{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T07:55:07Z","timestamp":1790668507844,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1011808","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,12,14]],"date-time":"2023-12-14T00:00:00Z","timestamp":1702512000000}}],"reference-count":59,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2023,12,4]],"date-time":"2023-12-04T00:00:00Z","timestamp":1701648000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key R&D Program of China","doi-asserted-by":"crossref","award":["2022YFC2604101 and 2021YFC2300702"],"award-info":[{"award-number":["2022YFC2604101 and 2021YFC2300702"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100012166","name":"National Key R&D Program of China","doi-asserted-by":"crossref","award":["2021YFA1300801 and 2021YFF0702004"],"award-info":[{"award-number":["2021YFA1300801 and 2021YFF0702004"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82172243 and 82372223"],"award-info":[{"award-number":["82172243 and 82372223"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["2042023kf1028 and 2042022dx0003"],"award-info":[{"award-number":["2042023kf1028 and 2042022dx0003"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Chronic hepatitis B virus (HBV) infection is a major cause of liver cirrhosis and liver cancer, despite strong prevention and treatment efforts. The study of the epigenetic modification of HBV has become a research hotspot, including the\n                    <jats:italic>N<\/jats:italic>\n                    6-methyladenosine (m\n                    <jats:sup>6<\/jats:sup>\n                    A) modification of HBV RNA, which plays complex roles in the HBV life cycle. In addition to m\n                    <jats:sup>6<\/jats:sup>\n                    A modification, 5-methylcytosine (m\n                    <jats:sup>5<\/jats:sup>\n                    C) is another major modification of eukaryotic mRNA. In this study, we explored the roles of m\n                    <jats:sup>5<\/jats:sup>\n                    C methyltransferase and demethyltransferase in the HBV life cycle. The results showed that m\n                    <jats:sup>5<\/jats:sup>\n                    C methyltransferase NSUN2 deficiency could negatively regulate the expression of HBV while m\n                    <jats:sup>5<\/jats:sup>\n                    C demethyltransferase TET2 deficiency positively regulates the expression of HBV. Subsequently, we combined both\n                    <jats:italic>in vitro<\/jats:italic>\n                    bisulfite sequencing and high-throughput bisulfite sequencing methods to determine the distribution and stoichiometry of m\n                    <jats:sup>5<\/jats:sup>\n                    C modification in HBV RNA. Two sites: C2017 and C131 with the highest-ranking methylation rates were identified, and mutations at these two sites could lead to the decreased expression and replication of HBV, while the mutation of the \u201cfake\u201d m\n                    <jats:sup>5<\/jats:sup>\n                    C site had no effect. Mechanistically, NSUN2-mediated m\n                    <jats:sup>5<\/jats:sup>\n                    C modification promotes the stability of HBV RNA. In addition, compared with wild-type HepG2-NTCP cells and primary human hepatocytes, the replication level of HBV after NSUN2 knockdown decreased, and the ability of the mutant virus to infect and replicate in wild-type HepG2-NTCP cells and PHHs was substantially impaired. Similar results were found in the experiments using C57BL\/6JGpt-\n                    <jats:italic>Nsun2<\/jats:italic>\n                    <jats:sup>+\/-<\/jats:sup>\n                    mice. Interestingly, we also found that HBV expression and core protein promoted the endogenous expression of NSUN2, which implied a positive feedback loop. In summary, our study provides an accurate and high-resolution m\n                    <jats:sup>5<\/jats:sup>\n                    C profile of HBV RNA and reveals that NSUN2-mediated m\n                    <jats:sup>5<\/jats:sup>\n                    C modification of HBV RNA positively regulates HBV replication by maintaining RNA stability.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1011808","type":"journal-article","created":{"date-parts":[[2023,12,4]],"date-time":"2023-12-04T13:29:42Z","timestamp":1701696582000},"page":"e1011808","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":54,"title":["NSUN2-mediated m5C modification of HBV RNA positively regulates HBV replication"],"prefix":"10.1371","volume":"19","author":[{"given":"Jiangpeng","family":"Feng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianmo","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiali","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peipei","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengbao","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shimin","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaichao","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianying","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiejie","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cong","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuchen","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1300-4652","authenticated-orcid":true,"given":"Yu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,12,4]]},"reference":[{"key":"ppat.1011808.ref001","first-page":"1","volume-title":"Hepatitis B Virus in Human Diseases.","author":"J. 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