Identification of symmetric methyltion of histone H4 arginine 3 on KSHV genome
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE82321 | GEO | 2016/06/08
SECONDARY ACCESSION(S): PRJNA324644
REPOSITORIES: GEO
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Project description:The objective of this study was to identify the symmetric methylation sites on KSHV genome during latency and lytic reactivation
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Project description:The objective of this study was to identify the symmetric methylation sites on KSHV genome during latency and lytic reactivation
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Project description:The objective of this study was to identify the symmetric methylation sites on KSHV genome during latency and lytic reactivation
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Project description:Enhancers play indispensable roles in cell proliferation and survival through spatiotemporally regulating gene transcription. In addition, active enhancers and super-enhancers often produce noncoding enhancer RNAs (eRNAs) that precisely control RNA polymerase II activity. Kaposi’s sarcoma-associated herpesvirus (KSHV) is a human oncogenic gamma-2 herpesvirus that causes Kaposi’s sarcoma and lymphoproliferative diseases of B-cell origin such as primary effusion lymphoma (PEL). It is well characterized that KSHV utilizes host epigenetic and nuclear machineries to control the switch between two life cycles, latency and lytic replication. However, how KSHV impacts the host epigenome at different stages of viral life cycle is not well understood. Using the analysis of global run-on sequencing (GRO-seq) and chromatin-immunoprecipitation sequencing (ChIP-seq), we profiled the dynamics of host transcriptional regulatory elements during latency and lytic replication of KSHV-infected PEL cells. This study showed that a number of critical host genes for KSHV latency, including MYC proto-oncogene, were under the control of super-enhancers and eRNAs that were globally repressed upon viral reactivation. A combination of circular chromosome conformation capture combined with sequencing (4C-seq), GRO-seq and ChIP-seq indicated that the eRNA-expressing super-enhance regions were located at downstream of the MYC gene in KSHV-infected PELs. Treatment of an epigenetic drug to block enhancer function or shRNA-mediated depletion of the eRNA expression significantly reduced MYC mRNA expression in KSHV-infected PELs. Finally, while cellular IRF4 acted upon the eRNAs and super-enhancers for MYC expression during latency, the KSHV viral IRF4 repressed cellular IRF4 expression upon reactivation, decreasing MYC expression and thereby, facilitating lytic replication. Taken together, these data suggest that KSHV acts as an epigenetic driver that modifies host epigenomic status by effectively regulating enhancer function upon reactivation.
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Project description:Identification of symmetric methylation of histone H4 arginine 3 on KSHV genome
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Project description:Chromatin-organizing factors, like CTCF and cohesins, have been implicated in the control of complex viral regulatory programs. We investigated the role of CTCF and cohesin in the control of the latent to lytic switch for Kaposi's Sarcoma-Associated Herpesvirus (KSHV). We found that cohesin subunits, but not CTCF, were required for the repression of KSHV immediate early gene transcription. Depletion of cohesin subunits Rad21, SMC1, or SMC3 resulted in lytic cycle gene transcription and viral DNA replication. In contrast, depletion of CTCF failed to induce lytic transcription or DNA replication. ChiP-Seq analysis revealed that cohesins and CTCF bound to several sites within the immediate early control regions for ORF50 and more distal 5' sites that also regulate the divergently transcribed ORF45-46-47 gene cluster. Rad21 depletion led to a robust increase in ORF45 and ORF47 transcripts, with similar kinetics to that observed with chemical induction by sodium butyrate. During latency, the chromatin between the ORF45 and ORF50 transcription start sites was enriched in histone H3K4me3 with elevated H3K9ac at the ORF45 promoter and elevated H3K27me3 at the ORF50 promoter. A paused form of RNA pol II was loosely associated with the ORF45 promoter region during latency, but was converted to an active elongating form upon reactivation induced by Rad21 depletion. Butyrate-induced transcription of ORF45 and ORF47 was resistant to cyclohexamide, suggesting that these genes have immediate early features similar to ORF50. Butyrate-treatment caused the rapid dissociation of cohesins and loss of CTCF binding at the immediate early gene locus, suggesting that cohesins may be a direct target of butyrate-mediated lytic induction. Our findings implicate cohesins as a major repressor of KSHV lytic gene activation, and function coordinately with CTCF to regulate the switch between latent and lytic gene activity. Study of chromatin-organizing factors, like CTCF and cohesins.
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Project description:Lytic reactivation from latency is critical for the pathogenesis of KSHV. We previously demonstrated that the 691 amino acid KSHV Rta transcriptional transactivator is necessary and sufficient to reactivate the virus from latency. Viral lytic cycle genes, including those expressing additional transactivators and putative oncogenes, are induced in a cascade fashion following Rta expression. In this study, we sought to define Rta’s direct targets during reactivation by generating a conditionally nuclear variant of Rta. WT Rta protein is constitutively localized to cell nuclei, and contains two putative nuclear localization signals (NLSs). Only one NLS (NLS-2; aa 516-530) was required for nuclear localization of Rta, and relocalized eGFP exclusively to cell nuclei. Analyses of Rta NLS mutants demonstrated that proper nuclear localization of Rta was required for transactivation and stimulation of viral reactivation. Fusion of Rta_NLS-1,2 to the hormone binding domain of the murine estrogen receptor generated a variant of Rta whose nuclear localization and ability to transactivate and induce reactivation were tightly controlled post-translationally by the synthetic hormone tamoxifen. We used this strategy in KSHV-infected cells treated with protein synthesis inhibitors to identify direct transcriptional targets of Rta. Only eight KSHV genes were activated by Rta in the absence of de novo protein synthesis. These direct transcriptional targets of Rta were transactivated to different magnitudes, and included the genes nut-1/PAN, ORF57/Mta, ORF56/Primase, K2/vIL-6, ORF37/SOX, K14/vOX, K9/vIRF1, and ORF52. Our data suggest that induction of most of the KSHV lytic cycle genes requires additional protein expression post-Rta. Keywords: Comparative transcriptome analysis by oligonucleotide microarray
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Project description:Kaposi’s Sarcoma associated herpesvirus (KSHV) is an oncogenic human virus and leading cause of mortality in HIV infection. Reactivation of KSHV from latent to lytic stage infection initiates a cascade of viral gene expression, and here we show how these changes remodel the host cell proteome to enable viral replication. By undertaking a systematic and unbiased analysis of changes to the endothelial cell proteome following lytic KSHV reactivation, we quantify >7000 cellular and 71 viral proteins. Lytic KSHV infection resulted in >2-fold downregulation of 291 cellular proteins, including PKR, the key cellular sensor of double-stranded RNA. A complementary KSHV genome-wide CRISPR genetic screen identified K5 as the viral gene responsible for the downregulation of two novel KSHV targets, Nectin-2 and CD155, both ligands of the NK cell DNAM-1 receptor. Despite the high episome copy number, we show that CRISPR Cas9 provides a remarkably efficient way to target KSHV genomes.
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Project description:Kaposi’s Sarcoma associated herpesvirus (KSHV) is an oncogenic human virus and leading cause of mortality in HIV infection. Reactivation of KSHV from latent to lytic stage infection initiates a cascade of viral gene expression, and here we show how these changes remodel the host cell proteome to enable viral replication. By undertaking a systematic and unbiased analysis of changes to the endothelial cell proteome following lytic KSHV reactivation, we quantify >7000 cellular and 71 viral proteins. Lytic KSHV infection resulted in >2-fold downregulation of 291 cellular proteins, including PKR, the key cellular sensor of double-stranded RNA. A complementary KSHV genome-wide CRISPR genetic screen identified K5 as the viral gene responsible for the downregulation of two novel KSHV targets, Nectin-2 and CD155, both ligands of the NK cell DNAM-1 receptor. Despite the high episome copy number, we show that CRISPR Cas9 provides a remarkably efficient way to target KSHV genomes.
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Project description:Eukaryotic genomes are structurally organized via the formation of multiple loops that create gene expression regulatory units called topologically associating domains (TADs). Here we revealed the KSHV TAD structure at 500 base pair resolution and constructed a 3D KSHV genomic structural model. The latent KSHV genome formed very similar TAD structures among three different naturally infected PEL cell lines. When KSHV reactivation was triggered, genomic loops within TADs were dramatically decreased, while contacts extending outside of TAD borders increased, leading to formation of a larger regulatory unit with a shift from repressive to active compartments (B to A). The 3D structural model proposes that the immediate-early promoter region is localized on the periphery of the 3D viral genome, while highly inducible non-coding RNA regions moved toward the inner space of the structure, resembling the coordination of a "bird cage" during reactivation. Finally, inhibition of the initial burst of lytic gene expression by stop codon insertion in the viral transactivator reduced genomic loops, while supplementing K-Rta expression in trans during establishment of latency attenuated the defect. Our studies suggest that the latent 3D genomic structural information is embedded in the lytic gene transcription program.
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