Comparative Analysis of CpG Islands among HBV Genotypes

Abstract

DNA methylation is being increasingly recognized to play a role in regulation of hepatitis B virus (HBV) gene expression. The aim of this study was to compare the CpG island distribution among different HBV genotypes. We analyzed 176 full-length HBV genomic sequences obtained from the GenBank database, belonging to genotypes A through J, to identify the CpG islands in the HBV genomes. Our results showed that while 79 out of 176 sequences contained three conventional CpG islands (I–III) as previously described, 83 HBV sequences harbored only two of the three known islands. Novel CpG islands were identified in the remaining 14 HBV isolates and named as CpG island IV, V, and VI. Among the eight known HBV genotypes and two putative genotypes, while HBV genomes containing three CpG islands were predominant in genotypes A, B, D, E, and I; genotypes C, F, G, and H tended to contain only two CpG islands (II and III). In conclusion, the CpG islands, which are potential targets for DNA methylation mediated by the host functions, differ among HBV genotypes, and these genotype-specific differences in CpG island distribution could provide new insights into the understanding of epigenetic regulation of HBV gene expression and hepatitis B disease outcome.

Epigenetic regulation of hepatitis B virus covalently closed circular DNA: Implications for epigenetic therapy against chronic hepatitis B

“…The HBV cccDNA genome contains three predicted CpG islands: (1) the region overlapping the start site of the S gene (Island 1); (2) the region encompassing enhancer I, the HBx gene promoter (Xp), and the core promoter (Cp) (Island 2); and (3) the region harboring the Sp1 promoter and the start codon of the pol gene (Island 3; Fig. ) . Among the 10 distinct genotypes (A‐J) of HBV, the methylation rates in Island 1 are variable, whereas Islands 2 and 3 are more conserved across genotypes .…”

“…(25,26) Among the 10 distinct genotypes (A-J) of HBV, the methylation rates in Island 1 are variable, whereas Islands 2 and 3 are more conserved across genotypes. (26) Methylation of the CpG islands on HBV cccDNA regulates HBV replication and gene expression. Zhang et al demonstrated that cccDNA CpG Island 1 is seldom methylated, methylation of CpG Island 2 is associated with low viremia, and methylation of CpG Island 3 may contribute to a lower serum HBsAg level in CHB patients.…”

Metabolism and function of hepatitis B virus cccDNA: Implications for the development of cccDNA-targeting antiviral therapeutics

“…HBV cccDNA contains three major CpG islands that can potentially be methylated (Zhang et al, 2013). Accumulating evidence suggests that variable degrees of CpG methylation were present in cccDNA from patients with chronic HBV infection.…”

DNA markers in molecular diagnostics for hepatocellular carcinoma

“…The HBV genome has 2–3 conventional CpG islands depending on the geno type [166,167]. Interestingly, these CpG islands are found at strate gic locations in the regulatory elements of the HBV genome [168].…”