title: HBx induces hypomethylation of distal intragenic CpG islands required for active expression of developmental regulators.
abstract: Epigenetic alterations caused by viral oncoproteins are strong initiation factors for cancer development, but their mechanisms are largely unknown. To identify the epigenetic effects of viral hepatitis B virus X (HBx) that lead to hepatocellular carcinoma (HCC), we profiled the DNA methylomes of normal and HBx transgenic mouse liver. Intriguingly, severe hypomethylation of intragenic CpG islands (CGIs) was observed in HBx liver before the full development of HCC. Normally, these CGIs were highly methylated (mCGIs) by the DNMT3L complex and marked with epigenetic signatures associated with active expression, such as H3K36me3. Hypomethylation of mCGI was caused by the downregulation of Dnmt3L and Dnmt3a due to HBx bound to their promoters, along with HDAC1. These events lead to the downregulation of many developmental regulators that could facilitate tumorigenesis. Here we provide an intriguing epigenetic regulation mediated by mCGI that is required for cell differentiation and describe a previously unidentified epigenetic role for HBx in promoting HCC development.
authors.affiliation: Department of Biochemistry, College of Life Science and Technology, Yonsei University, Seoul 120-749, Korea;
authors.forename: Sun-Min
authors.initials: SM
authors.lastname: Lee
authors.affiliation: Department of Integrated Omics for Biomedical Science, World Class University Program, Yonsei University, Seoul 120-749, Korea;
authors.forename: Young-gun
authors.initials: YG
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, College of Life Science and Technology, Yonsei University, Seoul 120-749, Korea;
authors.forename: Jae-Bum
authors.initials: JB
authors.lastname: Bae
authors.affiliation: Department of Biochemistry, College of Life Science and Technology, Yonsei University, Seoul 120-749, Korea;
authors.forename: Jung Kyoon
authors.initials: JK
authors.lastname: Choi
authors.affiliation: Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan;
authors.forename: Chiharu
authors.initials: C
authors.lastname: Tayama
authors.affiliation: Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan;
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Hata
authors.affiliation: Department of Life Science and the Center for Cellular Homeostasis, Ewha Woman's University of Life Science, Seoul 120-750, Korea; and.
authors.forename: Yungdae
authors.initials: Y
authors.lastname: Yun
authors.affiliation: Laboratory of Developmental Biology and Genomics, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Korea.
authors.forename: Je-Kyung
authors.initials: JK
authors.lastname: Seong
authors.affiliation: Department of Biochemistry, College of Life Science and Technology, Yonsei University, Seoul 120-749, Korea;Department of Integrated Omics for Biomedical Science, World Class University Program, Yonsei University, Seoul 120-749, Korea; yjkim@yonsei.ac.kr.
authors.forename: Young-Joon
authors.initials: YJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000821:virology*; D047369:Chromatin Immunoprecipitation; D003001:Cloning, Molecular; D018899:CpG Islands / Q000502:physiology*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation / Q000502:physiology*; D000090205:DNA Methyltransferase 3A; D044127:Epigenesis, Genetic / Q000235:genetics*; D020224:Expressed Sequence Tags; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D056945:Hep G2 Cells; D056284:Histone Deacetylase 1 / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000821:virology; D008113:Liver Neoplasms / Q000209:etiology / Q000821:virology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058977:Molecular Sequence Annotation; D011401:Promoter Regions, Genetic / Q000235:genetics; D017423:Sequence Analysis, RNA; D015534:Trans-Activators / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins
chemical_list: C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; C498796:Dnmt3l protein, mouse; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C484389:Hdac1 protein, mouse; D056284:Histone Deacetylase 1
keywords: DNA methylation; methylated CpG island; viral protein