DNA methylation at hepatitis B viral integrants is associated with methylation at flanking human genomic sequences

  1. Fumio Itoh1
  1. 1Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan;
  2. 2Internal Medicine, Kawasaki Rinko General Hospital, Kawasaki 210-0806, Japan;
  3. 3Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan;
  4. 4Department of Surgery, Institute of Gastroenterology, Tokyo Women’s Medical University, Tokyo 162-8666, Japan;
  5. 5Hepato-Biliary-Pancreatic Surgery Division, Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, University of Tokyo 113-8655, Japan;
  6. 6Department of Hepatobiliary Pancreatic Surgery, Graduate School, Tokyo Medical and Dental University, Tokyo 113-0034, Japan;
  7. 7Department of Infectious Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan;
  8. 8Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan
  1. Corresponding author: h-yama{at}marianna-u.ac.jp.

  1. ↵9 These authors contributed equally to this work.

Abstract

Integration of DNA viruses into the human genome plays an important role in various types of tumors, including hepatitis B virus (HBV)–related hepatocellular carcinoma. However, the molecular details and clinical impact of HBV integration on either human or HBV epigenomes are unknown. Here, we show that methylation of the integrated HBV DNA is related to the methylation status of the flanking human genome. We developed a next-generation sequencing-based method for structural methylation analysis of integrated viral genomes (denoted G-NaVI). This method is a novel approach that enables enrichment of viral fragments for sequencing using unique baits based on the sequence of the HBV genome. We detected integrated HBV sequences in the genome of the PLC/PRF/5 cell line and found variable levels of methylation within the integrated HBV genomes. Allele-specific methylation analysis revealed that the HBV genome often became significantly methylated when integrated into highly methylated host sites. After integration into unmethylated human genome regions such as promoters, however, the HBV DNA remains unmethylated and may eventually play an important role in tumorigenesis. The observed dynamic changes in DNA methylation of the host and viral genomes may functionally affect the biological behavior of HBV. These findings may impact public health given that millions of people worldwide are carriers of HBV. We also believe our assay will be a powerful tool to increase our understanding of the various types of DNA virus-associated tumorigenesis.

Footnotes

  • Received March 8, 2014.
  • Accepted December 29, 2014.

This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

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  1. Published in Advance February 4, 2015, doi: 10.1101/gr.175240.114 Genome Res. 25: 328-337 © 2015 Watanabe et al.; Published by Cold Spring Harbor Laboratory Press

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