LINC01431 Promotes Histone H4R3 Methylation to Impede HBV Covalently Closed Circular DNA Transcription by Stabilizing PRMT1.
LINC01431 Promotes Histone H4R3 Methylation to Impede HBV Covalently Closed Circular DNA Transcription by Stabilizing PRMT1.
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LINC01431 通过稳定 PRMT1 促进组蛋白 H4R3 甲基化以阻碍 HBV 共价闭合环状 DNA 转录
DOI：
10.1002/advs.202103135
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发表时间：
2022-05
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共价闭合环状DNA是乙肝病毒的转录模板，它与宿主蛋白和病毒蛋白相互作用，在细胞核内形成微染色体，对抗病毒药物具有耐药性。识别参与转录调控的宿主因子有望为乙肝治疗提供一个新的平台。最近的证据表明，长非编码RNA(Long Non Coding RNAs，lncRNAs)参与了宿主因子与各种病毒的相互作用，然而，针对和抑制cccDNA转录的lncRNAs还没有完全阐明。在此，作者将LINC01431确定为一种新的乙肝病毒转录宿主限制因子。机械上，LINC01431与I型蛋白精氨酸甲基转移酶(PRMT1)竞争性结合，阻断HBX介导的PRMT1泛素化和降解。因此，LINC01431增加了PRMT1在cccDNA上的占有率，导致H4R3me2a修饰增强，并减少了cccDNA结合组蛋白的乙酰化，从而抑制了cccDNA的转录。反过来，为了促进病毒复制，乙肝病毒通过HBx介导的转录因子锌指和同源异型盒2(ZHX2)的转录抑制LINC01431的表达。总之，本研究证明了LINC01431是一种新的ccCDNA微染色体的表观遗传调节因子，并强调了HBx-LINC01431-PRMT1在乙肝复制中的反馈环，这为乙肝的治疗提供了潜在的治疗靶点。
Covalently closed circular DNA (cccDNA) is the transcriptional template of hepatitis B virus (HBV), which interacts with both host and viral proteins to form minichromosome in the nucleus and is resistant to antiviral agents. Identification of host factors involved in cccDNA transcriptional regulation is expected to prove a new venue for HBV therapy. Recent evidence suggests the involvement of long noncoding RNAs (lncRNAs) in mediating the interaction of host factors with various viruses, however, lncRNAs that HBV targets and represses cccDNA transcription have not been fully elucidated. Here, the authors identified LINC01431 as a novel host restriction factor for HBV transcription. Mechanically, LINC01431 competitively bound with type I protein arginine methyltransferase (PRMT1) to block the HBx‐mediated PRMT1 ubiquitination and degradation. Consequently, LINC01431 increased the occupancy of PRMT1 on cccDNA, leading to enhanced H4R3me2a modification and reduced acetylation of cccDNA‐bound histones, thereby repressing cccDNA transcription. In turn, to facilitate viral replication, HBV transcriptionally repressed LINC01431 expression by HBx‐mediated repression of transcription factor Zinc fingers and homeoboxes 2 (ZHX2). Collectively, the study demonstrates LINC01431 as a novel epigenetic regulator of cccDNA minichromosome and highlights a feedback loop of HBx‐LINC01431‐PRMT1 in HBV replication, which provides potential therapeutic targets for HBV treatment.