title: Hepatitis B virus can be inhibited by DNA methyltransferase 3a via specific zinc-finger-induced methylation of the X promoter.
abstract: 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.
authors.affiliation: Laboratory of Molecular Immunology, State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200433, China. holyinshanghai@163.com.
authors.forename: L
authors.initials: L
authors.lastname: Xirong
authors.forename: L
authors.initials: L
authors.lastname: Rui
authors.forename: Y
authors.initials: Y
authors.lastname: Xiaoli
authors.forename: H
authors.initials: H
authors.lastname: Qiuyan
authors.forename: T
authors.initials: T
authors.lastname: Bikui
authors.forename: Z
authors.initials: Z
authors.lastname: Sibo
authors.forename: Z
authors.initials: Z
authors.lastname: Naishuo
mesh_terms: D000818:Animals; D001483:Base Sequence; D020134:Catalytic Domain; D018899:CpG Islands / Q000235:genetics; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D044127:Epigenesis, Genetic; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000235:genetics* / Q000254:growth & development*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics*; D014779:Virus Replication; D016335:Zinc Fingers
chemical_list: C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A