HOXA‐AS2 Epigenetically Inhibits HBV Transcription by Recruiting the MTA1‐HDAC1/2 Deacetylase Complex to Cccdna Minichromosome

AbstractPersistent transcription of HBV covalently closed circular DNA (cccDNA) is critical for chronic HBV infection. Silencing cccDNA transcription through epigenetic mechanisms offers an effective strategy to control HBV. Long non‐coding 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‐positive and HBV‐negative liver tissue. Through analysis, HOXA‐AS2 (HOXA cluster antisense RNA 2) is identified as a significantly upregulated lncRNA in HBV‐infected livers. Further experiments demonstrate that HBV DNA polymerase (DNA pol) induces HOXA‐AS2 after establishing persistent high‐level HBV replication. Functional studies reveal that HOXA‐AS2 physically binds to cccDNA and significantly inhibits its transcription. Mechanistically, HOXA‐AS2 recruits the MTA1‐HDAC1/2 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‐limit HBV replication, wherein the upregulation of lncRNA HOXA‐AS2, induced by HBV DNA pol, can epigenetically suppress cccDNA transcription.