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 isoform usage. Of these AFE events, we identified 50 unannotated transcription start sites (TSS) in mice using Oxford Nanopore native RNA sequencing, one of which is the cytosolic receptor for dsDNA and known inflammatory inducible gene, Aim2. We show that this unannotated AFE isoform of Aim2 is the predominant isoform transcribed 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.

中文翻译：

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炎症驱动第一外显子的替代使用，以调节免疫基因，包括新型铁调节的Aim2亚型。

确定先天免疫反应中基因调控的层次对于我们对细胞对疾病感染和失调反应的理解至关重要。我们确定了人类和小鼠的基因调节的保守机制，通过改变发炎后替代第一外显子（AFE）的用法，从而导致亚型用法的改变。在这些AFE事件中，我们使用牛津纳米孔天然RNA测序在小鼠中鉴定了50个未注释的转录起始位点（TSS），其中之一是dsDNA的胞质受体和已知的炎症诱导基因Aim2。我们显示，Aim2的这种未注释的AFE亚型是在炎症过程中转录的主要亚型，并且在其5'UTR中包含铁反应性元件，使mRNA翻译受铁水平调节。