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.
Sequencing data have been deposited in GEO under accession codes GSE141754.
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- Angela N Brooks
- Mark Akeson
- Susan Carpenter
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: All animal work was carried out in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The protocol was approved by the Institutional Animal Care and Use Committee at the University of California Santa Cruz (Protocol number CARPS1810).
- Timothy W Nilsen, Case Western Reserve University, United States
- Received: April 15, 2021
- Accepted: May 21, 2021
- Accepted Manuscript published: May 28, 2021 (version 1)
© 2021, Robinson et al.
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