Year-end Sale % OFF 
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.
Highlights
Trisomy 21 (T21) is the most common chromosomal abnormality in the human population, occurring in approximately 1 in 700 live births (Alexander et al, 2016)
We observed an uncharacteristic spike of differentially expressed genes (DEGs) at ~1.5-fold overexpression in T21 cells on a volcano plot, consistent with many chr21 genes being overexpressed solely due to increased gene dosage (Figure 1B)
We report here that T21 leads to consistent activation of the IFN pathway
Summary
Trisomy 21 (T21) is the most common chromosomal abnormality in the human population, occurring in approximately 1 in 700 live births (Alexander et al, 2016). The extra copy of chromosome 21 (chr21) impacts human development in diverse ways across every major organ system, causing the condition known as Down syndrome (DS). One of the most intriguing aspects of T21 is that it causes an altered disease spectrum in the population with DS, protecting these individuals from some diseases (e.g. solid tumors, hypertension), while strongly predisposing them to others (e.g. Alzheimer’s disease, leukemia, autoimmune disorders) (Alexander et al, 2016; Sobey et al, 2015; Bratman et al, 2014; Roberts and Izraeli, 2014; Anwar et al, 1998; Malinge et al, 2013; Hasle et al, 2016). Despite many years of study, the molecular, cellular, and physiological
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
