title: HBc binds to the CpG islands of HBV cccDNA and promotes an epigenetic permissive state.
abstract: HBV covalently closed circular DNA (cccDNA) is the template for the transcription of HBV. HBV core protein (HBc) is a main component of the HBV cccDNA minichromosome. However, the function of HBc in cccDNA is not fully understood. In light of recent findings that HBV cccDNA may be regulated epigenetically, we analyzed the binding of HBc to cccDNA and the impact of HBc on cccDNA epigenetic profile in the liver biopsy samples of 22 patients with chronic Hepatitis B (CHB). We found that HBc binding to HBV cccDNA occurred preferentially at CpG island 2, an important region for the regulation of HBV transcription. Furthermore, the relative abundances of HBc binding to CpG island 2 were positively correlated with the ratios of relaxed circular DNA to cccDNA and the levels of serum HBV DNA in those patients. Interestingly, the relative abundances of HBc binding to CpG island 2 were associated with the binding of CREB binding protein (CBP) and with hypomethylation in CpG island 2 of HBV cccDNA minichromosomes. However, relatively higher amounts of HBc binding to CpG island 2 of cccDNA were accompanied by lower amounts of HDAC1 binding. Multivariate analysis revealed that the abundances of HBc binding to CpG island 2 of cccDNA and positive HBeAg were independent factors associated with the replication of HBV (p = 0.001 for both). Apparently, HBc is a positive regulator of HBV transcription and replication, maintaining the permissive epigenetic state in the critical region of the HBV cccDNA minichromosomes.
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Pharmacogenomics, School of Pharmacy, The Fourth Military Medical University, Xi'an, China. gyanhai@fmmu.edu.cn
authors.forename: Yan-Hai
authors.initials: YH
authors.lastname: Guo
authors.forename: Yong-Nian
authors.initials: YN
authors.lastname: Li
authors.forename: Jin-Rong
authors.initials: JR
authors.lastname: Zhao
authors.forename: Ju
authors.initials: J
authors.lastname: Zhang
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yan
mesh_terms: D000328:Adult; D002875:Chromosomes; D018899:CpG Islands; D019175:DNA Methylation; D004270:DNA, Circular / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D005260:Female; D006512:Hepatitis B Core Antigens / Q000378:metabolism*; D006515:Hepatitis B virus / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011485:Protein Binding; D014158:Transcription, Genetic; D014779:Virus Replication; D055815:Young Adult
chemical_list: D004270:DNA, Circular; D006512:Hepatitis B Core Antigens