HBx induces hypomethylation of distal intragenic CpG islands required for active expression of developmental regulators

Proc Natl Acad Sci U S A. 2014 Jul 1;111(26):9555-60. doi: 10.1073/pnas.1400604111. Epub 2014 Jun 18.


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.

Keywords: DNA methylation; methylated CpG island; viral protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / etiology
  • Carcinoma, Hepatocellular / virology*
  • Chromatin Immunoprecipitation
  • Cloning, Molecular
  • CpG Islands / physiology*
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA Methylation / physiology*
  • DNA Methyltransferase 3A
  • Epigenesis, Genetic / genetics*
  • Expressed Sequence Tags
  • Gene Expression Regulation, Neoplastic / genetics*
  • Hep G2 Cells
  • Histone Deacetylase 1 / metabolism
  • Humans
  • Liver / metabolism
  • Liver / virology
  • Liver Neoplasms / etiology
  • Liver Neoplasms / virology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Molecular Sequence Annotation
  • Promoter Regions, Genetic / genetics
  • Sequence Analysis, RNA
  • Trans-Activators / metabolism*
  • Viral Regulatory and Accessory Proteins


  • DNMT3A protein, human
  • Dnmt3a protein, mouse
  • Trans-Activators
  • Viral Regulatory and Accessory Proteins
  • hepatitis B virus X protein
  • Dnmt3l protein, mouse
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA Methyltransferase 3A
  • Hdac1 protein, mouse
  • Histone Deacetylase 1

Associated data

  • GEO/GSE48052