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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
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