Inflammation drives alternative first exon usage to regulate immune genes including a novel iron-regulated isoform of Aim2

• DOI: 10.7554/elife.69431
• Publication Date: 2021-05-28T12:02:06Z
• Authors: Elektra K Robinson; Pratibha Jagannatha; Sergio Covarrubias; Matthew Cattle; Valeriya Smaliy; Rojin Safavi; Barbara Shapleigh; Robin Abu-Shumays; Miten Jain; Suzanne M Cloonan; Mark Akeson; Angela N Brooks; Susan Carpenter
• Keywords: Mouse; immunology; Mice; 2.1 Biological and endogenous factors; Innate; genetics; Aetiology; Biology (General); Promoter Regions, Genetic; Cells, Cultured; 0303 health sciences; Cultured; Q; R; Genomics; Exons; 3. Good health; DNA-Binding Proteins; Medicine; 570; QH301-705.5; 1.1 Normal biological development and functioning; Cells; Science; Immunology; Promoter Regions; splicing; 03 medical and health sciences; Genetic; Underpinning research; Genetics; genomics; Animals; Humans; human; mouse; Inflammation; Inflammatory and immune system; Gene Expression Profiling; Macrophages; Human Genome; Immunity; Genetics and Genomics; Immunity, Innate; Alternative Splicing; inflammation; Biochemistry and Cell Biology; 5' Untranslated Regions; Transcriptome

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 ofAim2is 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 ofAim2.