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

Watanabe, Yoshiyuki; Yamamoto, Hiroyuki; Oikawa, Ritsuko; Toyota, Minoru; Yamamoto, Masakazu; Kokudo, Norihiro; Tanaka, Shinji; Arii, Shigeki; Yotsuyanagi, Hiroshi; Koike, Kazuhiko; Itoh, Fumio

doi:10.1101/gr.175240.114

Cited by 34 publications

(54 citation statements)

References 37 publications

(56 reference statements)

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“…The present study showed a statistically significant correlation between the average methylation level of the HPV16 DNA and that of the flanking host genome in 3 HPV-HNSCC cell lines. This correlation may be explained by our previous observation, indicating that the HBV genome often became significantly methylated when integrated into highly methylated host sites 25 . To the best of our knowledge, this is the first report to show a relationship between DNA methylation in the integrated HPV16 genome and the methylation status of the flanking host genome at the integration breakpoints in HPV-HNSCC.…”

Section: Discussionmentioning

confidence: 65%

“…As our previous report also showed that methylation of the integrated HBV DNA is related to the methylation status of the flanking human genome 25 , we therefore hypothesized that DNA methylation in the integrated HPV16 genome is related to the methylation status of the integration sites within the host genome.…”

Section: Resultsmentioning

confidence: 92%

“…These results suggested that the DNA methylation status of the integrated HPV16 genome was affected by the methylation status of the human genome flanking integration breakpoints. As our previous report also showed that methylation of the integrated HBV DNA is related to the methylation status of the flanking human genome, 13 we therefore hypothesized that DNA methylation in the integrated HPV16 genome is related to the methylation status of the integration sites within the host genome.…”

Section: Cancer Genetics and Epigeneticsmentioning

confidence: 90%

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Identification of human papillomavirus (HPV) 16 DNA integration and the ensuing patterns of methylation in HPV‐associated head and neck squamous cell carcinoma cell lines

Hatano

Sano

Takahashi

et al. 2017

Intl Journal of Cancer

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Recent studies showed that human papillomavirus (HPV) integration contributes to the genomic instability seen in HPV-associated head and neck squamous cell carcinoma (HPV-HNSCC). However, the epigenetic alterations induced after HPV integration remains unclear. To identify the molecular details of HPV16 DNA integration and the ensuing patterns of methylation in HNSCC, we performed next-generation sequencing using a target-enrichment method for the effective identification of HPV16 integration breakpoints as well as the characterization of genomic sequences adjacent to HPV16 integration breakpoints with three HPV16-related HNSCC cell lines. The DNA methylation levels of the integrated HPV16 genome and that of the adjacent human genome were also analyzed by bisulfite pyrosequencing. We found various integration loci, including novel integration sites. Integration loci were located predominantly in the intergenic region, with a significant enrichment of the microhomologous sequences between the human and HPV16 genomes at the integration breakpoints. Furthermore, various levels of methylation within both the human genome and the integrated HPV genome at the integration breakpoints in each integrant were observed. Allele-specific methylation analysis suggested that the HPV16 integrants remained hypomethylated when the flanking host genome was hypomethylated. After integration into highly methylated human genome regions, however, the HPV16 DNA became methylated. In conclusion, we found novel integration sites and methylation patterns in HPV-HNSCC using our unique method. These findings may provide insights into understanding of viral integration mechanism and virus-associated carcinogenesis of HPV-HNSCC.

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Section: Discussionmentioning

confidence: 65%

Section: Resultsmentioning

confidence: 92%

Section: Cancer Genetics and Epigeneticsmentioning

confidence: 90%

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Identification of human papillomavirus (HPV) 16 DNA integration and the ensuing patterns of methylation in HPV‐associated head and neck squamous cell carcinoma cell lines

Hatano

Sano

Takahashi

et al. 2017

Intl Journal of Cancer

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“…Therefore, disturbance of the host genome, but not DNA methylation, might be more important in a subset of HBV- than that of HCV-related carcinogenesis. In addition, integration of HBV that could trigger the DNA methylation at flanking genomic sequences should give rise to the methylation difference between HBV- and HCV-positive livers [27]. …”

Section: Discussionmentioning

confidence: 99%

Hepatic DNA Methylation Is Affected by Hepatocellular Carcinoma Risk in Patients with and without Hepatitis Virus

Nishida

Iwanishi²,

Minami³

et al. 2015

Dig Dis

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Objectives: Several studies revealed that the proportion of hepatocellular carcinoma (HCC) without hepatitis virus infection (NBNC-HCC) is increasing. On the other hand, epigenetic alterations are reportedly responsible for HCC development. Here, we identified HCC risk factors that are associated with DNA methylation in the background liver tissue of NBNC-HCC patients. Methods: We performed methylation analysis in 37 pairs of virus-positive and 22 pairs of NBNC-HCC and non-cancerous livers using a HumanMethylation450 BeadChip array. After the selection of differentially methylated CpGs (DM-CpGs) in cancerous and non-cancerous livers, we analyzed DNA methylation of DM-CpGs within the adjacent non-cancerous liver tissue that is affected by specific HCC risk factors. Results: A total of 38,331 CpGs were selected as DM-CpGs using the following criteria: difference of β-value between HCC and non-cancerous liver ≥0.15 and false discovery rate (FDR) q < 1.0E-12. We subsequently selected the DM-CpGs that had methylation differences with the background liver tissue (that has FDR q < 0.35). Among the virus-positive patients, the type of hepatitis virus was mostly associated with differences in methylation within the background liver tissues. However, we found that background methylation patterns were most significantly associated with aging in NBNC patients. Interestingly, age-related methylation differences in DM-CpGs were also observed in NBNC-HCC tissues. Conclusions: Hepatitis viruses affect the methylation profiles within background liver tissues. However, difference in background methylation was mostly associated with age in NCBC-HCC patients; some age-related methylation events could contribute to emergence of NBNC-HCC in elderly individuals.

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“…BSVF used WGBS data, and other software used WGS data. * Supported by previous fluorescence in situ hybridization (FISH) experiments [8]. …”

Section: Introductionmentioning

confidence: 99%

BS-virus-finder: virus integration calling using bisulfite sequencing data

Gao

et al. 2017

GigaScience

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BackgroundDNA methylation plays a key role in the regulation of gene expression and carcinogenesis. Bisulfite sequencing studies mainly focus on calling single nucleotide polymorphism, different methylation region, and find allele-specific DNA methylation. Until now, only a few software tools have focused on virus integration using bisulfite sequencing data.FindingsWe have developed a new and easy-to-use software tool, named BS-virus-finder (BSVF, RRID:SCR_015727), to detect viral integration breakpoints in whole human genomes. The tool is hosted at https://github.com/BGI-SZ/BSVF.ConclusionsBS-virus-finder demonstrates high sensitivity and specificity. It is useful in epigenetic studies and to reveal the relationship between viral integration and DNA methylation. BS-virus-finder is the first software tool to detect virus integration loci by using bisulfite sequencing data.

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

Cited by 34 publications

References 37 publications

Identification of human papillomavirus (HPV) 16 DNA integration and the ensuing patterns of methylation in HPV‐associated head and neck squamous cell carcinoma cell lines

Identification of human papillomavirus (HPV) 16 DNA integration and the ensuing patterns of methylation in HPV‐associated head and neck squamous cell carcinoma cell lines

Hepatic DNA Methylation Is Affected by Hepatocellular Carcinoma Risk in Patients with and without Hepatitis Virus

BS-virus-finder: virus integration calling using bisulfite sequencing data

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