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Multiple nuclear receptors may regulate hepatitis B virus biosynthesis during development.

ABSTRACT: Hepatitis B virus (HBV) replicates by the reverse transcription of the viral 3.5 kb pregenomic RNA. Therefore the level of expression of this transcript in the liver is a primary determinant of HBV biosynthesis. In vivo neonatal transcription of the HBV 3.5 kb pregenomic RNA is developmental regulated by hepatocyte nuclear factor 4? (HNF4?). In addition, viral biosynthesis in non-hepatoma cells can be supported directly by this nuclear receptor. However HBV transcription and replication can be supported by additional nuclear receptors including the retinoid X receptor ?/peroxisome proliferator-activated receptor ? (RXR?/PPAR?), retinoid X receptor ?/farnesoid X receptor ? (RXR?/FXR?), liver receptor homolog 1 (LRH1) and estrogen-related receptors (ERR) in non-hepatoma cells. Therefore during neonatal liver development, HNF4? may progressively activate viral transcription and replication by binding directly to the proximal HNF4? recognition sequence within the nucleocapsid promoter. Alternatively, HNF4? may support viral biosynthesis in vivo indirectly by activating a network of liver-enriched nuclear receptors that, in combination, direct HBV 3.5 kb pregenomic RNA transcription and replication.

SUBMITTER: Reese V

PROVIDER: S-EPMC3773232 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

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Multiple nuclear receptors may regulate hepatitis B virus biosynthesis during development.

Reese Vanessa V Ondracek Caitlin C Rushing Christel C Li Lie L Oropeza Claudia E CE McLachlan Alan A

The international journal of biochemistry & cell biology 20091124 2

Hepatitis B virus (HBV) replicates by the reverse transcription of the viral 3.5 kb pregenomic RNA. Therefore the level of expression of this transcript in the liver is a primary determinant of HBV biosynthesis. In vivo neonatal transcription of the HBV 3.5 kb pregenomic RNA is developmental regulated by hepatocyte nuclear factor 4α (HNF4α). In addition, viral biosynthesis in non-hepatoma cells can be supported directly by this nuclear receptor. However HBV transcription and replication can be s ...[more]

PMID: 19941970

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Project description: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.IMPORTANCE 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.

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Multiple nuclear receptors may regulate hepatitis B virus biosynthesis during development.

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Multiple nuclear receptors may regulate hepatitis B virus biosynthesis during development.

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