HBc binds to the CpG islands of HBV cccDNA and promotes an epigenetic permissive state
HBc binds to the CpG islands of HBV cccDNA and promotes an epigenetic permissive state
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DOI：
10.4161/epi.6.6.15815
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发表时间：
2011-06-01
期刊：
影响因子：
3.7
通讯作者：
Yan, Zhen
中科院分区：
文献类型：
--
作者：
Guo, Yan-Hai;Li, Yong-Nian;Yan, Zhen
乙肝病毒共价闭合环状DNA(CccDNA)是乙肝病毒转录的模板。乙肝病毒核心蛋白(HBc)是HBVccDNA微染色体的主要组成部分。然而，Hbc在cccDNA中的功能还不完全清楚。根据最近发现的HBVcccDNA可能受表观遗传调控的研究结果，我们分析了22例慢性乙型病毒性肝炎(CHB)患者肝活检标本中Hbc与cccDNA的结合情况以及Hbc对cccDNA表观遗传学的影响。我们发现，HBc与HBVccDNA的结合优先发生在CpG岛2，这是一个重要的区域，调节乙肝病毒的转录。此外，患者HBC与CpG岛2结合的相对丰度与松弛环状DNA/cccDNA比值及血清HBVDNA水平呈正相关。有趣的是，HBC与CpG岛2结合的相对丰度与CREB结合蛋白(CBP)的结合和HBVccDNA微染色体CpG岛2的低甲基化有关。然而，相对较高的HBC与cccDNA的CpG岛2结合伴随着较低的HDAC 1结合量。多因素分析显示，HBc与cccDNACpG岛2结合的丰度和HBeAg阳性是影响乙肝病毒复制的独立因素(p=0.001)。显然，HBc是乙肝病毒转录和复制的正调控因子，在HBVccCDNA微染色体的关键区维持允许的表观遗传状态。
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 (CH B). 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 HDAC 1 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.