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

• Published in: eLife Vol. 10
• Main Authors: Robinson, Elektra K, Jagannatha, Pratibha, Covarrubias, Sergio, Cattle, Matthew, Smaliy, Valeriya, Safavi, Rojin, Shapleigh, Barbara, Abu-Shumays, Robin, Jain, Miten, Cloonan, Suzanne M, Akeson, Mark, Brooks, Angela N, Carpenter, Susan
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 28-05-2021; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: 5' Untranslated Regions; Alternative Splicing; Animals; Annotations; Bone marrow; Cells, Cultured; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Exons; Gene Expression Profiling; Gene regulation; Genes; Genetics and Genomics; Health aspects; human; Humans; Immune response; Immune system; Immunity, Innate - genetics; Immunology and Inflammation; Infections; Inflammation; Inflammation - genetics; Inflammation - immunology; Inflammation - metabolism; Inflammatory diseases; Innate immunity; Iron; Isoforms; Listeria; Macrophages; Macrophages - immunology; Macrophages - metabolism; Mice; Pathogens; Promoter Regions, Genetic; Regulatory sequences; RNA; Salmonella; splicing; Transcription; Transcriptome; Transcriptomes; mouse; genetics; inflammation; genomics; splicing; Macrophages; human; immunology
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.69431

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,
. We show that this unannotated AFE isoform of
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
.