1. Chromosomes and Gene Expression
  2. Human Biology and Medicine
Download icon

Trisomy 21 consistently activates the interferon response

Short Report
  • Cited 46
  • Views 6,077
  • Annotations
Cite this article as: eLife 2016;5:e16220 doi: 10.7554/eLife.16220

Abstract

Although it is clear that trisomy 21 causes Down syndrome, the molecular events acting downstream of the trisomy remain ill defined. Using complementary genomics analyses, we identified the interferon pathway as the major signaling cascade consistently activated by trisomy 21 in human cells. Transcriptome analysis revealed that trisomy 21 activates the interferon transcriptional response in fibroblast and lymphoblastoid cell lines, as well as circulating monocytes and T cells. Trisomy 21 cells show increased induction of interferon-stimulated genes and decreased expression of ribosomal proteins and translation factors. An shRNA screen determined that the interferon-activated kinases JAK1 and TYK2 suppress proliferation of trisomy 21 fibroblasts, and this defect is rescued by pharmacological JAK inhibition. Therefore, we propose that interferon activation, likely via increased gene dosage of the four interferon receptors encoded on chromosome 21, contributes to many of the clinical impacts of trisomy 21, and that interferon antagonists could have therapeutic benefits.

Article and author information

Author details

  1. Kelly D Sullivan

    Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, United States
    For correspondence
    kelly.d.sullivan@ucdenver.edu
    Competing interests
    No competing interests declared.
  2. Hannah C Lewis

    Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, United States
    Competing interests
    No competing interests declared.
  3. Amanda A Hill

    Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, United States
    Competing interests
    No competing interests declared.
  4. Ahwan Pandey

    Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, United States
    Competing interests
    No competing interests declared.
  5. Leisa P Jackson

    Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, United States
    Competing interests
    No competing interests declared.
  6. Joseph M Cabral

    Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, United States
    Competing interests
    No competing interests declared.
  7. Keith P Smith

    Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, United States
    Competing interests
    No competing interests declared.
  8. L Alexander Liggett

    Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, United States
    Competing interests
    No competing interests declared.
  9. Eliana B Gomez

    Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, United States
    Competing interests
    No competing interests declared.
  10. Matthew D Galbraith

    Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, United States
    Competing interests
    No competing interests declared.
  11. James DeGregori

    Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, United States
    Competing interests
    No competing interests declared.
  12. Joaquín M Espinosa

    Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, United States
    For correspondence
    joaquin.espinosa@ucdenver.edu
    Competing interests
    Joaquín M Espinosa, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9048-1941

Funding

Linda Crnic Institute for Down Syndrome

  • Joaquín M Espinosa

Howard Hughes Medical Institute

  • Joaquín M Espinosa

National Institutes of Health (R01CA117907, P30CA046934-27)

  • Joaquín M Espinosa

National Science Foundation (MCB-1243522)

  • Joaquín M Espinosa

Anna and John J. Sie Foundation

  • Joaquín M Espinosa

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of the University of Colorado. The protocol was approved by the University of Colorado IACUC (Protocol Number: B-41413(04)1E).

Human subjects: All individuals in this study were consented on Colorado Multiple Institutional Review Board (COMIRB)-approved protocols (Protocol Numbers: 11-1790 or 15-1774) and samples collected and processed as describe in the Materials and Methods.

Reviewing Editor

  1. Christopher K Glass, University of California, San Diego, United States

Publication history

  1. Received: March 19, 2016
  2. Accepted: July 28, 2016
  3. Accepted Manuscript published: July 29, 2016 (version 1)
  4. Version of Record published: September 6, 2016 (version 2)

Copyright

© 2016, Sullivan 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.

Metrics

  • 6,077
    Page views
  • 1,053
    Downloads
  • 46
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Chromosomes and Gene Expression
    2. Genetics and Genomics
    Nealia CM House et al.
    Research Article
    1. Chromosomes and Gene Expression
    2. Genetics and Genomics
    Elias T Friman et al.
    Research Article