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Silencing cccDNA transcription through epigenetic mechanisms offers an effective strategy to control HBV. Long non\u2010coding RNAs (lncRNAs), as important epigenetic regulators, have an unclear role in cccDNA transcription regulation. In this study, lncRNA sequencing (lncRNA seq) is conducted on five pairs of HBV\u2010positive and HBV\u2010negative liver tissue. Through analysis, HOXA\u2010AS2 (HOXA cluster antisense RNA 2) is identified as a significantly upregulated lncRNA in HBV\u2010infected livers. Further experiments demonstrate that HBV DNA polymerase (DNA pol) induces HOXA\u2010AS2 after establishing persistent high\u2010level HBV replication. Functional studies reveal that HOXA\u2010AS2 physically binds to cccDNA and significantly inhibits its transcription. Mechanistically, HOXA\u2010AS2 recruits the MTA1\u2010HDAC1\/2 deacetylase complex to cccDNA minichromosome by physically interacting with metastasis associated 1 (MTA1) subunit, resulting in reduced acetylation of histone H3 at lysine 9 (H3K9ac) and lysine 27 (H3K27ac) associated with cccDNA and subsequently suppressing cccDNA transcription. Altogether, the study reveals a mechanism to self\u2010limit HBV replication, wherein the upregulation of lncRNA HOXA\u2010AS2, induced by HBV DNA pol, can epigenetically suppress cccDNA transcription.<\/jats:p>","DOI":"10.1002\/advs.202306810","type":"journal-article","created":{"date-parts":[[2024,4,22]],"date-time":"2024-04-22T09:39:33Z","timestamp":1713778773000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["HOXA\u2010AS2 Epigenetically Inhibits HBV Transcription by Recruiting the MTA1\u2010HDAC1\/2 Deacetylase Complex to cccDNA Minichromosome"],"prefix":"10.1002","volume":"11","author":[{"given":"YiPing","family":"Qin","sequence":"first","affiliation":[{"name":"Institute for Viral Hepatitis Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education) Department of Infectious Diseases The Second Affiliated Hospital Chongqing Medical University  Chongqing 400010 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