayexpress
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Project description:During its long infection cycle, human cytomegalovirus (HCMV) extensively manipulates cellular gene expression to maintain conditions favorable for viral propagation. In order to reveal the signature of cellular genes that are manipulated by HCMV, we measured RNA abundance and rate of protein production through the course of HCMV infection. We characterized changes for most expressed cellular genes and although much of the regulation was transcriptional we uncover diverse and dynamic translational regulation for subsets of host genes, revealing unappreciated coordination in translational control that suggests common regulators Ribosome profiling and mRNA-seq along HCMV infection
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Project description:The human cytomegalovirus (HCMV) genome was sequenced 20 years ago. However, like other complex viruses, our understanding of its protein coding potential is far from complete. Here, we use ribosome profiling and transcript analysis to experimentally define the HCMV translation products and follow their temporal expression. We identified several hundred previously unidentified open reading frames and confirmed a fraction by mass spectrometry. We found that regulated use of alternative transcript start sites plays a broad role in enabling tight temporal control of HCMV protein expression and allowing multiple distinct polypeptides to be generated from a single genomic locus. Our results reveal an unanticipated complexity to the HCMV coding capacity and illustrate the role of regulated changes in transcript start sites in generating this complexity.
2012-10-17 | GSE41605 | GEO
Project description:Small RNA deep sequencing analysis was conducted on primary human fibroblasts infected with human cytomegalovirus (HCMV). HCMV-encoded miRNAs accumulated to ~20% of the total smRNA population at late stages of infection, and our analysis led to improvements in viral miRNA annotations and identification of novel HCMV miRNAs. Through crosslinking and immunoprecipitation of Argonaute-bound RNAs from infected cells, followed by high-throughput sequencing (Ago CLIP-seq), we obtained direct evidence for incorporation of all HCMV miRNAs into the endogenous host silencing machinery. Additionally, significant upregulation was observed during infection for a host miRNA cluster containing miR-96, miR-182 and miR-183. We also identified novel non-miRNA forms of virus-derived smRNAs, revealing greater complexity within the smRNA population during HCMV infection. High-throughput profiling of smRNAs, Ago1-, and Ago2-associated miRNAs from HCMV-infected fibroblast cells. Wild-type HCMV Towne (Genbank FJ616285.1) was used for these studies.
2011-11-10 | E-GEOD-33584 | biostudies-arrayexpress
Project description:We have established that human cytomegalovirus (HCMV) infection modulates the biology of target primary blood monocytes, allowing HCMV to use monocytes as 'vehicles' for its systemic spread. HCMV infection of monocytes results in rapid induction of PI(3)K and NF-kB activity. Integrins, which are upstream of the PI(3)K and NF-kB pathways, were shown to be involved in HCMV binding to and entry into fibroblasts, suggesting that receptor-ligand-mediated signaling following viral binding to integrins on monocytes could trigger the functional changes seen in infected monocytes. We now show that integrin engagement and the activation of the integrin/Src-signaling pathway is essential for the induction of HCMV-infected monocyte motility. To investigate how integrin engagement by HCMV triggers monocyte motility, we examined the infected monocyte transcriptome and found that the integrin/Src-signaling pathway regulates the expression of paxillin, which is an important signal transducer in the regulation of actin rearrangement during cell adhesion and movement. Functionally, we observed that paxillin is activated via the integrin/Src-signaling pathway and is required for monocyte motility. Because motility is intimately connected to cellular cytoskeletal organization, a process that is also important in viral entry, we investigated the role paxillin regulation plays in the process of viral entry of monocytes. New results confirmed that HCMV`s ability to enter target monocytes is significantly inhibited in cells deficient in paxillin expression or that had their integrin/Src/paxillin signaling pathway blocked. From our data, HCMV-cell interactions emerge as an essential trigger for the cellular changes that allow for HCMV entry and hematogenous dissemination. Monocytes were mock-infected, HCMV-infected, or pretreated with PP2 inhibitor prior to HCMV infection. There were three samples analyzed per individual replicate. Three replicates are included. comparative studies with a use of the specific Src kinase activity inhibitor
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Project description:Interactions between human cytomegalovirus (HCMV) infection and environmental factors can increase susceptibility to essential hypertension (EH). Although endothelial dysfunction is the initial factor of EH, the epigenetic mechanisms through which HCMV infection induces endothelial cell dysfunction are poorly understood. Here, we evaluated whether HCMV regulated endothelial cell function and assessed the underlying mechanisms. Microarray analysis in human umbilical vein endothelial cells (HUVECs) treated with HCMV AD169 strain in the presence of hyperglycemia and hyperlipidemia revealed differential expression of genes involved in hypertension.
2020-02-14 | GSE142762 | GEO
Project description:Human cytomegalovirus (HCMV) has been shown to have the potential to alter cellular gene expression early after infection. However, one-gene approaches and the use of closed system gene expression technologies have identified only few cellular genes whose activity changed immediate-early. We therefore used serial analysis of gene expression (SAGE) to investigate the transcriptional program of human fibroblasts in response to HCMV in the immediate-early phase of infection. Differential expression of various cellular genes was monitored. Transcriptional expression changes of genes coding for ribosomal proteins reflected a general cellular response to starvation and stress. But differential regulation of genes coding for transcription factors and proteins associated with cellular metabolism, homeostasis and cell structure may represent transcriptional alterations in response to HCMV infection. Expression kinetics by 5' nuclease fluorigenic real-time PCR of selected genes revealed partial protection of infected cells against initial stress-associated alterations of gene expression and indicated fluctuations of transcriptional levels over time. Additionally, agreement with the quantitative results obtained by SAGE was observed only for genes up-regulated in HCMV-infected cells. This finding pointed to various technical and statistical parameters that all may be critical for quantitative transcriptome studies using global approaches, especially when exploring biological systems in a critical phase of cellular physiology. Keywords: other
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