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Mapping the heterogeneity of histone modifications on hepatitis B virus-DNA using liver needle biopsies obtained from chronically infected patients

ABSTRACT: Covalently closed circular DNA (cccDNA) forms the basis for replication and persistence of hepatitis B virus (HBV) in the chronically infected liver. We have previously shown through the analysis of de novo HBV infected cell lines that viral transcription is subject to regulation by posttranslational modifications (PTMs) of histone proteins bound to cccDNA. We now report the successful adaptation of this ChIPseq approach for the analysis of fine-needle patient liver biopsy specimens to investigate the role of histone PTMs in chronically HBV-infected patients. Using 18 specimens from patients in different stages of chronic HBV infection our work shows that the profile of histone PTMs in chronic infection is more nuanced than observed in our previous work largely focused on acute infection in in vitro models. Specifically, we find that the majority of recovered HBV sequences are associated with the activating histone PTM H3K4me3, in line with our previous findings. We further find that the striking interpatient variability of its deposition in this patient cohort is linked to viral transcription and patient HBeAg status. Unexpectedly, we detect a significant localized deposition of the inhibitory histone PTM H3K9me3 on HBV-DNA in select patient biopsies which was not observed previously. Altogether, our results show that current in vitro models of HBV infection are unable to fully recapitulate the complex epigenetic landscape of chronic HBV infection observed in vivo and demonstrate that fine needle liver biopsy specimens can provide sufficient material to further investigate the interaction of viral and host proteins on HBV-DNA.

ORGANISM(S): Hepatitis B virus Homo sapiens

PROVIDER: GSE113879 | GEO | 2019/02/07

REPOSITORIES: GEO

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Mapping of histone modifications in episomal HBV cccDNA uncovers an unusual chromatin conformation amenable to epigenetic manipulation

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

Hepatitis B virus core protein is not required for cccDNA transcriptional regulation

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2023-03-03 | GSE225715 | GEO

A nucleosome switch primes Hepatitis B Virus infection [RNA-Seq]

2023-03-03 | GSE225714 | GEO

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2012-07-31 | E-GEOD-39579 | biostudies-arrayexpress

Proteo-Genomic Characterization and Mapping of Nucleosomes Decoded by Brd and HP1 Proteins (expression data)

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2012-07-30 | E-GEOD-39580 | biostudies-arrayexpress

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2021-04-22 | PXD019285 | Pride

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2022-05-31 | GSE146498 | GEO

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