Department of Genomic Function and Diversity, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
Division of Rheumatology, University of Colorado School of Medicine, Aurora, CO, USA; Department of Biomedical Informatics, Center for Health Artificial Intelligence, University of Colorado School of Medicine, Aurora, CO, USA.
Cell Genom. 2024 Oct 9;4(10):100654. doi: 10.1016/j.xgen.2024.100654. Epub 2024 Sep 16.
Type I interferon (IFN-I) plays an important role in the innate immune response through inducing IFN-I-stimulated genes (ISGs). However, how alternative splicing (AS) events, especially over time, affect their function remains poorly understood. We generated an annotation (113,843 transcripts) for IFN-I-stimulated human B cells called isoISG using high-accuracy long-read sequencing data from PacBio Sequel II/IIe. Transcript isoform profiling using isoISG revealed that isoform switching occurred in the early response to IFN-I so that ISGs would gain functional domains (e.g., C4B) or higher protein production (e.g., IRF3). Conversely, isoforms lacking functional domains increased during the late phase of IFN-I response, mainly due to intron retention events. This suggests that isoform switching both triggers and terminates IFN-I responses at the translation and protein levels. Furthermore, genetic variants influencing the isoform ratio of ISGs were associated with immunological and infectious diseases. AS has essential roles in regulating innate immune response and associated diseases.
I 型干扰素（IFN-I）通过诱导 IFN-I 刺激基因（ISGs）在先天免疫反应中发挥重要作用。然而，替代剪接（AS）事件如何影响它们的功能，尤其是随时间的推移，仍然知之甚少。我们使用 PacBio Sequel II/IIe 的高精度长读测序数据，为 IFN-I 刺激的人类 B 细胞生成了一个名为 isoISG 的注释（113843 个转录本）。使用 isoISG 进行转录本异构体分析表明，在 IFN-I 的早期反应中发生了异构体转换，从而使 ISGs 获得功能结构域（例如 C4B）或更高的蛋白质产量（例如 IRF3）。相反，在 IFN-I 反应的后期，缺乏功能结构域的异构体增加，主要是由于内含子保留事件。这表明异构体转换在翻译和蛋白质水平上既触发又终止 IFN-I 反应。此外，影响 ISGs 异构体比例的遗传变异与免疫和传染病有关。AS 在调节先天免疫反应和相关疾病方面发挥着重要作用。
