Inflammation drives alternative first exon usage to regulate immune genes including a novel iron-regulated isoform of Aim2.
Inflammation drives alternative first exon usage to regulate immune genes including a novel iron-regulated isoform of Aim2.
复制标题
炎症驱动替代性的首次外显子使用，以调节包括AIM2的新型铁调节的同工型，包括AIM2的新型免疫基因。
DOI：
10.7554/elife.69431
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发表时间：
2021-05-28
期刊：
影响因子：
7.7
通讯作者：
Carpenter S
中科院分区：
文献类型：
--
作者：
Robinson EK;Jagannatha P;Covarrubias S;Cattle M;Smaliy V;Safavi R;Shapleigh B;Abu-Shumays R;Jain M;Cloonan SM;Akeson M;Brooks AN;Carpenter S
确定先天免疫反应中基因调控的层次对于我们理解细胞对感染和疾病失调的反应至关重要。我们通过炎症后替代第一外显子（AFE）使用的变化，从而导致产生的亚型发生变化，确定了人类和小鼠基因调控的保守机制。在这些 AFE 事件中，我们使用长读天然 RNA 测序生成的从头转录组鉴定了小鼠中 95 个未注释的转录起始位点，其中之一位于 dsDNA 的胞质受体和已知的炎症诱导基因 Aim2 中。我们表明，Aim2 的这种未注释的 AFE 同工型是炎症期间表达的主要同工型，并且在其 5'UTR 中包含铁响应元件，使 mRNA 翻译能够受到铁水平的调节。这项工作强调了检查先天免疫反应中替代亚型变化和翻译调节的重要性，并揭示了 Aim2 的新调节机制。
Determining the layers of gene regulation within the innate immune response is critical to our understanding of the cellular responses to infection and dysregulation in disease. We identified a conserved mechanism of gene regulation in human and mouse via changes in alternative first exon (AFE) usage following inflammation, resulting in changes to the isoforms produced. Of these AFE events, we identified 95 unannotated transcription start sites in mice using a de novo transcriptome generated by long-read native RNA-sequencing, one of which is in the cytosolic receptor for dsDNA and known inflammatory inducible gene, Aim2. We show that this unannotated AFE isoform of Aim2 is the predominant isoform expressed during inflammation and contains an iron-responsive element in its 5′UTR enabling mRNA translation to be regulated by iron levels. This work highlights the importance of examining alternative isoform changes and translational regulation in the innate immune response and uncovers novel regulatory mechanisms of Aim2.