转录本异构体的功能和动态分析揭示了替代剪接在干扰素反应中的重要作用。

IF 11.1 Q1 CELL BIOLOGY Cell genomics Pub Date : 2024-10-09 Epub Date: 2024-09-16 DOI:10.1016/j.xgen.2024.100654
Mahoko Takahashi Ueda, Jun Inamo, Fuyuki Miya, Mihoko Shimada, Kensuke Yamaguchi, Yuta Kochi
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引用次数: 0

摘要

I型干扰素(IFN-I)通过诱导IFN-I刺激基因(ISGs)在先天性免疫反应中发挥着重要作用。然而,人们对替代剪接(AS)事件(尤其是随着时间的推移)如何影响它们的功能仍然知之甚少。我们利用 PacBio Sequel II/IIe 的高精度长读数测序数据为 IFN-I 刺激的人类 B 细胞生成了一个名为 isoISG 的注释(113,843 个转录本)。利用 isoISG 进行的转录本异构体分析表明,在对 IFN-I 的早期反应中会发生异构体转换,从而使 ISG 获得功能域(如 C4B)或产生更多的蛋白质(如 IRF3)。相反,在 IFN-I 反应的晚期阶段,缺乏功能域的同工酶增多,这主要是由于内含子滞留事件。这表明,异构体转换在翻译和蛋白质水平上触发和终止了 IFN-I 反应。此外,影响 ISGs 同工酶比例的基因变异与免疫学和传染病有关。AS在调节先天性免疫反应和相关疾病中发挥着重要作用。
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Functional and dynamic profiling of transcript isoforms reveals essential roles of alternative splicing in interferon response.

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.

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