Hepatitis B Virus Replication Is Regulated by the Acetylation Status of Hepatitis B Virus cccDNA-Bound H3 and H4 Histones

Pollicino, Teresa; Belloni, Laura; Raffa, G.; Pediconi, Natalia; Squadrito, Giovanni; Raimondo, Giovanni; Levrero, Massimo

doi:10.1053/j.gastro.2006.01.001

Cited by 401 publications

(455 citation statements)

References 35 publications

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“…In a recent review, Zdenko Herceg and Anupam Paliwal proposed three hypothetical models that combined the interactions between HBx and the various epigenetic factors to explain the gene expression modulation induced by the virus (Herceg and Paliwal, 2009). HBV replication is also associated with specific epigenetic marks such as the acetylation of H3 and H4 (Pollicino et al, 2006). At the same time, it seems that the expression of viral genes is regulated by DNA methylation.…”

Section: Hepatitis B Virusmentioning

confidence: 99%

Viral epigenomes in human tumorigenesis

Fernández

Esteller

2010

Oncogene

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Viruses are associated with 15-20% of human cancers worldwide. In the last century, many studies were directed towards elucidating the molecular mechanisms and genetic alterations by which viruses cause cancer. The importance of epigenetics in the regulation of gene expression has prompted the investigation of virus and host interactions not only at the genetic level but also at the epigenetic level. In this study, we summarize the published epigenetic information relating to the genomes of viruses directly or indirectly associated with the establishment of tumorigenic processes. We also review aspects such as viral replication and latency associated with epigenetic changes and summarize what is known about epigenetic alterations in host genomes and the implications of these for the tumoral process. The advances made in characterizing epigenetic features in cancer-causing viruses have improved our understanding of their functional mechanisms. Knowledge of the epigenetic changes that occur in the genome of these viruses should provide us with markers for following cancer progression, as well as new tools for cancer therapy.

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Section: Hepatitis B Virusmentioning

confidence: 99%

Viral epigenomes in human tumorigenesis

Fernández

Esteller

2010

Oncogene

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“…It has been shown that cccDNA can persist in cell nuclei as a stable chromatin-like episome associated with Ac H3 and Ac H4 histones when replication is active (Pollicino et al, 2006). Using a ChIP/cccDNA assay described recently (Pollicino et al, 2006), we found that H3 and H4 histones bound to cccDNA were acetylated, suggesting that cccDNA formed in HepG2 cells transduced with Bac-HBV-1.1-WT may be transcriptionally active.…”

Section: Discussionmentioning

confidence: 67%

“…Using a ChIP/cccDNA assay described recently (Pollicino et al, 2006), we found that H3 and H4 histones bound to cccDNA were acetylated, suggesting that cccDNA formed in HepG2 cells transduced with Bac-HBV-1.1-WT may be transcriptionally active. However, the acetylation of cccDNA-bound H3 and H4 histones was only transient in transduced HepG2 cells.…”

Section: Discussionmentioning

confidence: 89%

“…ChIP assays to detect cccDNA-bound acetylated histone H3 ( Ac H3) and acetylated histone H4 ( Ac H4) were performed as described previously (Pollicino et al, 2006). Real-time ChIP results were expressed as the percentage of the 'input'.…”

Section: Methodsmentioning

confidence: 99%

“…A recent study has demonstrated that HBV replication is regulated by the acetylation status of the cccDNA-bound H3/H4 histones (Pollicino et al, 2006). After transcription, the pgRNA, which is a 1.1-unit RNA copy of the genome, is reverse transcribed within the viral nucleocapsid to produce the 3.2 kb viral genomic RC-DNA (Seeger & Mason, 2000).…”

Section: Introductionmentioning

confidence: 99%

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Initiation of hepatitis B virus genome replication and production of infectious virus following delivery in HepG2 cells by novel recombinant baculovirus vector

Lucifora

Durantel

Belloni

et al. 2008

Journal of General Virology

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One of the major problems in gaining further insight into hepatitis B virus (HBV)/host-cell interactions is to improve the existing cellular models for the study of HBV replication. The first objective of this study was to improve the system based on transduction of HepG2 cells with a recombinant baculovirus to study HBV replication. A new HBV recombinant baculovirus, Bac-HBV-1.1, in which the synthesis of pre-genomic RNA is driven by a strong mammalian promoter, was generated. Transduction with this new recombinant baculovirus led to higher levels of HBV replication in HepG2 cells compared with levels obtained with previously described baculovirus vectors. The initiation of a complete HBV DNA replication cycle in Bac-HBV-1.1-transduced HepG2 cells was shown by the presence of HBV replicative intermediates, including covalently closed circular DNA (cccDNA). Only low levels of cccDNA were detected in the nucleus of infected cells. Data showed that cccDNA resulted from the recycling of newly synthesized nucleocapsids and was bound to acetylated histones in a chromatin-like structure. HBV particles released into the supernatant of transduced HepG2 cells were infectious in differentiated HepaRG cells. Several Bac-HBV-1.1 baculoviruses containing HBV strains carrying mutations conferring resistance to lamivudine and/or adefovir were constructed. Phenotypic analysis of these mutants confirmed the results obtained with the transfection procedures. In conclusion, an improved cell-culture system was established for the transduction of replication-competent HBV genomes. This will be useful for future studies of the fitness of HBV mutants.

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TGF‐β triggers HBV cccDNA degradation through AID‐dependent deamination

et al. 2016

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The covalently closed circular DNA (cccDNA) of hepatitis B virus (HBV) is a viral center molecule for HBV infection and persistence. However, the cellular restriction factors of HBV cccDNA are not well understood. Here, we show that TGF-b can induce nuclear viral cccDNA degradation and hypermutation via activation-induced cytidine deaminase (AID) deamination activity in hepatocytes. This suppression by TGF-b is abrogated when AID or the activity of uracil-DNA glycosylase (UNG) is absent, which indicates that AID deamination and the UNG-mediated excision of uracil act in concert to degrade viral cccDNA. Moreover, the HBV core protein promotes the interaction between AID and viral cccDNA. Overall, our results indicate a novel molecular mechanism that allows cytokine TGF-b to restrict viral nuclear cccDNA in innate immunity, thereby suggesting a novel method for potentially eliminating cccDNA.Keywords: AID; cccDNA; HBV; Hypermutation; UNG Highlights • AID triggers HBV cccDNA degradation via its deamination activity.• AID induces viral cccDNA hypermutation.• TGF-b reduces viral cccDNA through AID in hepatocytes.Almost 350 million people who are chronically infected with hepatitis B virus (HBV) worldwide are at high risk of developing liver cirrhosis and hepatocellular carcinoma. Thus, HBV infection is a major global health concern [1-3]. The covalently closed circular DNA (cccDNA) of HBV plays an essential role in virus replication and persistence. After entry into the hepatocytes, HBV first forms cccDNA in the host cell's nucleus before transcribing viral RNAs, including a replicative RNA intermediate called pregenomic (pg) RNA that encodes two viral proteins, HBV core (HBc), and HBV polymerase (Pol), which encapsidate pgRNA to form a nucleocapsid. HBV Pol reverse transcribes pgRNA to produce relaxed circular DNA

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Hepatitis B Virus Replication Is Regulated by the Acetylation Status of Hepatitis B Virus cccDNA-Bound H3 and H4 Histones

Cited by 401 publications

References 35 publications

Viral epigenomes in human tumorigenesis

Viral epigenomes in human tumorigenesis

Initiation of hepatitis B virus genome replication and production of infectious virus following delivery in HepG2 cells by novel recombinant baculovirus vector

TGF‐β triggers HBV cccDNA degradation through AID‐dependent deamination

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