1. Genetics and Genomics
  2. Immunology and Inflammation
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Inflammation drives alternative first exon usage to regulate immune genes including a novel iron regulated isoform of Aim2

Research Article
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Cite this article as: eLife 2021;10:e69431 doi: 10.7554/eLife.69431

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.

The following previously published data sets were used

Article and author information

Author details

  1. Elektra Kantzari Robinson

    Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, United States
    Competing interests
    No competing interests declared.
  2. Pratibha Jagannatha

    Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0257-3139
  3. Sergio Covarrubias

    Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, United States
    Competing interests
    No competing interests declared.
  4. Matthew Cattle

    Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, United States
    Competing interests
    No competing interests declared.
  5. Valeriya Smaliy

    Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, United States
    Competing interests
    No competing interests declared.
  6. Rojin Safavi

    Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, United States
    Competing interests
    No competing interests declared.
  7. Barbara Shapleigh

    Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, United States
    Competing interests
    No competing interests declared.
  8. Robin Abu-Shumays

    Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, United States
    Competing interests
    No competing interests declared.
  9. Miten Jain

    Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, United States
    Competing interests
    No competing interests declared.
  10. Suzanne M Cloonan

    Division of Pulmonary and Critical Care Medicine, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, United States
    Competing interests
    No competing interests declared.
  11. Mark Akeson

    Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, United States
    Competing interests
    Mark Akeson, holds options in Oxford Nanopore Technologies (ONT). MA is a paid consultant to ONT received reimbursement for travel, accommodation and conference fees to speak at events organized by ONT. MA is an inventor on 11 UC patents licensed to ONT (6,267,872, 6,465,193, 6,746,594, 6,936,433, 7,060,50, 8,500,982, 8,679,747, 9,481,908, 9,797,013, 10,059,988, and 10,081,835). MA received research funding from ONT..
  12. Angela N Brooks

    Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, United States
    For correspondence
    anbrooks@ucsc.edu
    Competing interests
    Angela N Brooks, received reimbursement for travel, accommodation and conference fees to speak at events organized by Oxford Nanopore Technologies (ONT)..
  13. Susan Carpenter

    Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, United States
    For correspondence
    sucarpen@ucsc.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1427-3897

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.

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).

Reviewing Editor

  1. Timothy W Nilsen, Case Western Reserve University, United States

Publication history

  1. Received: April 15, 2021
  2. Accepted: May 21, 2021
  3. Accepted Manuscript published: May 28, 2021 (version 1)

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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