Zhao Lingcai, Hou Chenglin, Hu Xifeng, Jiang Chenfeng, Li Shengmin, Xia Jun, Ping Jihui
MOE Joint International Research Laboratory of Animal Health and Food Safety, Engineering Laboratory of Animal Immunity of Jiangsu Province, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China.
Xinjiang Academy of Animal Sciences, Institute of Veterinary Medicine (Research Center of Animal Clinical), Urumqi, China.
mBio. 2025 Aug 13;16(8):e0137525. doi: 10.1128/mbio.01375-25. Epub 2025 Jul 8.
Non-coding RNAs are crucial orchestrators in the intricate dance between viruses and host cells, among which the expression and function of enhancer RNAs (eRNAs) during influenza virus infection remain largely unexplored. This study utilized whole transcriptome high-throughput sequencing to investigate the molecular mechanisms underpinning the species-specific regulation of influenza virus replication by the miR-302 cluster-IRFs-IRF1AS axis both and . Mechanistically, the CTNNB1-induced miR-302 cluster targeted various interferon regulatory factors (mainly IRF1 and IRF2) with varying affinities and silencing efficiencies, except for miR-302e and miR-302f. Furthermore, miR-302 cluster-IRFs triggered the induction of interferon-induced hub genes and hub lncRNAs defined through weighted gene co-expression network analysis. Importantly, the intricate interplay between IRFs, direct targets of the miR-302 cluster, and IRF1AS, an indirect target, in terms of gene loci and transcriptional regulation reveals a crosstalk in the miR-302 cluster-IRFs-IRF1AS axis. That is, on the one hand, IRF1 and IRF7 bind to the promoter of IRF1AS to promote the transcription of eRNAs. On the other hand, IRF1AS functions as an enhancer cluster that orchestrates and -regulates the transcription of IRF1, thereby rapidly amplifying the antiviral immune response initiated by miR-302 cluster-IRFs. In conclusion, we have unveiled a novel regulatory network governed by the miR-302 cluster-IRFs-IRF1AS, offering fresh perspectives on immune regulatory mechanisms.
Non-coding RNAs play a crucial role in regulating the three-dimensional structure of chromatin. They influence gene expression through various mechanisms and thereby contribute to the onset and progression of influenza A virus pathogenicity. Our comprehensive whole transcriptome sequencing analysis reveals a novel finding: the species-specific regulation of influenza virus replication by the miR-302 cluster-IRFs-IRF1AS axis. Our findings indicate that the miR-302 cluster-IRFs axis facilitates the transcription of key hub genes and hub lncRNAs, most of which significantly inhibit influenza virus replication. Notably, the downstream IRF1AS assembles into an enhancer cluster, orchestrating and -regulating the transcription of IRF1 to activate the interferon system. This investigation enhances our understanding of the regulatory network underlying viral infections and offers novel insights into immune regulatory mechanisms.
非编码RNA是病毒与宿主细胞之间复杂相互作用的关键协调者，其中流感病毒感染期间增强子RNA（eRNA）的表达和功能在很大程度上仍未得到探索。本研究利用全转录组高通量测序，研究了miR-302簇-干扰素调节因子（IRFs）-IRF1AS轴在物种特异性调节流感病毒复制过程中的分子机制。从机制上讲，CTNNB1诱导的miR-302簇以不同的亲和力和沉默效率靶向各种干扰素调节因子（主要是IRF1和IRF2），miR-302e和miR-302f除外。此外，miR-302簇-IRFs触发了通过加权基因共表达网络分析定义的干扰素诱导的枢纽基因和枢纽长链非编码RNA（lncRNAs）的诱导。重要的是，miR-302簇的直接靶点IRFs与间接靶点IRF1AS在基因位点和转录调控方面的复杂相互作用揭示了miR-302簇-IRFs-IRF1AS轴中的一种串扰。也就是说，一方面，IRF1和IRF7与IRF1AS的启动子结合，促进eRNA的转录。另一方面，IRF1AS作为一个增强子簇，协调并调节IRF1的转录，从而迅速放大由miR-302簇-IRFs启动的抗病毒免疫反应。总之，我们揭示了一个由miR-302簇-IRFs-IRF1AS控制的新型调控网络，为免疫调节机制提供了新的视角。
非编码RNA在调节染色质的三维结构中起着关键作用。它们通过各种机制影响基因表达，从而促成甲型流感病毒致病性的发生和发展。我们全面的全转录组测序分析揭示了一个新发现：miR-302簇-IRFs-IRF1AS轴对流感病毒复制的物种特异性调节。我们的研究结果表明，miR-302簇-IRFs轴促进了关键枢纽基因和枢纽lncRNAs的转录，其中大多数显著抑制流感病毒复制。值得注意的是，下游的IRF1AS组装成一个增强子簇，协调并调节IRF1的转录以激活干扰素系统。这项研究加深了我们对病毒感染潜在调控网络的理解，并为免疫调节机制提供了新的见解。
Zotero 插件
