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.

Data availability

The following data sets were generated

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.

Reviewing Editor

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

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.

Version 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

  • 9,283
    views
  • 1,461
    downloads
  • 217
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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)

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

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

  1. Kelly D Sullivan
  2. Hannah C Lewis
  3. Amanda A Hill
  4. Ahwan Pandey
  5. Leisa P Jackson
  6. Joseph M Cabral
  7. Keith P Smith
  8. L Alexander Liggett
  9. Eliana B Gomez
  10. Matthew D Galbraith
  11. James DeGregori
  12. Joaquín M Espinosa
(2016)
Trisomy 21 consistently activates the interferon response
eLife 5:e16220.
https://doi.org/10.7554/eLife.16220

Share this article

https://doi.org/10.7554/eLife.16220

Further reading

    1. Chromosomes and Gene Expression
    2. Developmental Biology
    F Javier DeHaro-Arbona, Charalambos Roussos ... Sarah Bray
    Research Article

    Developmental programming involves the accurate conversion of signalling levels and dynamics to transcriptional outputs. The transcriptional relay in the Notch pathway relies on nuclear complexes containing the co-activator Mastermind (Mam). By tracking these complexes in real time, we reveal that they promote the formation of a dynamic transcription hub in Notch ON nuclei which concentrates key factors including the Mediator CDK module. The composition of the hub is labile and persists after Notch withdrawal conferring a memory that enables rapid reformation. Surprisingly, only a third of Notch ON hubs progress to a state with nascent transcription, which correlates with polymerase II and core Mediator recruitment. This probability is increased by a second signal. The discovery that target-gene transcription is probabilistic has far-reaching implications because it implies that stochastic differences in Notch pathway output can arise downstream of receptor activation.

    1. Chromosomes and Gene Expression
    Rupam Choudhury, Anuroop Venkateswaran Venkatasubramani ... Axel Imhof
    Research Article

    Eukaryotic chromatin is organized into functional domains, that are characterized by distinct proteomic compositions and specific nuclear positions. In contrast to cellular organelles surrounded by lipid membranes, the composition of distinct chromatin domains is rather ill described and highly dynamic. To gain molecular insight into these domains and explore their composition, we developed an antibody-based proximity-biotinylation method targeting the RNA and proteins constituents. The method that we termed Antibody-Mediated-Proximity-Labelling-coupled to Mass Spectrometry (AMPL-MS) does not require the expression of fusion proteins and therefore constitutes a versatile and very sensitive method to characterize the composition of chromatin domains based on specific signature proteins or histone modifications. To demonstrate the utility of our approach we used AMPL-MS to characterize the molecular features of the chromocenter as well as the chromosome territory containing the hyperactive X-chromosome in Drosophila. This analysis identified a number of known RNA binding proteins in proximity of the hyperactive X and the centromere, supporting the accuracy of our method. In addition, it enabled us to characterize the role of RNA in the formation of these nuclear bodies. Furthermore, our method identified a new set of RNA molecules associated with the Drosophila centromere. Characterization of these novel molecules suggested the formation of R-loops in centromeres, which we validated using a novel probe for R-loops in Drosophila. Taken together, AMPL-MS improves the selectivity and specificity of proximity ligation allowing for novel discoveries of weak protein-RNA interactions in biologically diverse domains.