Hepatic deficiency of the pioneer transcription factor FoxA restricts hepatitis B virus biosynthesis by the developmental regulation of viral DNA methylation

Abstract

The FoxA family of pioneer transcription factors regulates 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 are responsible for approximately one million deaths worldwide annually due to liver cirrhosis and hepatocellular carcinoma.

FOXA2 promotes the proliferation, migration and invasion, and epithelial mesenchymal transition in colon cancer

“…Forkhead box (Fox) family genes are abundant in fungi and animal cells, and their main function is to regulate gene expression by binding with DNA promoter region as a transcription factor ( 10 ). Fox family is first discovered to regulate embryonic development, and more and more studies show that Fox family proteins play a key regulatory role in immune system, cell cycle, energy metabolism, and cell aging ( 11 , 12 ). FOXA2 gene, a member of Fox family, is localized at human chromosome 20p11, with a length of 45 kb ( 13 , 14 ).…”

Modulation of hepatitis B virus pregenomic RNA stability and splicing by histone deacetylase 5 enhances viral biosynthesis

“…RT-qPCR analysis of HBV RNAs was conducted as described previously [34]. Semi-quantitative PCR was conducted using a 15-sec extension phase and 40 cycles.…”

“… (A) Immunohistochemical staining of an HBV transgenic mouse liver showing the presence of nuclear HBcAg throughout the liver whereas cytoplasmic staining is located primarily in the centrolobular hepatocytes (adapted from [ 34 ]). (B) Single-cell RNAseq analysis of mouse liver tissue for HDACs and sirtuins (SIRTs) demonstrating that HDAC5 is highly expressed in the liver and exhibits zonation towards the pericentral area of the liver lobule (adapted from [ 33 ]).…”

“…There have been multiple reports linking HDACs to the accessibility of the transcriptional machinery to the HBV covalently closed circular DNA (cccDNA) present in cells as a nuclear chromatin template [ 27 – 32 ]. Interestingly, single-cell analysis of hepatocytes [ 33 ] revealed that the expression of HDAC5 correlates closely with the distinct zonal profile of viral biosynthesis [ 34 ] across the liver lobule in HBV transgenic mice ( S1 Fig ). The levels of the other classical HDAC transcripts are considerably lower than HDAC5 and they are not differentially expressed across the liver lobule ( S1B Fig ).…”

Host functions used by hepatitis B virus to complete its life cycle: Implications for developing host-targeting agents to treat chronic hepatitis B

“…The Fox A transcription factors, which are critical in mediating development and tissue specific expression, appear to be important to the regulation of the expression of the HBV genome, which contains multiple FoxA binding sites. Briefly, the HBV transgene in the hepatocytes of FoxA deficient mice was highly methylated, and was not efficiently transcribed (McFadden et al, 2017). It is worth noting that the above studies are largely performed with transfected HBV plasmid in cell culture or transgenic HBV DNA in mice.…”