Journal
BIOCHEMISTRY-MOSCOW
Volume 79, Issue 2, Pages 111-123Publisher
MAIK NAUKA/INTERPERIODICA/SPRINGER
DOI: 10.1134/S0006297914020047
Keywords
hepatitis B virus; X promoter; DNA methyltransferase; zinc finger; specific-site DNA methylation; gene regulation
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Funding
- Major National Projects for Infectious Diseases [2008ZX10002002, 2012ZX10002-006, 2012zx10002006-002-003]
- New Drug Research and Development [2009ZX0913-710]
- National Natural Science Foundation of China [30901315, 30970144]
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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.
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