PRMT5限制乙型肝炎病毒复制通过cccDNA的表观遗传抑制转录和干

StephenW

Hepatology. 2017 Feb 25. doi: 10.1002/hep.29133. [Epub ahead of print]
PRMT5 Restricts Hepatitis B Virus Replication via Epigenetic Repression of cccDNA Transcription and Interference with pgRNA Encapsidation.Zhang W1,2, Chen J1, Wu M2, Zhang X2, Zhang M2, Yue L1, Li Y1, Liu J1, Li B1, Shen F1, Wang Y1, Bai L1, Protzer U3, Levrero M4, Yuan Z1.
Author information
1Key Laboratory of Medical Molecular Virology, Ministry of Education and Health, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.2Research Unit, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.3Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany.4Cancer Research Center of Lyon (CRCL) - INSERM U1052, Lyon, France.

AbstractChronic hepatitis B virus (HBV) infection remains a major health problem worldwide. The covalently closed circular DNA (cccDNA) minichromosome, which serves as the template for the transcription of viral RNAs, plays a key role in viral persistence. While accumulating evidence suggests that cccDNA transcription is regulated by epigenetic machinery, particularly the acetylation of cccDNA-bound histone 3 (H3) and H4, the potential contributions of histone methylation and related host factors remain obscured. Here, by screening a series of methyltransferases and demethylases, we identified protein arginine methyltransferase 5 (PRMT5) as an effective restrictor of HBV transcription and replication. In the cell culture-based models for HBV infection and the liver tissues of patients with chronic HBV infection, we found that symmetric dimethylation of arginine 3 on H4 (H4R3me2s) on cccDNAwas a repressive marker of cccDNA transcription and was regulated by PRMT5 depending on its methyltransferase domain. Moreover, PRMT5-triggered H4R3me2s on the cccDNA minichromosome involved an interaction with the HBV core protein and the Brg1-based hSWI/SNF chromatin remodeler, which resulted in the downregulation of the binding of RNA Pol II to cccDNA. In addition to the inhibitory effect on cccDNA transcription, PRMT5 inhibited HBV core particle DNA production independent of its methyltransferase activity. Further study revealed that PRMT5 interfered with pre-genomic RNA (pgRNA) encapsidation by preventing its interaction with viral polymerase protein through binding to the RT-RH region of polymerase which is crucial for the polymerase-pgRNA interaction.
CONCLUSION: PRMT5 restricts HBV replication via two-part mechanisms including epigenetic suppression of cccDNA transcription and interference with pgRNA encapsidation. These findings improve the understanding of epigenetic regulation of HBV transcription and host-HBV interaction, thus provide new insights into targeted therapeutic intervention. This article is protected by copyright. All rights reserved.

© 2017 by the American Association for the Study of Liver Diseases.

KEYWORDS: H4R3me2s; HBV minichromosome; HBV polymerase; HBc; histone methylation

PMID:28236308DOI:10.1002/hep.29133

StephenW

肝脏病学。 doi：10.1002 / hep.29133。 [打印前的电子版]
PRMT5限制乙型肝炎病毒复制通过cccDNA的表观遗传抑制转录和干扰与pgRNA。
Zhang W1.2，Chen J1，Wu M2，Zhang X2，Zhang M2，Yue L1，Li Y1，Liu J1，Li B1，Shen F1，Wang Y1，Bai L1，Protzer U3，Levrero M4，Yuan Z1。
作者信息

1
    复旦大学上海医学院基础医学院教育与卫生部医学分子病毒学重点实验室，上海。
2
    复旦大学上海市公共卫生临床中心研究室，上海。
3
    Institute of Virology，TechnischeUniversitätMünchen/ Helmholtz ZentrumMünchen，Munich，Germany。
4
    癌症研究中心（CRCL） - INSERM U1052，里昂，法国。

抽象

慢性乙型肝炎病毒（HBV）感染仍然是全世界的主要健康问题。共价闭合的环状DNA（cccDNA）微染色体，其用作病毒RNA转录的模板，在病毒持久性中起关键作用。虽然积累的证据表明cccDNA转录由表观遗传机制，特别是cccDNA绑定组蛋白3（H3）和H4的乙酰化，组蛋白甲基化和相关的宿主因素的潜在贡献仍然模糊。在这里，通过筛选一系列甲基转移酶和脱甲基酶，我们确定蛋白精氨酸甲基转移酶5（PRMT5）作为HBV转录和复制的有效限制器。在基于细胞培养的HBV感染模型和慢性HBV感染患者的肝组织中，我们发现cccDNA上H4（H4R3me2s）上的精氨酸3的对称二甲基化是cccDNA转录的抑制性标记，并且受PRMT5调节甲基转移酶结构域。此外，在cccDNA微染色体上PRMT5触发的H4R3me2涉及与HBV核心蛋白和基于Brg1的hSWI / SNF染色质重塑的相互作用，其导致RNA Pol II与cccDNA的结合的下调。除了对cccDNA转录的抑制作用，PRMT5抑制HBV核心颗粒DNA生产独立于其甲基转移酶活性。进一步的研究表明PRMT5干扰前基因组RNA（pgRNA）衣壳，通过防止其与病毒聚合酶蛋白通过绑定到聚合酶的RT-RH区域的相互作用，这对聚合酶-pgRNA相互作用至关重要。
结论：

PRMT5通过两部分机制限制HBV复制，包括cccDNA转录的表观遗传抑制和对pgRNA衣壳化的干扰。这些发现改善了对HBV转录和宿主 - HBV相互作用的表观遗传调节的理解，因此提供了对靶向治疗干预的新见解。本文受版权保护。版权所有。

©2017由美国肝脏疾病研究协会。
关键词：

H4R3me2s; HBV微染色体; HBV聚合酶; HBc;组蛋白甲基化

PMID：
    28236308
DOI：
    10.1002 / hep.29133

kite2002005

然并卵

StephenW

回复 kite2002005 的帖子

没有一点用的意思

Protzer U和Levrero M是着名的德国,法国HBV研究者. 这项与中国研究人员的研究是非常好的迹象.

灵魂不屈

感谢分享！

csfluke

回复 kite2002005 的帖子

有了理论的突破，才有可能诞生新的药物！