Interferon Alpha Induces Multiple Cellular Proteins That Coordinately Suppress Hepadnaviral Covalently Closed Circular DNA Transcription
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ABSTRACT:
PROVIDER: PRJNA554783 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9691850.fastq.gz | Fastqsanger.gz | |||
| SRR9691851.fastq.gz | Fastqsanger.gz | |||
| SRR9691852.fastq.gz | Fastqsanger.gz | |||
| SRR9691853.fastq.gz | Fastqsanger.gz | |||
| SRR9691854.fastq.gz | Fastqsanger.gz |
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Project description:Covalently closed circular DNA (cccDNA) of hepadnaviruses exists as an episomal minichromosome in the nucleus of an infected hepatocyte and serves as the template for the transcription of viral mRNAs. It had been demonstrated by others and us that interferon alpha (IFN-α) treatment of hepatocytes induced a prolonged suppression of human and duck hepatitis B virus cccDNA transcription, which is associated with the reduction of cccDNA-associated histone modifications specifying active transcription (H3K9ac or H3K27ac), but not the histone modifications marking constitutive (H3K9me3) or facultative (H3K27me3) heterochromatin formation. In our efforts to identify IFN-induced cellular proteins that mediate the suppression of cccDNA transcription by the cytokine, we found that downregulating the expression of signal transducer and activator of transcription 1 (STAT1), structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1), or promyelocytic leukemia (PML) protein increased basal level of cccDNA transcription activity and partially attenuated IFN-α suppression of cccDNA transcription. In contrast, ectopic expression of STAT1, SMCHD1, or PML significantly reduced cccDNA transcription activity. SMCHD1 is a noncanonical SMC family protein and implicated in epigenetic silencing of gene expression. PML is a component of nuclear domain 10 (ND10) and is involved in suppressing the replication of many DNA viruses. Mechanistic analyses demonstrated that STAT1, SMCHD1, and PML were recruited to cccDNA minichromosomes and phenocopied the IFN-α-induced posttranslational modifications of cccDNA-associated histones. We thus conclude that STAT1, SMCHD1, and PML may partly mediate the suppressive effect of IFN-α on hepadnaviral cccDNA transcription.IMPORTANCE Pegylated IFN-α is the only therapeutic regimen that can induce a functional cure of chronic hepatitis B in a small, but significant, fraction of treated patients. Understanding the mechanisms underlying the antiviral functions of IFN-α in hepadnaviral infection may reveal molecular targets for development of novel antiviral agents to improve the therapeutic efficacy of IFN-α. By a loss-of-function genetic screening of individual IFN-stimulated genes (ISGs) on hepadnaviral mRNAs transcribed from cccDNA, we found that downregulating the expression of STAT1, SMCHD1, or PML significantly increased the level of viral RNAs without altering the level of cccDNA. Mechanistic analyses indicated that those cellular proteins are recruited to cccDNA minichromosomes and induce the posttranslational modifications of cccDNA-associated histones similar to those induced by IFN-α treatment. We have thus identified three IFN-α-induced cellular proteins that suppress cccDNA transcription and may partly mediate IFN-α silencing of hepadnaviral cccDNA transcription.
| S-EPMC7431811 | biostudies-literature
Project description:To identify the cellular genes that mediate IFN-α suppression of cccDNA transcription, the total intracellular RNA were extracted from untreated or recombinant chicken IFN-α (rChIFN-α)-treated cells, and mRNA sequencing (mRNA-Seq) assays were performed in triplicate. And we found that treatment of dstet5 cells with 10 ng/ml of rChIFN-α for 6 h altered the expression of more than 100 cellular genes by more than 2 folds.
2020-06-17 | GSE134325 | GEO
Project description:Hepatitis B virus (HBV) contains a partially double-stranded relaxed circular DNA (rcDNA) genome that is converted into a covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocyte by cellular DNA repair machinery. cccDNA associates with nucleosomes to form a minichromosome that transcribes RNA to support the expression of viral proteins and reverse transcriptional replication of viral DNA. In addition to the de novo synthesis from incoming virion rcDNA, cccDNA can also been synthesized from rcDNA in the progeny nucleocapsids in the cytoplasm of infected hepatocytes via the intracellular amplification pathway. In our efforts to identify cellular DNA repair proteins required for cccDNA synthesis by a chemogenetic screen, we found that B02, a small molecular inhibitor of DNA homologous recombination repair protein RAD51, significantly enhanced the synthesis of cccDNA via intracellular amplification pathway in human hepatoma cells. Ironically, neither siRNA knockdown of RAD51 expression nor treatment with another structurally distinct RAD51 inhibitor or activator altered cccDNA amplification. However, further mechanistic studies revealed that B02 treatment significantly elevated the levels of multiple heat shock protein mRNA and siRNA knockdown of HSPA1A expression or treatment with HSPA1 inhibitors significantly attenuated B02 enhancement of cccDNA amplification. Moreover, B02 enhanced cccDNA amplification was efficiently inhibited by compounds that selectively inhibit DNA polymerase α or topoisomerase II, the enzymes required for cccDNA intracellular amplification. Our results thus indicate that B02 treatment induces a heat shock protein-mediated cellular response that positively regulates the conversion of rcDNA into cccDNA via the authentic intracellular amplification pathway
2022-12-08 | GSE209863 | GEO
Project description:Heat Shock Protein Family A Member 1 Promotes Intracellular Amplification of Hepatitis B Virus Covalently Closed Circular DNA
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Project description:Circular RNA expression profiling of human nucleus pulposus derived from patients with IDD in comparison with those derived from cadaveric disc as normal control. We have identified the expression profiles of miRNAs (GSE63492), lncRNAs, mRNAs (GSE56081) in IDD using 5 normal discs as control and 5 IDD discs. Accumulating evidence indicates that circRNAs are key regulators of gene expression by interacting with miRNAs. circRNA is a novel type of RNA that, unlike linear RNA, forms a covalently closed continuous loop, and is highly represented in the eukaryotic transcriptome. Two-condition experiment: control nucleus pulposus vs. degenerative nucleus pulposus. Biological replicates: 5 control, 5 degenerated, independently harvested (the same samples as GSE56081 and GSE63492). Four replicates per array.
2016-08-04 | E-GEOD-67566 | biostudies-arrayexpress
Project description:Circular RNAs (circRNAs) are covalently closed endogenous RNA molecules with tissue- and disease specific expression patterns, which have potential as diagnostic and prognostic biomarkers in cancer. The landscape of circRNA expression has not been characterized in B-cell malignancies. We quantified circular RNA expression by total RNA sequencing of four different Mantle Cell Lymphoma cell lines, REC-1, Granta-519, Z138 and UPN2 and the Multiple Myeloma cell line, H929.
2017-12-15 | GSE108111 | GEO
Project description:Recently, it has been demonstrated that genomes of many species express single stranded RNAs with covalently closed ends, named circular RNAs. Their regulatory potential and functional relevance are just starting to be revealed. Here we present a novel computational tool, seekCRIT (seek for differentially expressed Circular RNAs In Transcriptome), that identifies circular RNAs and detects their differential expression between two conditions. Using seekCRIT we identified the circular RNAs that are expressed in the neural retina and determined that the majority of them (74%) are expressed in both, ischemic and normal conditions. We identified over 40 circular RNAs that were differentially expressed between both conditions and validated these experimentally using qRT-PCR. The high validation rate of 90% with a false discovery rate (FDR) of < 5% demonstrates the accuracy and reliability of seekCRIT.
2021-02-02 | GSE114896 | GEO
Project description:The hepatitis B virus (HBV) genome exists in two forms: circular covalently closed DNA (cccDNA) and relaxed circular DNA (RCDNA). Here, we investigated the presence of differences in the sequences of both forms in paired samples of serum and liver tissue. The serum and liver biopsy samples were collected at the same time from 67 chronically infected patients. The genotyping of the RCDNA and cccDNA was performed using mass spectrometry analysis. The HBV mutations located in the HBV pol (P) and the HBV basal core promoter/pre-core (BCP/PC) regions were included. The BCP/PC and P sequences of the RCDNA extracted from liver and blood samples were different in 39% and 16% of patients, respectively. Differences were also found between RCDNA and cccDNA extracted from the same liver specimen. Moreover, the cccDNA BCP/PC region sequence had an impact on various virological and clinical parameters. We demonstrated that there are differences between the RCDNA and cccDNA sequences that were extracted from the same liver tissue. However, further investigations are needed to analyze whether the mutations in the cccDNA are conserved and whether cccDNA serves as a 'mutation storage' pool for HBV. This result could have profound implications for the subsequent therapy choices for treatment-experienced patients.
| S-EPMC5520316 | biostudies-literature
Project description:Covalently closed circular RNA molecules (circRNAs) have recently emerged as a class of RNA isoforms with widespread and tissue specific expression across animals, oftentimes independent of the corresponding linear mRNAs. circRNAs are remarkably stable and sometimes highly expressed molecules. Here, we sequenced RNA in human peripheral whole blood to determine the potential of circRNAs as biomarkers in an easily accessible body fluid. We report the reproducible detection of thousands of circRNAs. Importantly, we observed that hundreds of circRNAs are much higher expressed than corresponding linear mRNAs. Thus, circRNA expression in human blood reveals and quantifies the activity of hundreds of coding genes not accessible by classical mRNA specific assays. Our findings suggest that circRNAs could be used as biomarker molecules in standard clinical blood samples. Sequencing of blood RNA from five healthy individuals (biological replicates) plus technical replicate of one sample and detection of circRNAs.
2015-10-26 | E-GEOD-73570 | biostudies-arrayexpress
Project description:Circular RNA expression profiling of human nucleus pulposus derived from patients with IDD in comparison with those derived from cadaveric disc as normal control. We have identified the expression profiles of miRNAs (GSE63492), lncRNAs, mRNAs (GSE56081) in IDD using 5 normal discs as control and 5 IDD discs. Accumulating evidence indicates that circRNAs are key regulators of gene expression by interacting with miRNAs. circRNA is a novel type of RNA that, unlike linear RNA, forms a covalently closed continuous loop, and is highly represented in the eukaryotic transcriptome.
2016-08-04 | GSE67566 | GEO