Table 1.
An outline of the main research findings on the (A) methylation and (B) acetylation mechanisms involved in HBV infection.
| Reference | |
|---|---|
| (A) Findings on HBV DNA methylation | |
| Methylation of integrated HBV DNA. | Chen et al., 1988 |
| HBx induces DNMT activity and hypermethylation of tumor suppressor gene promoters via DNMT3A1 and DNMT3A2 methylation. | Park et al., 2007 |
| Island II methylation correlates with low or no HBsAg production. cccDNA methylation correlates with viral gene expression levels. | Vivekanandan et al., 2008a |
| Methylation of integrated and non-integrated liver HBV DNA in islands I (60%) and II (50%). Unmethylated serum HBV DNA. |
Vivekanandan et al., 2008b |
| cccDNA methylation correlates with HBeAg-positivity in CHB patients and impairs virion productivity. | Guo et al., 2009 |
| HBV DNA is unmethylated in early carcinogenesis and highly methylated in cancer. Methylation of HBcAg and HBsAg genes inhibits their expression. |
Fernandez et al., 2009 |
| HBx recruits DNMT3A and induces the methylation and transcriptional silencing of IL-4 receptor and metallothionein-1F. | Zheng et al., 2009 |
| HBx expression correlates with DNMT1 and DNMT3A and hypermethylation of the p16INK4A promoter in CHB patients. | Zhu et al., 2010 |
| cccDNA methylation is associated with HBV viremia and aging in cirrhotic CHB patients. | Kim et al., 2011 |
| HBV DNA methylation correlates with decreased viral replication and gene expression. | Vivekanandan et al., 2009 |
| Increased expression of DNMT3 down-regulates viral protein and pgRNA production. HBV induces DNMT overexpression and correlates with methylation of host CpG islands. |
Vivekanandan et al., 2010 |
| HBV DNA methylation in CHB implicates island I in14%, island II 0.6% and island III 3.7% of cases. HBV DNA is unmethylated in CHB and highly methylated in HBV-related cancer. |
Kaur et al., 2010 |
| HBV DNA is unmethylated in occult HBV. CpG island I methylation correlates with HCC development. |
|
| HBV CpG island distribution differs between HBV genotypes. | Zhang et al., 2013 |
| HBx induces the hypermethylation of the uPA promoter (via the recruitment of DNMT3A2) leading to liver regeneration impairment. | Park et al., 2013 |
| (B) Findings on the acetylation of the cccDNA minichromosome | |
| Low HBV replication correlates with cccDNA hypoacetylation and the recruitment of p300/CBP and HDAC1. Histone deacetylase inhibitors restore HBV replication. |
Pollicino et al., 2006 |
| HBx recruitment onto cccDNA correlates with HBV replication and acetyltransferase upregulation. In the absence of HBx, HBV decreased replication correlates with cccDNA hypoacetylation; p300 inhibition; reduced pgRNA, and deacetylase increase. |
Belloni et al., 2009 |
| IFN-α treatment reduces DHBV acetylation of cccDNA-bound H3K9 and H3K27 histones but has no effect on cccDNA-bound H3K9me3 and H3K27me2 demethylases. HDAC inhibitors block DHBV cccDNA transcription but not the long-lasting IFN-α-induced suppression of cccDNA. |
Liu et al., 2013 |
| IFN-α inhibits viral transcription by cccDNA hypoacetylation through active recruitment onto cccDNA of HDAC and of the transcriptional repressor complex. | Belloni et al., 2012 |
| IL6 induces cccDNA hypoacetylation and silencing by reducing the binding of transcription factors (HNF1α, HNF4α, and STAT3) onto cccDNA. | Palumbo et al., 2015 |
| HBx recruitment onto cccDNA activates HBV transcription by counteracting chromatin-mediated transcriptional repression established by SETDB1, HP1 and H3K9me3. | Riviere et al., 2015 |
| IFN-α represses HBV by reducing active PTMs in cccDNA and that this effect can be recapitulated with the C646 agent (inhibits p300/CBP) The repressive mark H3K27me3 is underrepresented in cccDNA |
Tropberger et al., 2015 |
DNMT, DNA methyltransferase; uPA, urokinase-type plasminogen activator; CBP, CREB-binding protein; pgRNA, pregenomic RNA; cccDNA, covalently closed circular DNA; DHBV, duck hepatitis B virus; HDAC, histone deacetylase; HNF1α, hepatocyte nuclear factor 1α; HNF4α, hepatocyte nuclear factor 4α; SETDB1, SET domain, bifurcated 1; HP1, heterochromatin protein 1 factors; and PTM, posttranslational covalent modifications.