ChIP-Seq data of H3K79succ modification of mononuclear bodies in PHH cells infected with HBV
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE188634 | GEO | 2021/11/14
REPOSITORIES: GEO
Similar Datasets
Project description:Interindividual differences in hepatic metabolism, which are mainly due to genetic polymorphism in its gene, have a large influence on individual drug efficacy and adverse reaction. Hepatocyte-like cells (HLCs) differentiated from human induced pluripotent stem (iPS) cells have the potential to predict interindividual differences in drug metabolism capacity and drug response. However, it remains uncertain whether human iPSC-derived HLCs can reproduce the interindividual difference in hepatic metabolism and drug response. We found that cytochrome P450 (CYP) metabolism capacity and drug responsiveness of the primary human hepatocytes (PHH)-iPSHLCs were highly correlated with those of PHHs, suggesting that the PHH-iPS-HLCs retained donor-specific CYP metabolism capacity and drug responsiveness. We also demonstrated that the interindividual differences, which are due to the diversity of individual SNPs in the CYP gene, could also be reproduced in PHH-iPS-HLCs. We succeeded in establishing, to our knowledge, the first PHH-iPS-HLC panel that reflects the interindividual differences of hepatic drugmetabolizing capacity and drug responsiveness.
2014-11-12 | GSE61287 | GEO
Project description:: Hepatitis B virus (HBV) remains a major public health threat with more than 296 million people chronically infected worldwide at high risk to develop hepatocellular carcinoma. Current therapies are effective in suppressing HBV replication but rarely lead to cure. The fundamental limitation rests on the fact that current therapies do not affect the HBV covalently closed circular DNA (cccDNA), which serves as the template for viral transcription and replication and is highly stable in infected cells to ensure viral persistence. In this study, we aim to identify and elucidate the functional role of cccDNA-associated host factors using affinity purification and protein mass spectrometry in HBV-infected cells. HBV core protein (HBc) is associated with cccDNA. We used an anti-HBc antibody to pull down HBcAg-associated cccDNA complex in nuclear extract of HBV-infected HepG2-NTCP cells. By protein mass spectrometry, we identified many host proteins, including previously known proteins, that are associated with HBV cccDNA. Some of these proteins were functionally validated to play a role in HBV cccDNA activities.
2024-06-16 | PXD042733 | Pride
Project description:Hepatitis B virus (HBV) persists by depositing a covalently closed circular DNA (cccDNA) in the nucleus of infected cells that cannot be targeted by available antivirals. Cytokine treatments can diminish HBV cccDNA via APOBEC3-mediated deamination. Here we show that overexpression of APOBEC3A alone, however, was not sufficient to reduce cccDNA in HBV-infected cells. This required addition of interferon indicating that cccDNA degradation requires an additional, interferon-stimulated gene (ISG). Transcriptome analyses identified ISG20 as the only type I and II interferon-induced, nucleus-resident protein with annotated nuclease activity. ISG20 expression was detected in human livers in acute, self-limiting but not in chronic hepatitis B. ISG20 depletion abolished the interferon-induced loss of cccDNA, and co-expression of ISG20 and APOBEC3A was sufficient to diminish cccDNA. In conclusion, non-cytolytic HBV cccDNA decline requires induction of a deaminase and nuclease. Our findings highlight that ISGs cooperate for their antiviral function and this cooperativity may be explored for therapeutic targeting.
2021-04-22 | PXD019285 | Pride
Project description:Background & Aims: Hepatitis B virus (HBV) infection is a major health burden worldwide and currently there is no cure. The persistence of HBV covalently closed circular DNA (cccDNA) is the major obstacle for antiviral treatment. HBV core protein (HBc) has merged as a promising antiviral target, as it plays important roles in critical steps of viral life cycle. However, whether HBc could regulate HBV cccDNA transcription remains to be illustrated. Methods: Synthesized HBV cccDNA and HBVcircle with or without HBc deficiency were transfected into hepatocytes. A recently reported Adeno-Associated Virus (AAV) mediated HBV cccDNA mouse model was employed. Two capsid assembly modulators (CAMs) were used. HBV replication markers were evaluated. Chromatin immunoprecipitation (ChIP) or ChIP sequencing assays were conducted with different transcription factors, histones and RNA polymerase 2. Results: In HBV cccDNA and HBVcircle transfection assays, lack of HBc showed no effect on transcription of HBV RNA as well as HBV surface antigen production. Reconstitution of HBc did not change cccDNA derived HBV markers. Similar results were obtained in vivo, from mouse cccDNA model. ChIP data revealed similar transcription regulation of HBc deficient cccDNA chromatin with wide type cccDNA. Furthermore, CAMs treatment could not alter cccDNA transcription. Conclusions: Our results indicate that HBc neither affects histone modifications and transcription factors binding of cccDNA, nor influences cccDNA transcription. Although CAMs could reduce HBc binding to cccDNA, it does not suppress cccDNA transcriptional activity. Thus, therapeutic targeting capsid or HBc is not sufficient to reduce cccDNA transcription.
2022-04-01 | GSE199653 | GEO
Project description:Chronic hepatitis B virus (HBV) infection affects 240 million people worldwide and is a major risk factor for liver failure and hepatocellular carcinoma. Current antiviral therapy inhibits cytoplasmic HBV genomic replication, but is not curative since it does not eliminate nuclear HBV cccDNA, the genomic form that templates viral transcription and sustains viral persistence. Novel approaches that directly target the transcriptional regulation of cccDNA would therefore be highly desirable. cccDNA is assembled with cellular histone proteins into chromatin, but little is known about the regulation of HBV chromatin by histone posttranslational modifications (PTMs). Here, using a new cccDNA ChIP-Seq approach, we report the first genome-wide maps of PTMs in cccDNA-containing chromatin from de novo infected HepG2 cells, primary human hepatocytes and from HBV infected liver tissue. We find high levels of PTMs associated with active transcription enriched at specific sites within the HBV genome, and surprisingly very low levels of PTMs linked to transcriptional repression even at silent HBV promoters. We show that transcription and active PTMs in HBV chromatin are reduced by the activation of an innate immunity pathway, and that this can be recapitulated with a small molecule epigenetic modifying agent, opening the possibility that chromatin-based regulation of cccDNA transcription could be a new therapeutic approach to chronic HBV infection.
2015-10-08 | GSE68402 | GEO
Project description:Hepatitis B virus (HBV) infection is a major health problem worldwide and chronically infected individuals are at high risk of developing cirrhosis and hepatocellular carcinoma (HCC). The molecular mechanisms whereby HBV causes HCC are largely unknown. By using a biologically relevant system of HBV infection of primary human hepatocytes (PHHs), we studied how HBV perturbs gene expressions and signaling pathways of infected hepatocytes, and whether these effects are relevant to productive HBV infection and HBV-associated HCC. Using a human growth factor antibody array, we first showed that HBV infection induced a distinct profile of growth factor production by PHHs, marked particularly by significantly lower levels of transforming growth factor (TGF)-β family of proteins in the supernatant. Transcriptome profiling next revealed multiple changes in cell proliferation and cell cycle control pathways in response to HBV infection. A human cell cycle PCR array validated deregulation of more than 20 gene associated with cell cycle in HBV-infected PHHs. Cell cycle analysis demonstrated that HBV-infected PHHs are enriched in the G2/M phase as compared to the predominantly G0/G1 phase of cultured PHHs. HBV proviral host factors, such as PPARA, RXRA and CEBPB, were up-regulated upon HBV infection and particularly enriched in cells at the G2/M phase. Together, these results support that HBV deregulates cell cycle control to render a cellular environment that is favorable for productive HBV infection. By perturbing cell cycle regulation of infected cells, HBV may coincidently induce a premalignant phenotype that predispose infected hepatocytes to subsequent malignant transformation.
2018-08-08 | GSE118295 | GEO
Project description:Covalently closed circular DNA (cccDNA) forms the basis for replication and persistence of hepatitis B virus (HBV) in the chronically infected liver. In this study we sought to identify host factors interacting with the HBV genome. Nucleolin (Ncl) was identified as a potential interactor of HBV cccDNA. This interaction was veriefied using an established ChIPseq protocol. The data show that Ncl binds cccDNA albeit at lower levels than HBcAg. Ncl deposition occurs across the genome without a clear localization and a variable pattern of deposition between experiments. This verifies the interaction of Ncl with HBV-cccDNA.
2021-12-31 | GSE123715 | GEO
Project description:Here, we examined the host response relative of SACC-PHHs infected with either hepatitis B virus (HBV) alone or both HBV/hepatitis delta virus (HDV) co-infection compared to non-infected controls.
2019-06-18 | GSE112118 | GEO
Project description:Hepatitis B virus (HBV) persists by depositing a covalently closed circular DNA (cccDNA) in the nucleus that cannot be targeted by available antivirals. Cytokine treatments can purge cccDNA from the nucleus of infected cells by APOBEC3-mediated deamination. cccDNA levels in HBV-infected cells were not reduced by overexpression of APOBEC3A alone, but only after simultaneous addition of interferon. This indicated the need of an additional, interferon-induced factor (ISG). Microarray analysis identified ISG20 as the only nuclease located to the nucleus induced by type I and II interferons. ISG20 was confirmed to be expressed in acute, self-limiting but not in chronic hepatitis B in human livers. ISG20 knockdown abolished the interferon-induced loss of cccDNA, and co-expression of ISG20 and APOBEC3A was sufficient to diminish cccDNA without further treatment. To conclude, nucleolar ISG20 was identified as the nuclease contributing to interferon-induced purging of HBV cccDNA, opening new avenues for antiviral targeting.
2020-07-22 | GSE134929 | GEO
Project description:Chronic infection of Hepatitis B virus (HBV) remains a public health problem worldwide. HBV infection relies on the persistence of covalently closed circular DNA (cccDNA) in the nucleus and actively cccDNA transcription. To understand HBV cccDNA transcription regulation at single cell level, we isolated primary human hepatocytes from liver humanized FRG mice infected by one or more (two or three) HBV genotypes, and we quantified transcripts of HBV structural genes in single cells. HBV transcripts were ascribed to the transcription of individual HBV genes by 5’ end sequencing thus avoiding the ambiguity caused by the overlap of viral genome coding at the 3’ ends. Transcripts from different cccDNA in single cells were separated according to the single-nucleotide polymorphism (SNP) among different HBV genotypes. We found that the transcription of HBV follows “all-or-none” pattern in single cells: either all of the individual cccDNA molecules actively transcribe simultaneously, or, none of them generates transcripts of the structural genes. In vitro cell infection assays with recombinant HBV are consistent with the sequencing results of ex vivo samples from natural HBV infection, and also confirm that such a pattern is apparently controlled by the expression of HBx protein. These results strongly support a synchronized transcription model of HBV cccDNA molecules in single hepatocytes, and provide new insight helpful for developing HBV cure strategy.
2022-12-01 | GSE156690 | GEO