Inflammation drives alternative first exon usage to regulate immune genes including a novel iron regulated isoform of Aim2
- University of California, Santa Cruz, United States
- Weill Cornell Medicine, United States
Abstract
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.
Data availability
Sequencing data have been deposited in GEO under accession codes GSE141754.
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A Stringent Systems Approach Uncovers Gene-Specific Mechanisms Regulating InflammationNCBI Gene Expression Omnibus, GSE67357.
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A Stringent Systems Approach Uncovers Gene-Specific Mechanisms Regulating InflammationNCBI Gene Expression Omnibus, GSE74191.
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A Stringent Systems Approach Uncovers Gene-Specific Mechanisms Regulating InflammationNCBI Gene Expression Omnibus, GSE67343.
Article and author information
Author details
Pratibha Jagannatha
Funding
NIH Office of the Director (HG010053)
- Angela N Brooks
Oxford Nanopore Technologies (SC20130149)
- Mark Akeson
UCSC Committee on Research (COR)
- Susan Carpenter
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Timothy W Nilsen, Case Western Reserve University, United States
Ethics
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).
Version history
- Received: April 15, 2021
- Accepted: May 21, 2021
- Accepted Manuscript published: May 28, 2021 (version 1)
- Version of Record published: July 6, 2021 (version 2)
Copyright
© 2021, Robinson et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Inflammation drives alternative first exon usage to regulate immune genes including a novel iron regulated isoform of Aim2
eLife 10:e69431.
https://doi.org/10.7554/eLife.69431
Further reading
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