Department of Biological Sciences, Kent State University, Kent, OH, USA.
Department of Biological Sciences, Kent State University, Kent, OH, USA; Brain Health Research Institute, Kent State University, Kent, OH, USA; Healthy Communities Research Institute, Kent State University, Kent, OH, USA.
Virus Res. 2024 Aug;346:199413. doi: 10.1016/j.virusres.2024.199413. Epub 2024 Jun 13.
The conversion of Adenosine (A) to Inosine (I), by Adenosine Deaminases Acting on RNA or ADARs, is an essential post-transcriptional modification that contributes to proteome diversity and regulation in metazoans including humans. In addition to its transcriptome-regulating role, ADARs also play a major part in immune response to viral infection, where an interferon response activates interferon-stimulated genes, such as ADARp150, in turn dynamically regulating host-virus interactions. A previous report has shown that infection from reoviruses, despite strong activation of ADARp150, does not influence the editing of some of the major known editing targets, while likely editing others, suggesting a potentially nuanced editing pattern that may depend on different factors. However, the results were based on a handful of selected editing sites and did not cover the entire transcriptome. Thus, to determine whether and how reovirus infection specifically affects host ADAR editing patterns, we analyzed a publicly available deep-sequenced RNA-seq dataset, from murine fibroblasts infected with wild-type and mutant reovirus strains that allowed us to examine changes in editing patterns on a transcriptome-wide scale. To the best of our knowledge, this is the first transcriptome-wide report on host editing changes after reovirus infection. Our results demonstrate that reovirus infection induces unique nuanced editing changes in the host, including introducing sites uniquely edited in infected samples. Genes with edited sites are overrepresented in pathways related to immune regulation, cellular signaling, metabolism, and growth. Moreover, a shift in editing targets has also been observed, where the same genes are edited in infection and control conditions but at different sites, or where the editing rate is increased for some and decreased for other differential targets, supporting the hypothesis of dynamic and condition-specific editing by ADARs.
腺嘌呤核苷（A）向肌苷核苷（I）的转化，由作用于 RNA 的腺苷脱氨酶或 ADARs 完成，是真核生物包括人类中蛋白质组多样性和调控的必要转录后修饰。除了其转录组调节作用外，ADARs 在病毒感染的免疫反应中也起着重要作用，干扰素反应激活干扰素刺激基因，如 ADARp150，进而动态调节宿主-病毒相互作用。之前的一项报告表明，尽管强烈激活了 ADARp150，但呼肠孤病毒的感染并不影响一些主要已知编辑靶标的编辑，而可能编辑其他靶标，这表明存在潜在的微妙编辑模式，可能取决于不同的因素。然而，这些结果是基于少数选定的编辑位点得出的，并未涵盖整个转录组。因此，为了确定呼肠孤病毒感染是否以及如何具体影响宿主 ADAR 编辑模式，我们分析了一个公开的深度测序 RNA-seq 数据集，该数据集来自感染野生型和突变型呼肠孤病毒株的鼠成纤维细胞，使我们能够在全转录组范围内研究编辑模式的变化。据我们所知，这是第一篇关于呼肠孤病毒感染后宿主编辑变化的全转录组报告。我们的研究结果表明，呼肠孤病毒感染会导致宿主产生独特的微妙编辑变化，包括在感染样本中引入独特编辑的位点。具有编辑位点的基因在与免疫调节、细胞信号转导、代谢和生长相关的途径中过表达。此外，还观察到编辑靶标的转移，相同的基因在感染和对照条件下被编辑，但在不同的位点，或者一些差异靶标的编辑率增加，而另一些则减少，这支持了 ADAR 动态和条件特异性编辑的假设。
