Hepatitis B virus (HBV) infection is a worldwide health problem. It is estimated that there are 200 to 500 million HBV chronic carriers in the world for whom, to date, there is no reliable treatment. HBV causes both acute and chronic liver disease and is responsible for an estimated one million deaths annually. Therefore, effective treatments for HBV infection are urgently required. The long-term objective of this project is to understand the in vivo role of the liver-enriched FoxA/HNF3 transcription factors in regulating hepatitis B virus (HBV) biosynthesis. The observation that FoxA/HNF3-deficient HBV transgenic mice are viable but lack detectable HBV transcription and replication (i.e. they are effectively cured) suggests FoxA/HNF3 plays an important role in the hepatocyte-specific transcription factor network governing both the hepatic phenotype and viral biosynthesis. The observation that FoxA/HNF3-deficient HBV transgenic mice display hypermethylation of HBV genomic DNA suggests that FoxA/HNF3 may epigenetically govern HBV transcription by modulating viral chromatin structure in vivo and hence determine the level of viral biosynthesis. Examination of viral chromatin organization, specifically changes in DNA methylation, DNaseI hypersensitivity and nucleosome phasing, in combination with alterations in the levels of transcription factor occupancy at viral transcriptional regulatory sequences in the FoxA/HNF3 deficient mice will address the possible mechanism of action of FoxA/HNF3 in governing HBV RNA synthesis in vivo. This analysis will yield insight into the basic nature of the hepatocyte-specific transcriptin factor network changes leading to the complete loss of viral biosynthesis while still maintaining all essential hepatic functions. Defining the nature of the changes and the molecular signals responsible for these alterations may lead to the identification of cellular therapeutic targets tht are amenable to the development of novel modalities to treat chronic HBV infection.
Hepatitis B virus is a major human pathogen that replicates by reverse transcription of its pregenomic RNA within the viral capsid. Viral transcription, and hence replication, are regulated by FoxA/HNF3 transcription factors in vivo. A detailed understanding of the mechanism by which these transcription factors governs viral biosynthesis and liver physiology may permit the more effective design of antiviral therapies targeting this essential step in the viral life cycle.
| McFadden, Vanessa C; Shalaby, Rasha E; Iram, Saira et al. (2017) Hepatic deficiency of the pioneer transcription factor FoxA restricts hepatitis B virus biosynthesis by the developmental regulation of viral DNA methylation. PLoS Pathog 13:e1006239 |
