title: 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.
authors.affiliation: Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, United States.|Department of Pharmacology, University of Colorado School of Medicine, Aurora, United States.|Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, United States.|Howard Hughes Medical Institute, Chevy Chase, United States.
authors.forename: Kelly D
authors.initials: KD
authors.lastname: Sullivan
authors.affiliation: Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, United States.|Department of Pharmacology, University of Colorado School of Medicine, Aurora, United States.
authors.forename: Hannah C
authors.initials: HC
authors.lastname: Lewis
authors.affiliation: Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, United States.|Department of Pharmacology, University of Colorado School of Medicine, Aurora, United States.
authors.forename: Amanda A
authors.initials: AA
authors.lastname: Hill
authors.affiliation: Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, United States.|Department of Pharmacology, University of Colorado School of Medicine, Aurora, United States.|Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, United States.|Howard Hughes Medical Institute, Chevy Chase, United States.
authors.forename: Ahwan
authors.initials: A
authors.lastname: Pandey
authors.affiliation: Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, United States.|Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, United States.|Howard Hughes Medical Institute, Chevy Chase, United States.
authors.forename: Leisa P
authors.initials: LP
authors.lastname: Jackson
authors.affiliation: Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, United States.|Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, United States.|Howard Hughes Medical Institute, Chevy Chase, United States.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Cabral
authors.affiliation: Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, United States.
authors.forename: Keith P
authors.initials: KP
authors.lastname: Smith
authors.affiliation: Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, United States.|Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, United States.
authors.forename: L Alexander
authors.initials: LA
authors.lastname: Liggett
authors.affiliation: Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, United States.|Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, United States.|Howard Hughes Medical Institute, Chevy Chase, United States.
authors.forename: Eliana B
authors.initials: EB
authors.lastname: Gomez
authors.affiliation: Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, United States.|Department of Pharmacology, University of Colorado School of Medicine, Aurora, United States.|Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, United States.|Howard Hughes Medical Institute, Chevy Chase, United States.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Galbraith
authors.affiliation: Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, United States.|Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, United States.|Department of Pediatrics, University of Colorado School of Medicine, Aurora, United States.|Integrated Department of Immunology, University of Colorado School of Medicine, Aurora, United States.|Section of Hematology, University of Colorado School of Medicine, Aurora, United States.|Department of Medicine, University of Colorado School of Medicine, Aurora, United States.
authors.forename: James
authors.initials: J
authors.lastname: DeGregori
authors.affiliation: Linda Crnic Institute for Down Syndrome, University of Colorado School of Medicine, Aurora, United States.|Department of Pharmacology, University of Colorado School of Medicine, Aurora, United States.|Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, United States.|Howard Hughes Medical Institute, Chevy Chase, United States.
authors.forename: Joaquín M
authors.identifier: 0000-0001-9048-1941
authors.initials: JM
authors.lastname: Espinosa
mesh_terms: D002478:Cells, Cultured; D004314:Down Syndrome / Q000473:pathology*; D005347:Fibroblasts / Q000502:physiology*; D020869:Gene Expression Profiling; D006801:Humans; D007113:Immunity, Innate; D007372:Interferons / Q000378:metabolism*; D009000:Monocytes / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D007372:Interferons
keywords: JAK inhibitors; chromosomes; down syndrome; genes; human; human biology; interferon; medicine; mouse; ruxolitinib; trisomy 21