干扰素-α通过调节组蛋白H3K79的GCN5介导的琥珀酰化来清除HBV

StephenW

IFN-α confers epigenetic regulation of HBV cccDNA minichromosome by modulating GCN5-mediated succinylation of histone H3K79 to clear HBV cccDNA
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  2
Affiliations
Affiliations

    1
    Nankai University, 94 Weijin Road, Tianjin, 300071, People's Republic of China.
    2
    Nankai University, 94 Weijin Road, Tianjin, 300071, People's Republic of China. [email protected].

    PMID: 32894195 DOI: 10.1186/s13148-020-00928-z

Abstract

Background: 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.

Results: 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.

Conclusions: 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.

Keywords: Epigenetic regulation; GCN5; HBV; HBV cccDNA minichromosome; Histone succinylation; Interferon-α.

StephenW

干扰素-α通过调节组蛋白H3K79的GCN5介导的琥珀酰化来清除HBV cccDNA，从而赋予HBV cccDNA微型染色体表观遗传调控
影苑1，宏峰苑1，光阳1，浩林韵1，曼昭1，刘子贤1，赵丽娜1，余耕1，刘磊1，王佳培1，张慧慧1，王玉飞1，肖晓1董张2
隶属关系
隶属关系

    1个
    中国，天津，天津市渭津路94号，南开大学，邮编300071。
    2
    中国，天津，天津市卫进路94号，南开大学，邮编300071。 [email protected]。

    PMID：32894195 DOI：10.1186 / s13148-020-00928-z

抽象

背景：乙型肝炎病毒共价封闭的环状DNA（HBV cccDNA）由组蛋白和非组蛋白组装成核内的染色质样cccDNA微型染色体。具有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。但是，人们尚不清楚IFN-α在GCN5介导的cccDNA抑制中的潜在机制。在这里，我们探讨了HBV cccDNA小染色体的表观遗传调控中IFN-α对GCN5介导的琥珀酰化的影响。

结果：已在HBV感染的人肝嵌合小鼠和HBV表达细胞系中观察到了cccDNA微染色体的琥珀酰化修饰。此外，在系统中鉴定出由GCN5引起的组蛋白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导致了从头感染HBV的HepaRG细胞上清液中HBV DNA，HBsAg和HBeAg的水平降低。一致地，在被HBV感染的人肝嵌合小鼠的肝脏中，组蛋白H3K79琥珀酰化的水平显着升高。 GCN5或GCN5突变体的敲低或过表达可能会影响GCN5与cccDNA或H3K79琥珀酰化的结合，从而导致cccDNA转录活性的改变。此外，Southern印迹分析验证了siGCN5降低了细胞中cccDNA的水平，表明GCN5介导的组蛋白H3K79的琥珀酰化有助于cccDN A小染色体的表观遗传调控。令人惊讶的是，IFN-α有效抑制了从头感染的HepG2-NTCP和HBV感染的HepaRG细胞中HBV cccDNA微型染色体中的组蛋白H3K79琥珀酰化。

结论：IFN-α通过调节组蛋白H3K79的GCN5介导的琥珀酰化来清除HBV cccDNA，从表观遗传学上调节HBV cccDNA微型染色体。我们的发现为IFN-α调节HBV cccDNA微型染色体的表观遗传调控机制提供了新见解。

关键词：表观遗传调控； GCN5；乙肝病毒HBV cccDNA微染色体；组蛋白琥珀酰化；干扰素-α。

StephenW

https://clinicalepigeneticsjourn ... /s13148-020-00928-z

windu

好像现在也没有得出结论，为什么有的人用干扰素效果很好，有的人效果一般，如果能把这个原因弄明白，也能提升治愈率