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Foxa-deficiency Restricts Hepatitis B Virus Biosynthesis Through Epigenic Silencing [Bisulfite-Seq]

ABSTRACT: In the HBV transgenic mouse model of chronic infection, the forkhead box protein A/hepatocyte nuclear factor 3 (Foxa/HNF3) family of pioneer transcription factors are required to support postnatal viral demethylation and subsequent HBV transcription and replication. Liver-specific Foxa-deficient mice with hepatic expression of only Foxa3 do not support HBV replication but display biliary epithelial hyperplasia with bridging fibrosis. However, liver-specific Foxa-deficient mice with hepatic expression of only Foxa1 or Foxa2 also successfully restrict viral transcription and replication but display only minimal alterations in liver physiology. These observations suggest that the level of Foxa activity, rather than the combination of specific Foxa genes, is a key determinant of HBV biosynthesis. Together, these findings suggest that targeting Foxa activity could lead to HBV DNA methylation and transcriptional inactivation, resulting in the resolution of chronic HBV infections which are responsible for approximately one million deaths annually worldwide.

ORGANISM(S): Mus musculus

PROVIDER: GSE263033 | GEO | 2024/07/16

REPOSITORIES: GEO

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Foxa-deficiency Restricts Hepatitis B Virus Biosynthesis Through Epigenic Silencing [NanoSting]

Project description:In the HBV transgenic mouse model of chronic infection, the forkhead box protein A/hepatocyte nuclear factor 3 (Foxa/HNF3) family of pioneer transcription factors are required to support postnatal viral demethylation and subsequent HBV transcription and replication. Liver-specific Foxa-deficient mice with hepatic expression of only Foxa3 do not support HBV replication but display biliary epithelial hyperplasia with bridging fibrosis. However, liver-specific Foxa-deficient mice with hepatic expression of only Foxa1 or Foxa2 also successfully restrict viral transcription and replication but display only minimal alterations in liver physiology. These observations suggest that the level of Foxa activity, rather than the combination of specific Foxa genes, is a key determinant of HBV biosynthesis. Together, these findings suggest that targeting Foxa activity could lead to HBV DNA methylation and transcriptional inactivation, resulting in the resolution of chronic HBV infections which are responsible for approximately one million deaths annually worldwide.

2024-07-16 | GSE263120 | GEO

HEPATIC DEFICIENCY OF THE PIONEER TRANSCRIPTION FACTOR FOXA RESTRICTS HEPATITIS B VIRUS BIOSYNTHESIS BY THE DEVELOPMENTAL REGULATION OF VIRAL DNA METHYLATION

Project description:The FoxA family of pioneer transcription factors regulate hepatitis B virus (HBV) transcription, and hence viral replication. Hepatocyte-specific FoxA-deficiency in the HBV transgenic mouse model of chronic infection prevents the transcription of the viral DNA genome as a result of the failure of the developmentally controlled conversion of 5-methylcytosine residues to cytosine during postnatal hepatic maturation. These observations suggest that pioneer transcription factors such as FoxA, which mark genes for expression at subsequent developmental steps in the cellular differentiation program, mediate their effects by reversing the DNA methylation status of their target genes to permit their ensuing expression when the appropriate tissue-specific transcription factor combinations arise during development. Furthermore, as the FoxA-deficient HBV transgenic mice are viable, the specific developmental timing, abundance and isoform type of pioneer factor expression must permit all essential liver gene expression to occur at a level sufficient to support adequate liver function. This implies that pioneer transcription factors can recognize and mark their target genes in distinct developmental manners dependent upon, at least in part, the concentration and affinity of FoxA for its binding sites within enhancer and promoter regulatory sequence elements. This selective marking of cellular genes for expression by the FoxA pioneer factor compared to HBV may offer the opportunity for the specific silencing of HBV gene expression and hence the resolution of chronic HBV infections which annually are responsible for approximately one million deaths worldwide due to liver cirrhosis and hepatocellular carcinoma.

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Collapse of the hepatic gene regulatory network in the absence of FoxA factors

Project description:FoxA transcription factors are critical for liver development through their pioneering activity, which initiates a highly complex network thought to become resistant to the loss of any individual hepatic transcription factor via mutual redundancy. To investigate the dispensability of FoxA factors for this regulatory network, we ablated all FoxA genes in the adult liver. Remarkably, loss of FoxA caused a rapid and massive reduction in the expression of key liver genes back to the low levels of the fetal prehepatic endoderm stage, leading to necrosis and lethality within days. Mechanistically, we found FoxA proteins to be required for maintaining chromatin activity, nucleosome positioning and binding by other hepatic transcription factors. Thus, the hepatic gene regulatory network is dependent on the FoxA proteins throughout life.

2020-07-10 | GSE140423 | GEO

Relative DNA methylation and demethylation efficiencies during postnatal liver development regulate hepatitis B virus biosynthesis

Project description:HBV transcription and replication increases progressively throughout postnatal liver development with maximal viral biosynthesis occurring at around four 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 correlates 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 counter-balancing processes might permit the specific silencing of HBV gene expression with the loss of viral biosynthesis and the resolution of chronic HBV infections.

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Targets of transduced Foxa and Hnf4alpha proteins in mouse embryonic fibroblasts (MEFs).

Project description:We have found three specific combinations of two transcription factors, comprising Hnf4alpha plus Foxa1, Foxa2 or Foxa3, could convert mouse embryonic fibroblasts (MEFs) into cells that closely resemble hepatocytes in vitro. Then we used ChIP-seq to explore the targets of the transduced Foxa and Hnf4alpha proteins in MEFs.

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Project description:Background and Aims: Chronic HBV infection is a major cause of liver disease and cancer. Virus-host interactions and the pathogenesis of virus-induced liver disease are only partially understood. Hypoxia has been shown to play a major role in disease biology and carcinogenesis and HBV replicates a naturally hypoxic organ. In this study we aimed to investigate the role of liver hypoxia for HBV infection. Methods: Using cell culture, animal models and human tissues we investigated the impact of hyproxia on the HBV life cycle. Results: Establishing liver cell-based model systems that mimic hepatic oxygen, we uncover a major role of hypoxia in regulating HBV transcription. Hypoxia-inducible factors (HIFs) perturb HBV replication and expression in cell-based and animal models. Conservation of hypoxia responsive elements in the viral basal core promoter uncover an essential role for HIFs in regulating the hepadnaviridae family of hepatotropic viruses. Conclusions: Identifying a role for this conserved oxygen sensors in regulating HBV replication provides a new understanding of virus-host interactions and liver disease biology, improve state-of-the-art HBV model systems and unravels new opportunities for therapeutic targeting of chronic hepatitis B.

2023-07-20 | PXD020086 | Pride

Foxa and Hnf4alpha targets during conversion from mouse embryonic fibroblasts (MEFs) to hepatocyte-like (iHep) cells

Project description:We have found three specific combinations of two transcription factors, comprising Hnf4alpha plus Foxa1, Foxa2 or Foxa3, could convert mouse embryonic fibroblasts (MEFs) into cells that closely resemble hepatocytes in vitro. Then we used ChIP-seq to explore the targets of Foxa and Hnf4alpha during conversion event to iHep cells.

2020-08-06 | GSE90536 | GEO

Targets of DNA binding, N-terminal, or C-terminal domain swapped mutant forms fo Foxa proteins in induced hepatocyte-like (iHep) cells.

Project description:We have found that three specific combinations of two transcription factors, comprising Hnf4alpha plus Foxa1, Foxa2 or Foxa3, could convert mouse embryonic fibroblasts (MEFs) into cells that closely resemble hepatocytes in vitro, and DNA binding, N-terminal, and C-terminal domains (DBD, NTD, and CTD, respectively) of Foxa proteins are swappable in the direct reprogramming of the iHep cells. Then we used ChIP-seq to explore the targets of the domain swapped mutant forms of Foxa proteins during conversion event to iHep cells.

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Foxa and Hnf4alpha targets during conversion from mouse embryonic fibroblasts (MEFs) to hepatocyte-like (iHep) cells and hepatocytes (Hep).

Project description:We have found three specific combinations of two transcription factors, comprising Hnf4alpha plus Foxa1, Foxa2 or Foxa3, could convert mouse embryonic fibroblasts (MEFs) into cells that closely resemble hepatocytes in vitro. Then we used ChIP-seq to explore the targets of Foxa and Hnf4alpha during conversion event to iHep cells. Besides we performed for hepatocytes.

2020-08-06 | GSE90538 | GEO

Gene expression analysis in human colon cancer cells and liver cancer cells with FoxA knockdown.

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