{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T19:47:26Z","timestamp":1770752846891,"version":"3.50.0"},"reference-count":36,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2024,4,22]],"date-time":"2024-04-22T00:00:00Z","timestamp":1713744000000},"content-version":"vor","delay-in-days":21,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100005089","name":"Beijing Municipal Natural Science Foundation","doi-asserted-by":"publisher","award":["2022YFA1303600"],"award-info":[{"award-number":["2022YFA1303600"]}],"id":[{"id":"10.13039\/501100005089","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82272315"],"award-info":[{"award-number":["82272315"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Medical Virology"],"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The clearance or transcriptional silencing of integrated HBV DNA is crucial for achieving a functional cure in patients with chronic hepatitis B\u00a0and reducing the risk of hepatocellular carcinoma development. The PLC\/PRF\/5\u00a0cell line is commonly used as an <jats:italic>in vitro<\/jats:italic> model for studying HBV integration. In this study, we employed a range of multi\u2010omics techniques to gain a panoramic understanding of the characteristics of HBV integration in PLC\/PRF\/5\u00a0cells and to reveal the transcriptional regulatory mechanisms of integrated HBV DNA. Transcriptome long\u2010read sequencing (ONT)\u00a0was conducted to analyze and characterize the transcriptional activity of different HBV DNA integration sites in PLC\/PRF\/5\u00a0cells. Additionally, we collected data related to epigenetic regulation, including whole\u2010genome bisulfite sequencing (WGBS),\u00a0histone chromatin immunoprecipitation sequencing (ChIP\u2010seq),\u00a0and assays for transposase\u2010accessible chromatin using sequencing (ATAC\u2010seq),\u00a0to explore the potential mechanisms involved in the transcriptional regulation of integrated HBV DNA. Long\u2010read RNA sequencing analysis revealed significant transcriptional differences at various integration sites in the PLC\/PRF\/5\u00a0cell line, with higher HBV DNA transcription levels at integration sites on chr11, chr13, and the chr13\/chr5 fusion chromosome t (13:5). Combining long\u2010read DNA and RNA sequencing results, we found that transcription of integrated HBV DNA generally starts downstream of the SP1, SP2, or XP promoters. ATAC\u2010seq data confirmed that chromatin accessibility has limited influence on the transcription of integrated HBV DNA in the PLC\/PRF\/5\u00a0cell line. Analysis of\u00a0WGBS data showed that the methylation intensity of integrated HBV DNA was highly negatively correlated with its transcription level (<jats:italic>r<\/jats:italic>\u2009=\u2009\u22120.8929, <jats:italic>p<\/jats:italic>\u2009=\u20090.0123). After AzaD treatment, the transcription level of integrated HBV DNA significantly increased, especially for the integration chr17, which had the highest level of methylation. Through ChIP\u2010seq\u00a0data, we observed the association between histone modification of H3K4me3 and H3K9me3 with the transcription of integrated HBV DNA. Our findings suggest that the SP1, SP2 and XP in integrated HBV DNA, methylation level of surrounding host chromosome, and histone modifications affect the transcription of integrated HBV DNA in PLC\/PRF\/5\u00a0cells. This provides important clues for future studies on the expression and regulatory mechanisms of integrated HBV.<\/jats:p>","DOI":"10.1002\/jmv.29614","type":"journal-article","created":{"date-parts":[[2024,4,22]],"date-time":"2024-04-22T11:14:44Z","timestamp":1713784484000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Multi\u2010omics panoramic analysis of\u00a0HBV integration, transcriptional regulation, and epigenetic modifications in PLC\/PRF\/5 cell line"],"prefix":"10.1002","volume":"96","author":[{"given":"Guiwen","family":"Guan","sequence":"first","affiliation":[{"name":"Department of Microbiology &amp; Infectious Disease Center, School of Basic Medical Sciences Peking University Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abudurexiti","family":"Abulaiti","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, School of Basic Medical Sciences Peking University Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chenxiao","family":"Qu","sequence":"additional","affiliation":[{"name":"Department of Microbiology &amp; Infectious Disease Center, School of Basic Medical Sciences Peking University Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chia\u2010Chen","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Microbiology &amp; Infectious Disease Center, School of Basic Medical Sciences Peking University Beijing China"},{"name":"National Heart and Lung Institute Faculty of Medicine (NHLI) Imperial College London London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhiqiang","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Microbiology &amp; Infectious Disease Center, School of Basic Medical Sciences Peking University Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Yang","sequence":"additional","affiliation":[{"name":"Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Southern Medical University Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ting","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Microbiology &amp; Infectious Disease Center, School of Basic Medical Sciences Peking University Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaojie","family":"Chen","sequence":"additional","affiliation":[{"name":"Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital Capital Medical University Beijing China"},{"name":"Clinical Research Center for Pediatric Liver Transplantation of Capital Medical University Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhao","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Microbiology &amp; Infectious Disease Center, School of Basic Medical Sciences Peking University Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1832-3209","authenticated-orcid":false,"given":"Fengmin","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Microbiology &amp; Infectious Disease Center, School of Basic Medical Sciences Peking University Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiangmei","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Microbiology &amp; Infectious Disease Center, School of Basic Medical Sciences Peking University Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,4,22]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)01468-4"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/HEP.0000000000000430"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aan0241"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/jgh.14075"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2021.04.051"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2010.10.027"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/286531a0"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2021.676957"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2021.07.023"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btab705"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bty149"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-17-0337"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btr167"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btx633"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1923"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-018-4559-3"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2008-9-9-r137"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku365"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1080\/22221751.2019.1625728"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1534\/g3.118.200900"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00299-21"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.184.4139.868"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.3109\/00365548909167454"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.24362"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.1840190106"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1006\/viro.1996.0613"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-9525(97)01268-7"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-020-01969-6"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0056711"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1205699"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-10-451237"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2013.12.014"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.4161\/epi.3.3.6249"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0110442"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.175240.114"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02036-18"}],"container-title":["Journal of Medical Virology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jmv.29614","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,17]],"date-time":"2025-04-17T19:16:50Z","timestamp":1744917410000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jmv.29614"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4]]},"references-count":36,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2024,4]]}},"alternative-id":["10.1002\/jmv.29614"],"URL":"https:\/\/doi.org\/10.1002\/jmv.29614","archive":["Portico"],"relation":{},"ISSN":["0146-6615","1096-9071"],"issn-type":[{"value":"0146-6615","type":"print"},{"value":"1096-9071","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4]]},"assertion":[{"value":"2023-10-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-04-08","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-04-22","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e29614"}}