Trisomy 21 consistently activates the interferon response
- PMID: 27472900
- PMCID: PMC5012864
- DOI: 10.7554/eLife.16220
Trisomy 21 consistently activates the interferon response
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.
Keywords: JAK inhibitors; chromosomes; down syndrome; genes; human; human biology; interferon; medicine; mouse; ruxolitinib; trisomy 21.
Conflict of interest statement
JME: Reviewing editor, eLife. The other authors declare that no competing interests exist.
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Signaling a link between interferon and the traits of Down syndrome.Elife. 2016 Sep 6;5:e20196. doi: 10.7554/eLife.20196. Elife. 2016. PMID: 27599162 Free PMC article.
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