HDAC11 restricts HBV replication through epigenetic repression of cccDNA transcription
HDAC11 restricts HBV replication through epigenetic repression of cccDNA transcription
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HDAC11 通过表观遗传抑制 cccDNA 转录来限制 HBV 复制
DOI：
10.1016/j.antiviral.2019.104619
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发表时间：
2019-12-01
影响因子：
7.6
通讯作者：
Chen, Xinwen
中科院分区：
文献类型：
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作者：
Yuan, Yifei;Zhao, Kaitao;Chen, Xinwen
B型肝炎病毒（HBV）感染仍然是世界范围内重要的公共卫生问题。共价闭合环状DNA（cccDNA）是HBV感染持续存在和抗病毒治疗失败的分子基础。在目前的研究中，我们证明了组蛋白去乙酰化酶11（HDAC11）抑制HBV转染的Huh7细胞中的HBV转录和复制。通过使用HBV体外感染系统，发现HDAC11影响cccDNA的转录活性，但不影响cccDNA的产生。利用染色质免疫沉淀（ChIP）测定来分析cccDNA的表观遗传修饰。结果显示HDAC11特异性降低cccDNA结合的组蛋白H3的乙酰化水平，但不影响组蛋白H4的乙酰化水平。此外，HDAC11过表达降低了cccDNA结合的乙酰化H3K9（H3K9ac）和H3K27（H3K27ac）的水平。总之，HDAC11通过cccDNA转录的表观遗传抑制来限制HBV复制。这些发现揭示了HDAC11在HBV感染中的新作用，进一步拓宽了我们对HDAC11功能和HDACs在HBV cccDNA表观遗传调控中作用的认识。
Hepatitis B virus (HBV) infection remains an important public health problem worldwide. Covalently closed circular DNA (cccDNA) exhibits as an individual minichromosome and is the molecular basis of HBV infection persistence and antiviral treatment failure. In the current study, we demonstrated that histone deacetylase 11 (HDAC11) inhibits HBV transcription and replication in HBV-transfected Huh7 cells. By using an HBV in vitro infection system, HDAC11 was found to affect the transcriptional activity of cccDNA but did not affect cccDNA production. Chromatin immunoprecipitation (ChIP) assays were utilized to analyze the epigenetic modifications of cccDNA. The results show that HDAC11 specifically reduced the acetylation level of cccDNA-bound histone H3 but did not affect that of histone H4. Furthermore, HDAC11 overexpression decreased the levels of cccDNA-bound acetylated H3K9 (H3K9ac) and H3K27 (H3K27ac). In conclusion, HDAC11 restricts HBV replication through epigenetic repression of cccDNA transcription. These findings reveal the novel role of HDAC11 in HBV infection, further broadening our knowledge regarding the functions of HDAC11 and the roles of HDACs in the epigenetic regulation of HBV cccDNA.