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Trisomy 21 consistently activates the interferon response

ABSTRACT: This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

ORGANISM(S): Homo sapiens

SUBMITTER: Ahwan Pandey

PROVIDER: E-GEOD-79843 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Trisomy 21 consistently activates the interferon response.

Sullivan Kelly D KD Lewis Hannah C HC Hill Amanda A AA Pandey Ahwan A Jackson Leisa P LP Cabral Joseph M JM Smith Keith P KP Liggett L Alexander LA Gomez Eliana B EB Galbraith Matthew D MD DeGregori James J Espinosa Joaquín M JM

eLife 20160729

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 s ...[more]

PMID: 27472900

Similar Datasets

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.

| S-EPMC5012864 | biostudies-literature

Random-primed mRNA-sequencing transcriptomic dataset for 70 primary human cardiomyocyte cell samples

Project description:Each of 70 cell samples either at the control condition or treated with FDA-approved cancer drugs is sequenced by the single-ended random-primed mRNA-sequencing method with a read length of 100 base pairs, and a total of 70 raw sequence data files in the FASTQ format are generated. These sequence data files are then analyzed by a high-performance computational pipeline and ranked lists of gene signatures and biological processes related to drug-induced cardiotoxicity are generated for each drug. The raw sequence datasets and the analysis results have been carefully controlled for data quality, and they are made publicly available at the Gene Expression Omnibus (GEO) database repository of NIH. As such, this broad drug-stimulated transcriptomi dataset is valuable for the prediction of drug toxicities and their mitigations.

2020-11-09 | LDS-1587 | LINCS

3'-DGE mRNA-sequencing transcriptomic dataset for 914 primary human cardiomyocyte cell samples

Project description:Each of 914 cell samples either at the control condition or treated with FDA-approved cancer drugs is sequenced by the single-ended 3'-DGE mRNA-sequencing method with a read length of 46 base pairs, and a total of 914 raw sequence data files in the FASTQ format are generated. These sequence data files are then analyzed by a high-performance computational pipeline and ranked lists of gene signatures and biological processes related to drug-induced cardiotoxicity are generated for each drug. The raw sequence datasets and the analysis results have been carefully controlled for data quality, and they are made publicly available at the Gene Expression Omnibus (GEO) database repository of NIH. As such, this broad drug-stimulated transcriptomi dataset is valuable for the prediction of drug toxicities and their mitigations.

2020-11-09 | LDS-1592 | LINCS

shRNA cassette sequencing from disomic and trisomic fibroblasts cultured in the presence of shRNA kinome library for 14 days

Project description:Kinome-wide shRNA screen to identify kinases differentially required for survival of cells disomic and trisomic for chromosome 21 Cells were transduced in triplicate and propagated for 14 days to allow for enrichement or depletion of shRNAs from the population

2016-07-29 | E-GEOD-79840 | biostudies-arrayexpress

Trisomy 21 consistently activates the interferon response

Project description:This SuperSeries is composed of the SubSeries listed below.

2016-07-29 | GSE79843 | GEO

Combining transcriptome and proteome analysis to identify and characterize the RpoS regulon in Pseudomonas fluorescens

Project description:Background: Microorganisms are the major cause of food spoilage during storage, processing and distribution. Pseudomonas fluorescens is a typical spoilage bacterium that contributes to a large extent to the spoilage process of proteinaceous food. RpoS is considered an important global regulator involved in stress survival and virulence in many pathogens. Our previous work revealed that RpoS contributed to the spoilage activities of P. fluorescens by regulating resistance to different stress conditions, extracellular acylated homoserine lactone (AHL) levels, extracellular protease and total volatile basic nitrogen (TVB-N) production. However, RpoS-dependent genes in P. fluorescens remained undefined. Results: RNA-seq transcriptomics analysis combined with quantitative proteomics analysis basing on multiplexed isobaric tandem mass tag (TMT) labeling was performed for the P. fluorescens wild-type strain UK4 and its derivative carrying a rpoS mutation. A total of 375 differentially expressed genes (DEGs) and 212 differentially expressed proteins (DEPs) were identified in these two backgrounds. The DGEs were further verified by qRT-PCR tests, and the genes directly regulated by RpoS were confirmed by 5’-RACE-PCR sequencing. The combining transcriptome and proteome analysis revealed a role of this regulator in several cellular processes, including polysaccharide metabolism, intracellular secretion and extracellular structures, cell well biogenesis, stress responses, ammonia and biogenic amine production, which may contribute to biofilm formation, stress resistance and spoilage activities of P. fluorescens. Moreover, in this work we indeed observed that RpoS contributed to the production of the macrocolony biofilm’s matrix.

2019-11-12 | PXD010845 | Pride

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

Project description: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.

| S-EPMC6800452 | biostudies-literature

ATACseq : role of trisomy 21, GATAs mutation and associated mutations in the development of trisomy 21

Project description:Acute megakaryoblastic leukemia of Down syndrome (DS-AMKL) is a model of clonal evolution from a preleukemic transient myeloproliferative disorder requiring both a trisomy 21 (T21) and a GATA1s mutation to a leukemia driven by additional driver mutations. We modelled this leukemic evolution through stepwise gene editing of GATA1s, SMC3+/- and MPLW515K providing 20 different trisomy or disomy 21 iPSC clones. The CD41+/CD42+ MK were sorted (10 000 to 30 000 cells) and submitted to cell lysis, transposition, and purification steps. The transposed DNA fragments were amplified by PCR 12 times using adapters from the Nextera Index Kit (Illumina). PCR purification was performed using MinElute PCR Purification Kit (Qiagen, 28004) to remove large fragments and remaining primers. Library quality was assessed using an Agilent 2100 Bioanalyzer (Agilent Technologies 5067-4626). Libraries were sequenced using NovaSeq-6000 sequencer (Illumina; 50 bp paired-end reads).

2022-06-15 | E-MTAB-11044 | biostudies-arrayexpress

Trisomy 21 and facial developmental instability.

Project description:The most common live-born human aneuploidy is trisomy 21, which causes Down syndrome (DS). Dosage imbalance of genes on chromosome 21 (Hsa21) affects complex gene-regulatory interactions and alters development to produce a wide range of phenotypes, including characteristic facial dysmorphology. Little is known about how trisomy 21 alters craniofacial morphogenesis to create this characteristic appearance. Proponents of the "amplified developmental instability" hypothesis argue that trisomy 21 causes a generalized genetic imbalance that disrupts evolutionarily conserved developmental pathways by decreasing developmental homeostasis and precision throughout development. Based on this model, we test the hypothesis that DS faces exhibit increased developmental instability relative to euploid individuals. Developmental instability was assessed by a statistical analysis of fluctuating asymmetry. We compared the magnitude and patterns of fluctuating asymmetry among siblings using three-dimensional coordinate locations of 20 anatomic landmarks collected from facial surface reconstructions in four age-matched samples ranging from 4 to 12 years: (1) DS individuals (n?=?55); (2) biological siblings of DS individuals (n?=?55); 3) and 4) two samples of typically developing individuals (n?=?55 for each sample), who are euploid siblings and age-matched to the DS individuals and their euploid siblings (samples 1 and 2). Identification in the DS sample of facial prominences exhibiting increased fluctuating asymmetry during facial morphogenesis provides evidence for increased developmental instability in DS faces. We found the highest developmental instability in facial structures derived from the mandibular prominence and lowest in facial regions derived from the frontal prominence.

| S-EPMC3744194 | biostudies-literature

Translating dosage compensation to trisomy 21.

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'.

| S-EPMC3848249 | biostudies-literature

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