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Trisomy 21 activates the kynurenine pathway via increased dosage of interferon receptors.

ABSTRACT: Trisomy 21 (T21) causes Down syndrome (DS), affecting immune and neurological function by ill-defined mechanisms. Here we report a large metabolomics study of plasma and cerebrospinal fluid, showing in independent cohorts that people with DS produce elevated levels of kynurenine and quinolinic acid, two tryptophan catabolites with potent immunosuppressive and neurotoxic properties, respectively. Immune cells of people with DS overexpress IDO1, the rate-limiting enzyme in the kynurenine pathway (KP) and a known interferon (IFN)-stimulated gene. Furthermore, the levels of IFN-inducible cytokines positively correlate with KP dysregulation. Using metabolic tracing assays, we show that overexpression of IFN receptors encoded on chromosome 21 contribute to enhanced IFN stimulation, thereby causing IDO1 overexpression and kynurenine overproduction in cells with T21. Finally, a mouse model of DS carrying triplication of IFN receptors exhibits KP dysregulation. Together, our results reveal a mechanism by which T21 could drive immunosuppression and neurotoxicity in DS.

SUBMITTER: Powers RK

PROVIDER: S-EPMC6800452 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Trisomy 21 consistently activates the interferon response.

Project description: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.

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Trisomy 21 consistently activates the interferon response

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2016-07-29 | E-GEOD-79843 | biostudies-arrayexpress

Trisomy 21 consistently activates the interferon response

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Project description:Down's syndrome is a common disorder with enormous medical and social costs, caused by trisomy for chromosome 21. We tested the concept that gene imbalance across an extra chromosome can be de facto corrected by manipulating a single gene, XIST (the X-inactivation gene). Using genome editing with zinc finger nucleases, we inserted a large, inducible XIST transgene into the DYRK1A locus on chromosome 21, in Down's syndrome pluripotent stem cells. The XIST non-coding RNA coats chromosome 21 and triggers stable heterochromatin modifications, chromosome-wide transcriptional silencing and DNA methylation to form a 'chromosome 21 Barr body'. This provides a model to study human chromosome inactivation and creates a system to investigate genomic expression changes and cellular pathologies of trisomy 21, free from genetic and epigenetic noise. Notably, deficits in proliferation and neural rosette formation are rapidly reversed upon silencing one chromosome 21. Successful trisomy silencing in vitro also surmounts the major first step towards potential development of 'chromosome therapy'.

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Project description:Trisomy 21 consistently activates the interferon response

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Translating Dosage Compensation to Trisomy 21

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Translating Dosage Compensation to Trisomy 21

Project description:Down syndrome is a common disorder with enormous medical and social costs, caused by trisomy for Chr21. We tested the concept that gene imbalance across an extra chromosome can be de facto corrected in DS patient stem cells by manipulating a single gene, XIST. Using zinc finger nucleases, we targeted a large, inducible XIST transgene into the Chr21 DYRK1A locus, in DS pluripotent stem cells. XIST RNA coats Chr21 and triggers stable heterochromatin modifications, chromosome-wide transcriptional silencing and DNA methylation to form a M-bM-^@M-^\Chr21 Barr Body.M-bM-^@M-^] This provides a model to study human chromosome inactivation and creates a system to investigate genomic expression changes and cellular pathologies of trisomy 21, free from genetic and epigenetic noise. In this study, we used microarrays to understand the genome-wide impacts of inducible XIST expression on Chr21 in trisomy 21 human iPS cell lines, and to evaluate the extent of Chr21 silencing trisomic samples versus a disomic male iPS cell line. Three independently targeted subclones plus the parental Chr21 trisomic (non-targeted) iPS cell line were grown M-BM-1 doxycycline (2 M-BM-5g/ml) for 22 d. Normal male iPS line was also cultured for 22 d and total RNA was extracted with a High Pure RNA extraction kit (Roche) in triplicate for each, processed with a Gene Chip 3M-bM-^@M-^Y IVT Express Kit (Affymetrix), and hybridized to Affymetrix human gene expression PrimeView arrays. Array normalization was performed with Affymetrix Expression Console Software with Robust Multichip Analysis (RMA). Probesets with the top 60% of signal values were considered present and M-bM-^@M-^\expressedM-bM-^@M-^] and were used for all further analysis. In total 9 RNA samples were prepared in triplicate for a total of 27 arrays.

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Epigenetic-genetic chromosome dosage approach for fetal trisomy 21 detection using an autosomal genetic reference marker.

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