Trisomy 21 consistently activates the interferon response
- University of Colorado School of Medicine, United States
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
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RNAseq from disomic and trisomic Fibroblasts and LymphoblastsPublicly available at NCBI Gene Expression Omnibus (accession no: GSE79843).
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shRNA cassette sequencing from disomic and trisomic fibroblasts cultured in the presence of shRNA kinome library for 14 daysPublicly available at NCBI Gene Expression Omnibus (accession no: GSE79843).
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RNAseq from disomic and trisomic T cells and monocytesPublicly available at NCBI Gene Expression Omnibus (accession no: GSE79843).
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RNAseq from Dp16 and control micePublicly available at NCBI Gene Expression Omnibus (accession no: GSE79843).
Article and author information
Author details
Joaquín M Espinosa
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
- 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
- Received: March 19, 2016
- Accepted: July 28, 2016
- Accepted Manuscript published: July 29, 2016 (version 1)
- 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.
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Trisomy 21 consistently activates the interferon response
eLife 5:e16220.
https://doi.org/10.7554/eLife.16220
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