Browse > Article
http://dx.doi.org/10.5352/JLS.2022.32.2.94

Core Promoter Mutation of ntC1731T and G1806A of Hepatitis B Virus Increases HBV Gene Expression  

Cho, Ja Young (Biotechnology Research Division, National Institute of Fisheries Science)
Yi, Yi Kyaw (Advanced Molecular Research Centre, Department of Medical Research)
Seong, Mi So (Department of Molecular Biology, Pusan National University)
Cheong, JaeHun (Department of Molecular Biology, Pusan National University)
Publication Information
Journal of Life Science / v.32, no.2, 2022 , pp. 94-100 More about this Journal
Abstract
Chronic infection by hepatitis B virus (HBV) greatly increases the risk for liver cirrhosis and hepatocellular carcinoma (HCC). The outcome of HBV infection is shaped by the complex interplay of the mode of transmission, host genetic factors, viral genotype, adaptive mutations, and environmental factors. The pregenomic RNA transcription of HBV for their replication is regulated by the core promoter activation. Core promoter mutations have been the reason for acute liver failure and are associated with HCC development. We obtained HBV genes from a patient in Myanmar who was infected with HBV and identified gene variations in the core promoter region. For measuring the relative transactivation activity of the core promoter, we prepared the core-promoter reporter construct. Among the gene variations of the core promoter, the mutations of C1731T and G1806A were associated with increase in the transactivation of the HBV core promoter. Through computer analysis for searching for a tentative transcription factor binding site, we showed that the mutations of C1713T and G1806A newly created C/EBPβ and XBP1-responsive elements of the core promoter, respectively. The ectopic expression of C/EBPβ largely increased the HBV core promoter containing the C1713T mutation and that of XBP1 activated the M95 promoter containing the G1806A mutation. Our efforts to treat and prevent HBV infections are hampered by the emergence of drug-resistant mutations and vaccine-escape mutations. Our results provide the biological properties and clinical significance of specific HBV core promoter mutations.
Keywords
$C/EBP{\beta}$; core promoter; HBV; virus mutation; XBP1;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Lopez-Cabrera, M., Letovsky, J., Hu, K. Q. and Siddiqui, A. 1991. Transcriptional factor C/EBP binds to and transactivates the enhancer element II of the hepatitis B virus. Virology 183, 825-829.   DOI
2 Moriyama, K., Okamoto, H., Tsuda, F. and Mayumi, M. 1996. Reduced precore transcription and enhanced core-pregenome transcription of hepatitis B virus DNA after replacement of the precore-core promoter with sequences associated with e antigen-seronegative persistent infections. Virology 226, 269-280.   DOI
3 Conjeevaram, H. S. and Lok, A. S. 2003. Management of chronic heaptitis B. J. Hepatol. 38, 90-103.   DOI
4 Tsai, A., Kawai, S., Kwei, K. Gewaily, D., Hutter, A., Tong, D. R., Li, J., Wands, J. R. and Tong, S. 2009. Chimeric constructs between two hepatitis B virus genomes confirm transcriptional impact of core promoter mutations and reveal multiple effects of core gene mutations. Virology 387, 364-372.   DOI
5 Wang, J., Huang, H., Liu, Y., Chen, R., Yan, Y., Shi, S., Xi, J., Zou, J., Yu, G., Feng, X. and Lu, F. 2020. HBV genome and life cycle. Adv. Exp. Med. Biol. 1179, 17-37.   DOI
6 Zheng, Y., Li, J. and Ou, J. H. 2004. Regulation of hepatitis B virus core promoter by transcription factors HNF1 and HNF4 and the viral X protein. J. Virol. 78, 6908-6914.   DOI
7 Pollicino, T., Bellinghieri, L., Restuccia, A., Raffa, G., Musolino, C., Alibrandi, A., Teti, D. and Raimondo, G. 2013. Hepatitis B virus (HBV) induces the expression of interleukin-8 that in turn reduces HBV sensitivity to interferon-alpha. Virology 444, 317-328.   DOI
8 Costa, R. H., Kalinichenko, V. V., Holterman, A. X. and Wang, X. 2003. Transcription factors in liver development, differentiation, and regeneration. Hepatology 38, 1331-1347.   DOI
9 Kamijo, N., Matsumoto, A., Umemura, T., Shibata, S., Ichikawa, Y., Kimura, T., Komatsu, M. and Tanaka, E. 2015. Mutations of pre-core and basal core promoter before and after hepatitis B e antigen seroconversion. World J. Gastroenterol. 21, 541-548.   DOI
10 McMahon, B. J. 2009. The natural history of chronic hepatitis B virus infection. Hepatology 49, S45-55.   DOI
11 Datta S. 2008. An overview of molecular epidemiology of hepatitis B virus (HBV) in india. Virol. J. 5, 156.   DOI
12 Hunt, C. M., McGill, J. M., Allen, M. I. and Condreay, L. D. 2000. Clinical relevance of hepatitis B viral mutations. Hepatology 31, 1037-1044.   DOI
13 Poli, V. 1998. The role of C/EBP isoforms in the control of inflammatory and native immunity functions. J. Biol. Chem. 273, 29279-29282.   DOI
14 Scaglioni, P. P., Melegari, M. and Wands, J. R. 1997. Biologic properties of hepatitis B viral genomes with mutations in the precore promoter and precore open reading frame. Virology 233, 374-381.   DOI
15 Wu, J. F. and Chang, M. H. 2015. Natural history of chronic hepatitis B virus infection from infancy to adult life-the mechanism of inflammation triggering and long-term impacts. J. Biomed. Sci. 22, 92.   DOI
16 Quarleri, J. 2014. Core promoter: a critical region where the hepatitis B virus makes decisions. World J. Gastroenterol. 20, 425-435.   DOI
17 Buckwold, V. E., Xu, Z., Chen, M., Yen, T. S. and Ou, J. H. 1996. Effects of a naturally occurring mutation in the hepatitis B virus basal core promoter on precore gene expression and viral replication. J. Virol. 70, 5845-5851.   DOI
18 Chang, M. H. 2007. Hepatitis B virus infection. Semin. Fetal Neonatal Med. 12, 160-167.   DOI
19 Custer, B. 2004. Global epidemiology of hepatitis B virus. J. ClinGastroenterol. 38, S158-168.
20 Hsu, Y. S., Chien, R. N., Yeh, C. T., Sheen, I. S., Chiou, H. Y., Chu, C. M. and Liaw, Y. F. 2002. Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B. Hepatology 35, 1522-1527.   DOI
21 Block, T. M., Guo, H. and Guo, J. T. 2007. Molecular virology of hepatitis B virus for clinicians. Clin. Liver Dis. 11, 685-706.   DOI
22 Kao, J. H., Wu, N. H., Chen, P. J., Lai, M. Y. and Chen, D. S. 2000. Hepatitis genotypes and the response to interferon therapy. J. Hepatol. 33, 998-1002.   DOI
23 Chong, C. L., Chen, M. L., Wu, Y. C., Tsai, K. N., Huang, C. C., Hu, C. P., Jeng, K. S., Chou, Y. C. and Chang, C. 2011. Dynamics of HBV cccDNA expression and transcription in different cell growth phase. J. Biomed. Sci. 18, 96.   DOI
24 Akira, S., Isshiki, H., Sugita, T., Tanabe, O., Kinoshita, S., Nishio, Y., Nakajima, T., Hirano, T. and Kishimoto, T. 1990. A nuclear factor for IL-6 expression (NF-IL6) is a member of a C/EBP family. EMBO J. 9, 1897-1906.   DOI
25 Allweiss, L. and Dandri, M. 2017. The role of cccDNA in HBV maintenance. Viruses 9, 156.   DOI
26 An, P., Xu, J., Yu, Y. and Winkler, C. A. 2018. Host and viral genetic variation in HBV-related hepatocellular carcinoma. Front. Genet. 9, 261.   DOI
27 Beck, J. and Nassal, M. 2007. Hepatitis B virus replication. World J. Gastroenterol. 13, 48-64.   DOI
28 Belyhun, Y., Liebert, U. G. and Maier, M. 2018. Analysis of HBV basal core promoter/precore gene variability in patients with HBV drug resistance and HIV co-infection in Northwest Ethiopia. PLoS One 13, e0191970.   DOI
29 Brunetto, M. R., Oliveri, F., Coco, B., Leandro, G., Colombatto, P., Gorin, J. M. and Bonino, F. 2002. Outcome of anti-HBe positive chronic hepatitis B in alpha-interferon treated and untreated patients: a long term cohort study. J. Hepatol. 36, 263-270.