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Hepatitis B Virus Can Be Inhibited by DNA Methyltransferase 3a via Specific Zinc-Finger-Induced Methylation of the X Promoter

L. Xirong1,2,3, L. Rui1, Y. Xiaoli1, H. Qiuyan1, T. Bikui1, Z. Sibo1, and Z. Naishuo1,2*

1Laboratory of Molecular Immunology, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China; E-mail: holyinshanghai@163.com; nzhu@fudan.edu.cn

2Shanghai Xinxing Medicine Co., LTD, Shanghai 200135, China; E-mail: naishuoz@sina.com

3Institute of Biomedical Sciences, Fudan University, Shanghai 200433, China; fax: (86) 21-5566-4032; E-mail: lixirong@fudan.edu.cn

* To whom correspondence should be addressed.

Received September 2, 2013; Revision received November 11, 2013
In this work we explored whether DNA methyltransferase 3a (Dnmt3a) targeted to the HBV X promoter (XP) causes epigenetic suppression of hepatitis B virus (HBV). The C-terminus of Dnmt3a (Dnmt3aC) was fused to a six-zinc-finger peptide specific to XP to form a fused DNA methyltransferase (XPDnmt3aC). The binding and methyl-modifying specificity of XPDnmt3aC were verified with an electrophoretic mobility shift assay and methylation-specific PCR, respectively. XP activity and HBV expression were clearly downregulated in HepG2 cells transfected with plasmid pXPDnmt3aC. The injection of XPDnmt3aC into HBV transgenic (TgHBV) mice also showed significant inhibition, leading to low serum HBV surface protein (HBsAg) levels and a reduced viral load. Thus, XPDnmt3aC specifically silenced HBV via site-selective DNA methylation delivered by zinc-finger peptides. This study establishes the foundation of an epigenetic way of controlling HBV-related diseases.
KEY WORDS: hepatitis B virus, X promoter, DNA methyltransferase, zinc finger, specific-site DNA methylation, gene regulation

DOI: 10.1134/S0006297914020047