HOXA-AS2 Epigenetically Inhibits HBV Transcription by Recruiting the MTA1-HDAC1/2 Deacetylase Complex to cccDNA Minichromosome,Advanced Science

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HOXA-AS2 Epigenetically Inhibits HBV Transcription by Recruiting the MTA1-HDAC1/2 Deacetylase Complex to cccDNA Minichromosome
Advanced Science ( IF 14.3 ) Pub Date : 2024-04-22 , DOI: 10.1002/advs.202306810
YiPing Qin _{1,

2} , JiHua Ren ₁ , HaiBo Yu ₁ , Xin He ₁ , ShengTao Cheng ₁ , WeiXian Chen ₁ , Zhen Yang ₁ , FengMing Sun ₃ , ChunDuo Wang ₁ , SiYu Yuan ₁ , Peng Chen ₁ , DaiQing Wu ₁ , Fang Ren ₁ , AiLong Huang ₁ , Juan Chen _{1,

4}

Affiliation

Persistent 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.

中文翻译：

HOXA-AS2 通过将 MTA1-HDAC1/2 脱乙酰酶复合物招募到 cccDNA 微型染色体上，从表观遗传学角度抑制 HBV 转录

HBV 共价闭合环状 DNA (cccDNA) 的持续转录对于慢性 HBV 感染至关重要。通过表观遗传机制沉默 cccDNA 转录提供了控制 HBV 的有效策略。长非编码RNA（lncRNA）作为重要的表观遗传调控因子，在cccDNA转录调控中的作用尚不清楚。在这项研究中，对五对 HBV 阳性和 HBV 阴性肝组织进行了 lncRNA 测序 (lncRNA seq)。通过分析，HOXA-AS2（HOXA簇反义RNA 2）被确定为HBV感染肝脏中显着上调的lncRNA。进一步的实验表明，在建立持续的高水平 HBV 复制后，HBV DNA 聚合酶 (DNA pol) 会诱导 HOXA-AS2。功能研究表明 HOXA-AS2 与 cccDNA 物理结合并显着抑制其转录。从机制上讲，HOXA-AS2 通过与转移相关 1 (MTA1) 亚基发生物理相互作用，将 MTA1-HDAC1/2 脱乙酰酶复合物招募到 cccDNA 微型染色体上，从而导致与转移相关的组蛋白 H3 在赖氨酸 9 (H3K9ac) 和赖氨酸 27 (H3K27ac) 处的乙酰化减少cccDNA 并随后抑制 cccDNA 转录。总而言之，该研究揭示了一种自我限制 HBV 复制的机制，其中 HBV DNA pol 诱导的 lncRNA HOXA-AS2 上调可以表观遗传地抑制 cccDNA 转录。

更新日期：2024-04-22

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