HBV X蛋白突变影响HBV转录以及组蛋白修饰酶与共价闭合的环状

StephenW

Sci Rep. 2020 Jan 21;10(1):802. doi: 10.1038/s41598-020-57637-z.
HBV X protein mutations affect HBV transcription and association of histone-modifying enzymes with covalently closed circular DNA.
Chong CK1, Cheng CYS1, Tsoi SYJ1, Huang FY1, Liu F1, Fung J1,2, Seto WK1,2, Lai KK3,4,5, Lai CL1,2, Yuen MF6,7, Wong DK8,9.
Author information

1
    Department of Medicine, The University of Hong Kong, Hong Kong, China.
2
    State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China.
3
    Department of Pathology, City of Hope National Medical Center, Duarte, CA, USA.
4
    Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA, USA.
5
    City of Hope Comprehensive Cancer, Duarte, CA, USA.
6
    Department of Medicine, The University of Hong Kong, Hong Kong, China. [email protected].
7
    State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China. [email protected].
8
    Department of Medicine, The University of Hong Kong, Hong Kong, China. [email protected].
9
    State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China. [email protected].

Abstract

The hepatitis B X protein (HBx) plays a role in the epigenetic regulation of hepatitis B virus (HBV) replication. This study investigated the effects of HBx mutations on HBV transcription and the recruitment of HBx, histone acetyl-transferase P300 and histone deacetylase 1 (HDAC1) to circularized HBV DNA (which resembles covalently closed circular DNA [cccDNA]). Compared with wild type, majority of mutants had lower levels of intracellular HBV RNA (44-77% reduction) and secretory HBsAg (25-81% reduction), and 12 mutants had a reduction in intracellular encapsidated HBV DNA (33-64% reduction). Eight mutants with >70% reduction in HBV RNA and/or HBsAg were selected for chromatin immunoprecipitation analysis. Four HBx mutants with mutations in amino acid residues 55-60 and 121-126 had a lower degree of HBx-cccDNA association than wild type HBx (mean % input: 0.02-0.64% vs. 3.08% in wild type). A reduced association between cccDNA and P300 (mean % input: 0.69-1.81% vs. 3.48% in wild type) and an augmented association with HDAC1 (mean % input: 4.01-14.0% vs. 1.53% in wild type) were detected. HBx amino acid residues 55-60 and 121-126 may play an important role in HBV transcription regulation, via their impeded interaction with cccDNA and altered recruitment of histone modifying enzymes to cccDNA.

PMID:
    31964944
DOI:
    10.1038/s41598-020-57637-z

StephenW

Sci Rep.2020年1月21日； 10（1）：802。 doi：10.1038 / s41598-020-57637-z。
HBV X蛋白突变影响HBV转录以及组蛋白修饰酶与共价闭合的环状DNA的关联。
Chong CK1，Cheng CYS1，Tsoi SYJ1，Huang FY1，Liu F1，Fung J1,2，Seto WK1,2，Lai KK3,4,5，Lai CL1,2，Yuen MF6,7，Wong DK8,9。
作者信息

1个
    香港大学医学系，中国香港。
2
    香港大学，肝脏研究国家重点实验室，中国香港。
3
    美国加利福尼亚州杜阿尔特，希望之城国家医学中心病理科。
4
    美国加利福尼亚州杜阿尔特，希望之城贝克曼研究所分子医学系。
5
    希望之城综合癌症，美国加利福尼亚州杜阿尔特。
6
    香港大学医学系，中国香港。 [email protected]。
7
    香港大学，肝脏研究国家重点实验室，中国香港。 [email protected]。
8
    香港大学医学系，中国香港。 [email protected]。
9
    香港大学，肝脏研究国家重点实验室，中国香港。 [email protected]。

抽象

乙型肝炎X蛋白（HBx）在乙型肝炎病毒（HBV）复制的表观遗传调控中起作用。这项研究调查了HBx突变对HBV转录和HBx，组蛋白乙酰转移酶P300和组蛋白脱乙酰基酶1（HDAC1）募集到环化HBV DNA（类似于共价闭合的环状DNA [cccDNA]）的影响。与野生型相比，大多数突变体的细胞内HBV RNA水平降低（降低44-77％）和分泌型HBsAg（降低25-81％），并且12个突变体的细胞内衣壳化HBV DNA降低（降低33-64％） ）。选择八种HBV RNA和/或HBsAg降低> 70％的突变体进行染色质免疫沉淀分析。四个具有氨基酸残基55-60和121-126突变的HBx突变体的HBx-cccDNA关联度低于野生型HBx（平均输入百分比：0.02-0.64％，而野生型为3.08％）。检测到cccDNA与P300之间的关联减少（平均输入百分比：0.69-1.81％，而野生型为3.48％），并且与HDAC1的关联增加（平均输入百分比：4.01-14.0％，相对于野生型1.53％）。 HBx氨基酸残基55-60和121-126通过阻碍与cccDNA的相互作用以及改变组蛋白修饰酶向cccDNA的募集，可能在HBV转录调控中发挥重要作用。

PMID：
    31964944
DOI：
    10.1038 / s41598-020-57637-z

StephenW

https://www.nature.com/articles/s41598-020-57637-z.pdf