title: Mapping of histone modifications in episomal HBV cccDNA uncovers an unusual chromatin organization amenable to epigenetic manipulation.
abstract: 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 because it does not directly affect nuclear HBV closed circular DNA (cccDNA), the genomic form that templates viral transcription and sustains viral persistence. Novel approaches that directly target cccDNA regulation 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, to our knowledge, 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 effect 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.
authors.affiliation: Department of Infectious Diseases, Novartis Institutes for BioMedical Research, Emeryville, CA 94608 don.ganem@novartis.com philipp.tropberger@novartis.com.
authors.forename: Philipp
authors.initials: P
authors.lastname: Tropberger
authors.affiliation: Department of Infectious Diseases, Novartis Institutes for BioMedical Research, Emeryville, CA 94608.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Mercier
authors.affiliation: Department of Infectious Diseases, Novartis Institutes for BioMedical Research, Emeryville, CA 94608.
authors.forename: Margaret
authors.initials: M
authors.lastname: Robinson
authors.affiliation: Department of Infectious Diseases, Novartis Institutes for BioMedical Research, Emeryville, CA 94608.
authors.forename: Weidong
authors.initials: W
authors.lastname: Zhong
authors.affiliation: Department of Infectious Diseases, Novartis Institutes for BioMedical Research, Emeryville, CA 94608 don.ganem@novartis.com philipp.tropberger@novartis.com.
authors.forename: Don E
authors.initials: DE
authors.lastname: Ganem
authors.affiliation: Department of Infectious Diseases, Novartis Institutes for BioMedical Research, Emeryville, CA 94608.
authors.forename: Meghan
authors.initials: M
authors.lastname: Holdorf
mesh_terms: D002843:Chromatin / Q000378:metabolism*; D004279:DNA, Viral / Q000235:genetics*; D044127:Epigenesis, Genetic; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000235:genetics*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D010957:Plasmids / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D004279:DNA, Viral; D006657:Histones
keywords: HBV; cccDNA; chromatin; epigenetics; hepatitis B virus