HBx induces hypomethylation of distal intragenic CpG islands required for active expression of developmental regulators
Abstract
Epigenetic dysregulation by oncoviral protein plays a key role in tumor development. DNA methylome analysis of hepatitis B virus X (HBx)-induced hepatocellular carcinoma (HCC) revealed drastic changes in host epigenome, but in an unconventional way: intragenic CpG islands (CGIs) were dramatically demethylated. We showed methylated intragenic CGIs as previously unidentified regulatory elements associated with active expression. The methylated CGIs are marked with distinct epigenetic signatures and require DNA methyltransferase (DNMT) 3L complex for their high methylation levels. By directly suppressing Dnmt3L and Dnmt3a promoters, HBx induces hypomethylation of the intragenic CGIs and downregulation of the associated developmental regulators. We provide previously unreported functional identification of intragenic CGIs that may enhance our understanding of epigenetic regulation and a new epigenetic role for HBx in promoting HCC development.
- Publication:
-
Proceedings of the National Academy of Science
- Pub Date:
- July 2014
- DOI:
- 10.1073/pnas.1400604111
- Bibcode:
- 2014PNAS..111.9555L