• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

HOXA-AS2 通过募集 MTA1-HDAC1/2 去乙酰化酶复合物到cccDNA 微染色体抑制 HBV 转录。

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

机构信息

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, China.

Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, 400030, China.

出版信息

Adv Sci (Weinh). 2024 Jun;11(24):e2306810. doi: 10.1002/advs.202306810. Epub 2024 Apr 22.

DOI:10.1002/advs.202306810
PMID:38647380
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11200093/
Abstract

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.

摘要

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 转录为控制 HBV 提供了一种有效策略。长非编码 RNA（lncRNA）作为重要的表观遗传调节剂，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，发现 HOXA-AS2（HOXA 簇反义 RNA 2）是 HBV 感染肝脏中显著上调的 lncRNA。进一步的实验表明，HBV DNA 聚合酶（DNA pol）在建立持续高水平 HBV 复制后诱导 HOXA-AS2。功能研究表明，HOXA-AS2 与 cccDNA 物理结合，并显著抑制其转录。从机制上讲，HOXA-AS2 通过与转移相关蛋白 1（MTA1）亚基相互作用，将 MTA1-HDAC1/2 去乙酰化酶复合物募集到 cccDNA 微染色体上，导致与 cccDNA 相关的组蛋白 H3 赖氨酸 9（H3K9ac）和赖氨酸 27（H3K27ac）乙酰化减少，并随后抑制 cccDNA 转录。总的来说，该研究揭示了一种自我限制 HBV 复制的机制，其中由 HBV DNA pol 诱导的 lncRNA HOXA-AS2 的上调可以通过表观遗传抑制 cccDNA 转录。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cf0/11200093/ae1a9210f5c6/ADVS-11-2306810-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cf0/11200093/74a3d63f849f/ADVS-11-2306810-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cf0/11200093/e037dfbbc1d4/ADVS-11-2306810-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cf0/11200093/17cb6758539f/ADVS-11-2306810-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cf0/11200093/49844e113742/ADVS-11-2306810-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cf0/11200093/f13a2bb6f4ad/ADVS-11-2306810-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cf0/11200093/7357b7f75d99/ADVS-11-2306810-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cf0/11200093/7faec0337aa2/ADVS-11-2306810-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cf0/11200093/76327fd064ac/ADVS-11-2306810-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cf0/11200093/ae1a9210f5c6/ADVS-11-2306810-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cf0/11200093/74a3d63f849f/ADVS-11-2306810-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cf0/11200093/e037dfbbc1d4/ADVS-11-2306810-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cf0/11200093/17cb6758539f/ADVS-11-2306810-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cf0/11200093/49844e113742/ADVS-11-2306810-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cf0/11200093/f13a2bb6f4ad/ADVS-11-2306810-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cf0/11200093/7357b7f75d99/ADVS-11-2306810-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cf0/11200093/7faec0337aa2/ADVS-11-2306810-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cf0/11200093/76327fd064ac/ADVS-11-2306810-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5cf0/11200093/ae1a9210f5c6/ADVS-11-2306810-g004.jpg

相似文献

1
HOXA-AS2 Epigenetically Inhibits HBV Transcription by Recruiting the MTA1-HDAC1/2 Deacetylase Complex to cccDNA Minichromosome.HOXA-AS2 通过募集 MTA1-HDAC1/2 去乙酰化酶复合物到cccDNA 微染色体抑制 HBV 转录。
Adv Sci (Weinh). 2024 Jun;11(24):e2306810. doi: 10.1002/advs.202306810. Epub 2024 Apr 22.
2
HBV X protein mutations affect HBV transcription and association of histone-modifying enzymes with covalently closed circular DNA.HBV X 蛋白突变影响 HBV 转录和组蛋白修饰酶与共价闭合环状 DNA 的结合。
Sci Rep. 2020 Jan 21;10(1):802. doi: 10.1038/s41598-020-57637-z.
3
HDAC11 restricts HBV replication through epigenetic repression of cccDNA transcription.组蛋白去乙酰化酶 11 通过表观遗传抑制 cccDNA 转录来限制乙肝病毒复制。
Antiviral Res. 2019 Dec;172:104619. doi: 10.1016/j.antiviral.2019.104619. Epub 2019 Oct 7.
4
Nuclear HBx binds the HBV minichromosome and modifies the epigenetic regulation of cccDNA function.核 HBx 结合 HBV 微小染色体并修饰 cccDNA 功能的表观遗传调控。
Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):19975-9. doi: 10.1073/pnas.0908365106. Epub 2009 Nov 11.
5
Forkhead O Transcription Factor 4 Restricts HBV Covalently Closed Circular DNA Transcription and HBV Replication through Genetic Downregulation of Hepatocyte Nuclear Factor 4 Alpha and Epigenetic Suppression of Covalently Closed Circular DNA via Interacting with Promyelocytic Leukemia Protein.叉头框转录因子 4 通过与早幼粒细胞白血病蛋白相互作用，抑制肝细胞核因子 4α 的遗传下调和共价闭合环状 DNA 的表观遗传抑制，从而限制 HBV 共价闭合环状 DNA 的转录和 HBV 复制。
J Virol. 2022 Jul 13;96(13):e0054622. doi: 10.1128/jvi.00546-22. Epub 2022 Jun 13.
6
PRMT5 restricts hepatitis B virus replication through epigenetic repression of covalently closed circular DNA transcription and interference with pregenomic RNA encapsidation.PRMT5 通过对共价闭合环状 DNA 转录的表观遗传抑制和对前基因组 RNA 衣壳形成的干扰来限制乙型肝炎病毒复制。
Hepatology. 2017 Aug;66(2):398-415. doi: 10.1002/hep.29133. Epub 2017 Jun 19.
7
IFN-α inhibits HBV transcription and replication by promoting HDAC3-mediated de-2-hydroxyisobutyrylation of histone H4K8 on HBV cccDNA minichromosome in liver.IFN-α 通过促进肝内 HBV cccDNA 微染色体上组蛋白 H4K8 的去 2-羟异丁酰化来抑制 HBV 的转录和复制，该过程由 HDAC3 介导。
Acta Pharmacol Sin. 2022 Jun;43(6):1484-1494. doi: 10.1038/s41401-021-00765-7. Epub 2021 Sep 8.
8
An Alternatively Spliced Sirtuin 2 Isoform 5 Inhibits Hepatitis B Virus Replication from cccDNA by Repressing Epigenetic Modifications Made by Histone Lysine Methyltransferases.一种替代剪接的 Sirtuin 2 异构体 5 通过抑制组蛋白赖氨酸甲基转移酶所产生的表观遗传修饰来抑制 cccDNA 上的乙型肝炎病毒复制。
J Virol. 2020 Jul 30;94(16). doi: 10.1128/JVI.00926-20.
9
SIRT3 restricts hepatitis B virus transcription and replication through epigenetic regulation of covalently closed circular DNA involving suppressor of variegation 3-9 homolog 1 and SET domain containing 1A histone methyltransferases.SIRT3 通过抑制异染色质形成 3-9 同源物 1 和 SET 域包含 1A 组蛋白甲基转移酶对共价闭合环状 DNA 的表观遗传调控来限制乙型肝炎病毒的转录和复制。
Hepatology. 2018 Oct;68(4):1260-1276. doi: 10.1002/hep.29912. Epub 2018 Jul 25.
10
IL6 Inhibits HBV Transcription by Targeting the Epigenetic Control of the Nuclear cccDNA Minichromosome.白细胞介素6通过靶向细胞核共价闭合环状DNA微型染色体的表观遗传控制来抑制乙肝病毒转录。
PLoS One. 2015 Nov 18;10(11):e0142599. doi: 10.1371/journal.pone.0142599. eCollection 2015.

引用本文的文献

1
Genetic variation reveals a homeotic long noncoding RNA that modulates human hematopoietic stem cells.基因变异揭示了一种调控人类造血干细胞的同源异型长链非编码RNA。
bioRxiv. 2025 Jul 16:2025.07.16.664824. doi: 10.1101/2025.07.16.664824.
2
Acetylation in Viral Infection and Disease.病毒感染与疾病中的乙酰化作用
Results Probl Cell Differ. 2025;75:329-361. doi: 10.1007/978-3-031-91459-1_12.
3
Perspectives on NcRNAs in HBV/cccDNA-driven HCC progression.关于非编码RNA在乙肝病毒/共价闭合环状DNA驱动的肝癌进展中的观点。

本文引用的文献

1
The interplay of long noncoding RNAs and hepatitis B virus.长链非编码RNA与乙型肝炎病毒的相互作用
J Med Virol. 2023 Jan;95(1):e28058. doi: 10.1002/jmv.28058. Epub 2022 Aug 23.
2
LINC01431 Promotes Histone H4R3 Methylation to Impede HBV Covalently Closed Circular DNA Transcription by Stabilizing PRMT1.LINC01431 通过稳定 PRMT1 促进组蛋白 H4R3 甲基化，从而阻碍 HBV 共价闭合环状 DNA 转录。
Adv Sci (Weinh). 2022 May;9(16):e2103135. doi: 10.1002/advs.202103135. Epub 2022 Apr 10.
3
AP-2α and AP-2β cooperatively function in the craniofacial surface ectoderm to regulate chromatin and gene expression dynamics during facial development.
Cancer Cell Int. 2025 Jun 21;25(1):224. doi: 10.1186/s12935-025-03849-0.
4
Chronic Hepatitis B Virus Persistence: Mechanisms and Insights.慢性乙型肝炎病毒持续感染：机制与见解
Cureus. 2025 Feb 13;17(2):e78944. doi: 10.7759/cureus.78944. eCollection 2025 Feb.
5
Changes in the expression profile of serum lncRNAs in pregnant women with high hepatitis B viral load during antiviral and non-antiviral treatment.抗病毒和非抗病毒治疗期间乙肝病毒载量高的孕妇血清 lncRNAs 表达谱的变化。
BMC Pregnancy Childbirth. 2024 Oct 24;24(1):696. doi: 10.1186/s12884-024-06907-z.
AP-2α 和 AP-2β 在颅面外胚层中协同作用，调节面部发育过程中染色质和基因表达的动态变化。
Elife. 2022 Mar 25;11:e70511. doi: 10.7554/eLife.70511.
4
Metastatic tumor antigen 1 contributes to hepatocarcinogenesis posttranscriptionally through RNA-binding function.转移肿瘤抗原 1 通过其 RNA 结合功能在转录后促进肝癌发生。
Hepatology. 2023 Feb 1;77(2):379-394. doi: 10.1002/hep.32356. Epub 2022 Feb 14.
5
The methyltransferase METTL3 negatively regulates nonalcoholic steatohepatitis (NASH) progression.甲基转移酶 METTL3 负调控非酒精性脂肪性肝炎（NASH）进展。
Nat Commun. 2021 Dec 10;12(1):7213. doi: 10.1038/s41467-021-27539-3.
6
LncRNA HOXA-AS2 regulates microglial polarization via recruitment of PRC2 and epigenetic modification of PGC-1α expression.长链非编码 RNA HOXA-AS2 通过募集 PRC2 并对 PGC-1α 表达进行表观遗传修饰来调节小胶质细胞极化。
J Neuroinflammation. 2021 Sep 12;18(1):197. doi: 10.1186/s12974-021-02267-z.
7
LncRNA LINC00525 suppresses p21 expression via mRNA decay and triplex-mediated changes in chromatin structure in lung adenocarcinoma.长链非编码 RNA LINC00525 通过 mRNA 衰变和三链体介导的染色质结构改变抑制肺腺癌中 p21 的表达。
Cancer Commun (Lond). 2021 Jul;41(7):596-614. doi: 10.1002/cac2.12181. Epub 2021 Jun 9.
8
Translatomic profiling reveals novel self-restricting virus-host interactions during HBV infection.转录组谱分析揭示了 HBV 感染过程中新型的自我限制的病毒-宿主相互作用。
J Hepatol. 2021 Jul;75(1):74-85. doi: 10.1016/j.jhep.2021.02.009. Epub 2021 Feb 20.
9
Long noncoding RNA HOXA-AS2 functions as an oncogene by binding to EZH2 and suppressing LATS2 in acute myeloid leukemia (AML).长链非编码 RNA HOXA-AS2 通过与 EZH2 结合并抑制急性髓系白血病 (AML) 中的 LATS2 发挥癌基因作用。
Cell Death Dis. 2020 Dec 2;11(12):1025. doi: 10.1038/s41419-020-03193-3.
10
Hepatitis B Virus DNA Polymerase Restrains Viral Replication Through the CREB1/HOXA Distal Transcript Antisense RNA Homeobox A13 Axis.乙型肝炎病毒 DNA 聚合酶通过 CREB1/HOXA 远端转录反义 RNA 同源盒 A13 轴抑制病毒复制。
Hepatology. 2021 Feb;73(2):503-519. doi: 10.1002/hep.31284.