TY  - JOUR
A1  - Watanabe, Yoshiyuki
A1  - Yamamoto, Hiroyuki
A1  - Oikawa, Ritsuko
A1  - Toyota, Minoru
A1  - Yamamoto, Masakazu
A1  - Kokudo, Norihiro
A1  - Tanaka, Shinji
A1  - Arii, Shigeki
A1  - Yotsuyanagi, Hiroshi
A1  - Koike, Kazuhiko
A1  - Itoh, Fumio
T1  - DNA methylation at hepatitis B viral integrants is associated with methylation at flanking human genomic sequences
Y1  - 2015/03/01 
JF  - Genome Research 
JO  - Genome Research 
SP  - 328 
EP  - 337 
DO  - 10.1101/gr.175240.114 
VL  - 25 
IS  - 3 
UR  - http://genome.cshlp.org/content/25/3/328.abstract 
N2  - 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. 
ER  -