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IFN-α confers epigenetic regulation of HBV cccDNA minichromosome by modulating GCN5-mediated succinylation of histone H3K79 to clear HBV cccDNA.
Clinical Epigenetics ( IF 5.7 ) Pub Date : 2020-09-07 , DOI: 10.1186/s13148-020-00928-z
Ying Yuan 1 , Hongfeng Yuan 1 , Guang Yang 1 , Haolin Yun 1 , Man Zhao 1 , Zixian Liu 1 , Lina Zhao 1 , Yu Geng 1 , Lei Liu 1 , Jiapei Wang 1 , Huihui Zhang 1 , Yufei Wang 1 , Xiao-Dong Zhang 1
Affiliation  

Hepatitis B virus covalently closed circular DNA (HBV cccDNA) is assembled by histones and non-histones into a chromatin-like cccDNA minichromosome in the nucleus. The cellular histone acetyltransferase GCN5, displaying succinyltransferase activity, is recruited onto cccDNA to modulate HBV transcription in cells. Clinically, IFN-α is able to repress cccDNA. However, the underlying mechanism of IFN-α in the depression of cccDNA mediated by GCN5 is poorly understood. Here, we explored the effect of IFN-α on GCN5-mediated succinylation in the epigenetic regulation of HBV cccDNA minichromosome. Succinylation modification of the cccDNA minichromosome has been observed in HBV-infected human liver-chimeric mice and HBV-expressing cell lines. Moreover, histone H3K79 succinylation by GCN5 was identified in the system. Interestingly, the mutant of histone H3K79 efficiently blocked the replication of HBV, and interference with GCN5 resulted in decreased levels of HBV DNA, HBsAg, and HBeAg in the supernatant from de novo HBV-infected HepaRG cells. Consistently, the levels of histone H3K79 succinylation were significantly elevated in the livers of HBV-infected human liver-chimeric mice. The knockdown or overexpression of GCN5 or the mutant of GCN5 could affect the binding of GCN5 to cccDNA or H3K79 succinylation, leading to a change in cccDNA transcription activity. In addition, Southern blot analysis validated that siGCN5 decreased the levels of cccDNA in the cells, suggesting that GCN5-mediated succinylation of histone H3K79 contributes to the epigenetic regulation of cccDNA minichromosome. Strikingly, IFN-α effectively depressed histone H3K79 succinylation in HBV cccDNA minichromosome in de novo HepG2-NTCP and HBV-infected HepaRG cells. IFN-α epigenetically regulates the HBV cccDNA minichromosome by modulating GCN5-mediated succinylation of histone H3K79 to clear HBV cccDNA. Our findings provide new insights into the mechanism by which IFN-α modulate the epigenetic regulation of HBV cccDNA minichromosome.

中文翻译:

IFN-α 通过调节 GCN5 介导的组蛋白 H3K79 琥珀酰化清除 HBV cccDNA,赋予 HBV cccDNA 微染色体的表观遗传调控。

乙型肝炎病毒共价闭合环状 DNA (HBV cccDNA) 由组蛋白和非组蛋白组装成细胞核中的染色质样 cccDNA 微染色体。显示琥珀酰转移酶活性的细胞组蛋白乙酰转移酶 GCN5 被募集到 cccDNA 上以调节细胞中的 HBV 转录。临床上,IFN-α 能够抑制 cccDNA。然而,IFN-α 在 GCN5 介导的 cccDNA 抑制中的潜在机制知之甚少。在这里,我们探讨了 IFN-α 对 GCN5 介导的琥珀酰化在 HBV cccDNA 微染色体表观遗传调控中的影响。在 HBV 感染的人肝嵌合小鼠和 HBV 表达细胞系中观察到 cccDNA 微染色体的琥珀酰化修饰。此外,在系统中鉴定了 GCN5 的组蛋白 H3K79 琥珀酰化。有趣的是,组蛋白 H3K79 的突变体有效地阻断了 HBV 的复制,并且干扰 GCN5 导致从头感染 HBV 的 HepaRG 细胞上清液中 HBV DNA、HBsAg 和 HBeAg 的水平降低。一致地,组蛋白 H3K79 琥珀酰化水平在 HBV 感染的人肝嵌合小鼠的肝脏中显着升高。GCN5 或 GCN5 突变体的敲低或过表达可能影响 GCN5 与 cccDNA 或 H3K79 琥珀酰化的结合,导致 cccDNA 转录活性的变化。此外,Southern 印迹分析证实 siGCN5 降低了细胞中 cccDNA 的水平,表明 GCN5 介导的组蛋白 H3K79 琥珀酰化有助于 cccDNA 微染色体的表观遗传调控。引人注目的是,IFN-α 有效抑制 de novo HepG2-NTCP 和 HBV 感染的 HepaRG 细胞中 HBV cccDNA 微染色体中的组蛋白 H3K79 琥珀酰化。IFN-α 通过调节 GCN5 介导的组蛋白 H3K79 琥珀酰化清除 HBV cccDNA,在表观遗传上调节 HBV cccDNA 微染色体。我们的研究结果为 IFN-α 调节 HBV cccDNA 微染色体表观遗传调控的机制提供了新的见解。
更新日期:2020-09-08
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