Relative DNA Methylation and Demethylation Efficiencies during Postnatal Liver Development Regulate Hepatitis B Virus Biosynthesis

Hepatitis B virus (HBV) transcription and replication increase progressively throughout postnatal liver development with maximal viral biosynthesis occurring at around 4 weeks of age in the HBV transgenic mouse model of chronic infection. Increasing viral biosynthesis is associated with a correspond...

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Published in:	Journal of virology Vol. 95; no. 6
Main Authors:	Oropeza, Claudia E, Tarnow, Grant, Taha, Taha Y, Shalaby, Rasha E, Hyde, Marieta V, Maienschein-Cline, Mark, Green, Stefan J, McLachlan, Alan
Format:	Journal Article
Language:	English
Published:	United States American Society for Microbiology 24-02-2021
Subjects:	5-Methylcytosine - analogs & derivatives 5-Methylcytosine - metabolism Animals Animals, Newborn Demethylation Dioxygenases - genetics Dioxygenases - metabolism Disease Models, Animal DNA (Cytosine-5-)-Methyltransferases - genetics DNA (Cytosine-5-)-Methyltransferases - metabolism DNA Methylation DNA Replication DNA, Viral - biosynthesis DNA, Viral - metabolism Gene Expression Regulation, Developmental Gene Expression Regulation, Viral Genome and Regulation of Viral Gene Expression Genome Replication and Regulation of Viral Gene Expression Hepatitis B virus - physiology Hepatitis B, Chronic - metabolism Hepatitis B, Chronic - pathology Hepatitis B, Chronic - virology Hepatocyte Nuclear Factors - genetics Hepatocyte Nuclear Factors - metabolism Liver - growth & development Liver - metabolism Liver - virology Mice Mice, Transgenic RNA, Viral - biosynthesis Virus Replication hepatitis B virus (HBV) 5-methylcytosine (5mC) DNA methylation DNA demethylation liver development 5-hydroxymethylcytosine (5hmC) DNA methyltransferase (Dnmt) ten-eleven translocation (Tet) methylcytosine dioxygenase Forkhead box protein A (FoxA)
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Summary:	Hepatitis B virus (HBV) transcription and replication increase progressively throughout postnatal liver development with maximal viral biosynthesis occurring at around 4 weeks of age in the HBV transgenic mouse model of chronic infection. Increasing viral biosynthesis is associated with a corresponding progressive loss of DNA methylation. The loss of DNA methylation is associated with increasing levels of 5-hydroxymethylcytosine (5hmC) residues which correlate with increased liver-enriched pioneer transcription factor Forkhead box protein A (FoxA) RNA levels, a rapid decline in postnatal liver DNA methyltransferase (Dnmt) transcripts, and a very modest reduction in ten-eleven translocation (Tet) methylcytosine dioxygenase expression. These observations are consistent with the suggestion that the balance between active HBV DNA methylation and demethylation is regulated by FoxA recruitment of Tet in the presence of declining Dnmt activity. These changes lead to demethylation of the viral genome during hepatocyte maturation with associated increases in viral biosynthesis. Consequently, manipulation of the relative activities of these two counterbalancing processes might permit the specific silencing of HBV gene expression with the loss of viral biosynthesis and the resolution of chronic HBV infections. HBV biosynthesis begins at birth and increases during early postnatal liver development in the HBV transgenic mouse model of chronic infection. The levels of viral RNA and DNA synthesis correlate with pioneer transcription factor FoxA transcript plus Tet methylcytosine dioxygenase-generated 5hmC abundance but inversely with Dnmt transcript levels and HBV DNA methylation. Together, these findings suggest that HBV DNA methylation during neonatal liver development is actively modulated by the relative contributions of FoxA-recruited Tet-mediated DNA demethylation and Dnmt-mediated DNA methylation activities. This mode of gene regulation, mediated by the loss of DNA methylation at hepatocyte-specific viral and cellular promoters, likely contributes to hepatocyte maturation during liver development in addition to the postnatal activation of HBV transcription and replication.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Citation Oropeza CE, Tarnow G, Taha TY, Shalaby RE, Hyde MV, Maienschein-Cline M, Green SJ, McLachlan A. 2021. Relative DNA methylation and demethylation efficiencies during postnatal liver development regulate hepatitis B virus biosynthesis. J Virol 95:e02148-20. https://doi.org/10.1128/JVI.02148-20. Present address: Taha Y. Taha, Gladstone Institute of Virology, Gladstone Institutes, San Francisco, CA, USA; Rasha E. Shalaby, Department of Basic Medical Sciences, Faculty of Medicine, Galala University, Galala City, Egypt.
ISSN:	0022-538X 1098-5514
DOI:	10.1128/JVI.02148-20