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Multi-Omics Panoramic Analysis of HBV Integration, Transcriptional Regulation, Translation, and Epigenetic Modifications in the Classical HBV-Integrated Cell Line PLC/PRF/5
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  • Guiwen Guan,
  • Abudurexiti Abulaiti,
  • Chia-Chen Chen,
  • Zhiqiang Gu,
  • Jing Yang,
  • Ting Zhang,
  • Xiaojie Chen,
  • Zhao Zhou,
  • Fengmin Lu,
  • Xiangmei Chen
Guiwen Guan
Peking University School of Basic Medical Sciences

Corresponding Author:[email protected]

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Abudurexiti Abulaiti
Peking University School of Basic Medical Sciences
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Chia-Chen Chen
Peking University School of Basic Medical Sciences
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Zhiqiang Gu
Peking University School of Basic Medical Sciences
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Jing Yang
Guangdong Provincial People's Hospital
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Ting Zhang
Peking University School of Basic Medical Sciences
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Xiaojie Chen
Capital Medical University Affiliated Beijing Friendship Hospital
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Zhao Zhou
Peking University School of Basic Medical Sciences
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Fengmin Lu
Peking University School of Basic Medical Sciences

Corresponding Author:[email protected]

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Xiangmei Chen
Peking University School of Basic Medical Sciences

Corresponding Author:[email protected]

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Abstract

Background: The clearance or transcriptional silencing of integrated HBV DNA is crucial for achieving a functional cure in patients with chronic hepatitis B (CHB) and reducing the risk of hepatocellular carcinoma (HCC) development. The PLC/PRF/5 cell line is commonly used as an in vitro model for studying HBV integration. In this study, we employed a range of multi-omics techniques to gain a panoramic understanding of the characteristics of HBV integration in PLC/PRF/5 cells. Methods: Transcriptome long-read sequencing (ONT) was conducted to analyze characterize the transcriptional activity of different HBV DNA integrations in PLC/PRF/5 cells. Additionally, data pertaining to epigenetic regulation such as whole-genome bisulfite sequencing (WGBS), histone chromatin immunoprecipitation sequencing (ChIP-seq), and assay for transposase-accessible chromatin using sequencing (ATAC-seq) were collected to investigate the potential mechanisms associated with the transcriptional regulation of integrated HBV DNA. Result: Our findings indicate that transcriptional activity of integrated HBV DNA in PLC/PRF/5 cells is influenced by methylation levels of the surrounding host genome near the integration site. The result indicated that elevated methylation of the adjacent host genome adversely impacts transcription activity of integrated HBV DNA. Furthermore, we observed a positive association between histone modification H3K4me3 and the transcription of integrated HBV DNA. These results suggest that host may regulate transcriptional activity of integrated HBV DNA through DNA methylation and histone modifications. Potentially leading to the silencing of integrated HBV DNA. Conclusion: Our study brought a better understanding on the transcriptional regulation of integrated HBV DNA. This knowledge can be valuable in the development of novel strategy for functional cure of CHB.