Identification of dysregulated genes in lymphocytes from children with Down syndrome
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE7464 | GEO | 2007/04/25
SECONDARY ACCESSION(S): PRJNA100259
REPOSITORIES: GEO
Similar Datasets
Project description:The aim of this study was to analyze global changes of gene expression in lymphocytes from children with trisomy 21 by means of the serial analysis of gene expression (SAGE) methodology. Comparison between DS and normal profiles revealed that most of the transcripts were expressed at similar levels. Among the 242 significantly differentially expressed SAGE tags, many of them corresponded to genes involved in transcription, RNA processing, signaling, immune response and lipid metabolism. Our results indicate that trisomy 21 induces a modest dysregulation of disomic genes that may be related to the immunological perturbations seen in DS. Keywords: SAGE analysis in normal and Down syndrome lymphocytes Lymphocytes were isolated from peripheral blood of normal and karyotypically confirmed full trisomy 21 children. Children included in the study, ranging in age from 1-4 years, were self reported as free of chronic or acute infections. Total RNA was isolated with TRIzol reagent (Invitrogen). The SAGE libraries were constructed using pooled RNA from six DS children (DS library) and six normal children (control group) to eliminate any individual variation. SAGE was performed by means of the I-SAGE kit (Invitrogen) following the manufacturer’s instructions.
2007-04-25 | E-GEOD-7464 | biostudies-arrayexpress
Project description:Trisomy 21- driven transcriptional alterations in human thymus were characterized through gene coexpression network (GCN) and microRNA-target analyses. We used whole thymic tissue (corticomedullar sections) - obtained at heart surgery from Down syndrome (DS) and karyotipically normal individuals (CT) - and a network-based approach for GCN analysis that allows the identification of modular transcriptional repertoires and the interactions between all the system’s constituents through community detection. Changes in the degree of connections observed for hierarchically important hubs/genes in CT and DS gene networks corresponded to sub-network changes, i.e. module (communities) changes. Distinct communities of highly interconnected gene sets were topologically identified for DS and CT networks. The role of microRNAs in modulating the expression of highly connected genes in CT and DS was revealed through microRNA-target analysis. Trisomy 21 gene dysregulation in thymus may well be depicted as the breakdown and altered reorganization of functional modules.
2017-02-09 | GSE69210 | GEO
Project description:Trisomy 21- driven transcriptional alterations in human thymus were characterized through gene coexpression network (GCN) and microRNA-target analyses. We used whole thymic tissue (corticomedullar sections) - obtained at heart surgery from Down syndrome (DS) and karyotipically normal individuals (CT) - and a network-based approach for GCN analysis that allows the identification of modular transcriptional repertoires and the interactions between all the system’s constituents through community detection. Changes in the degree of connections observed for hierarchically important hubs/genes in CT and DS gene networks corresponded to sub-network changes, i.e. module (communities) changes. Distinct communities of highly interconnected gene sets were topologically identified for DS and CT networks. The role of microRNAs in modulating the expression of highly connected genes in CT and DS was revealed through microRNA-target analysis. Trisomy 21 gene dysregulation in thymus may well be depicted as the breakdown and altered reorganization of transcriptional modules.
2017-02-09 | GSE70573 | GEO
Project description:Down syndrome (DS), caused by an extra copy of chromosome 21, affects 1 in 750 live births and is characterised by cognitive impairment and a constellation of congenital defects. Currently, little is known about the molecular pathogenesis and no direct genotype-phenotype relationship has yet been confirmed. Since DS amniocytes are expected to have a distinct biological behaviour compared to normal amniocytes, we hypothesise that relative quantification of proteins produced from trisomy and euploid (chromosomally normal) amniocytes will reveal dysregulated molecular pathways. Chromosomally normal- and Trisomy 21-amniocytes were quantitatively analyzed by using Stable Isotope Labeling of Amino acids in Cell culture and tandem mass spectrometry. The most extensive proteome of amniocytes and amniotic fluid has been generated and differentially expressed proteins from amniocytes with Trisomy 21 revealed molecular pathways that seem to be most significantly affected by the presence of an extra copy of chromosome 21. Mass spectra were analyzed using Mascot (version 2.2, Matrix Science), executing a spectral search against a concatenated International Protein Index (IPI) human protein database (version 3.54 containing 39,925 entries) and a decoy database. Parameters included: trypsin enzyme specificity, SILAC double measurements of Lys6 and Arg8, 1 missed cleavage, minimum peptide length of 7 amino acids, minimum of 1 unique peptide, top 6 MS/MS peaks per 100 Da, peptide mass tolerance of 20 ppm for precursor ion and MS/MS tolerance of 0.5 Da. Oxidation of methionine and N-terminal protein acetylation for variable modifications and cysteine caramidomethylation for fixed modification. All entries were filtered using a false positive rate of 1% both at the peptide and protein levels, and false positives were removed. Quantification via normalised H/L ratios was based on minimum of 3 peptide ratio counts. Protein group entries with a normalised ratio significance B score of =< 0.05 or significance A score of =< 0.05 were retained for further analysis.
2013-09-27 | PXD000385 | Pride
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 “Chr21 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. 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.
2013-07-12 | GSE47014 | GEO
Project description:Aneuploidy and structural aberrations affecting chromosome 21 (Hsa21) are the most frequent in cytogentic events in acute myeloid leukemia. However, it remains unclear why leukemic blasts select for amplifications of Hsa21 or parts of it and why children with Down syndrome (i.e. trisomy 21) are at a high risk of developing leukemia. Here, we propose that disequilibrium of the RUNX1 isoforms and resultant RUNX1A dominance are key to trisomy 21-associated leukemogenesis. Using a Hsa21-focussed CRISPR-Cas9 screen, we uncovered a strong and specific RUNX1 dependency in myeloid leukemia associated with Down syndrome (ML-DS). High levels of RUNX1A – as seen in ML-DS – synergized with the pathognomonic Gata1s mutation in ML-DS pathogenesis, an effect that was reversed upon restoration of the normal RUNX1A:RUNX1C equilibrium. Mechanistically, RUNX1A displaces RUNX1C from its endogenous binding sites and recruits the MYC cofactor MAX to induce oncogenic programs and perturb normal differentiation. This presents a therapeutic vulnerability that can be exploited by interfering with MYC:MAX dimerization. Our study highlights the importance of alternative splicing in leukemogenesis, and paves the way for developing specific and targeted therapies for ML-DS as well as for other leukemias with Hsa21 aneuploidy or RUNX1 isoform disequilibrium.
2023-05-10 | PXD030616 | Pride
Project description:Down syndrome (DS), with trisomy of chromosome 21 (HSA21), is the commonest human aneuploidy. Pre-leukemic myeloproliferative changes in DS fetal livers precedes the acquisition of GATA1 mutations, transient myeloproliferative disorder (DS-TMD) and acute megakaryocytic leukemia (DS-AMKL). Trisomy of the Erg gene is required for myeloproliferation in the Ts(1716)65Dn DS mouse model. We demonstrate here that genetic changes due trisomy of Erg lead to lineage priming of primitive and early multipotential progenitor cells in Ts(1716)65Dn mice, excess megakaryocyte-erythroid progenitors, and malignant myeloproliferation. Correlation of gene expression changes caused by Erg trisomy in Ts(1716)65Dn multilineage progenitor cells with those associated with trisomy 21 in human DS HSCs support a role for ERG as a regulator of hematopoietic lineage potential, trisomy of which drives pre-leukemic changes in DS fetal livers that predispose to subsequent DS-TMD and DS-AMKL.
2015-04-15 | E-MTAB-2574 | biostudies-arrayexpress
Project description:This study examines cortical organoids generated from a panel of isogenic trisomic and disomic iPSC lines (subclones) as a model of early fetal brain development in Down syndrome. An initial experiment comparing organoids from one trisomic and one disomic line showed many genome-wide transcriptomic differences and modest differences in cell-type proportions, suggesting there may be a neurodevelopmental phenotype that is due to trisomy of chr 21. To better control for multiple sources of variation, we undertook a highly robust study of ∼1,200 organoids using an expanded panel of six all-isogenic lines, three disomic, and three trisomic. The power of this experimental design was indicated by strong detection of the ∼1.5- fold difference in chr21 genes. However, the numerous expression differences in non-chr21 genes seen in the smaller experiment fell away, and the differences in cell-type representation between lines did not correlate with trisomy 21. Results suggest that the initial smaller experiment picked up differences between small organoid samples and individual isogenic lines, which “averaged out” in the larger panel of isogenic lines. Our results indicate that even when organoid and batch variability are better controlled for, variation between isogenic cell lines (even subclones) may obscure, or be conflated with, subtle neurodevelopmental phenotypes that may be present in ∼2nd trimester DS brain development. Interestingly, despite this variability between organoid batches and lines, and the “fetal stage” of these organoids, an increase in secreted Aβ40 peptide levels—an Alzheimer-related cellular phenotype—was more strongly associated with trisomy 21 status than were neurodevelopmental shifts in cell-type composition.
2023-01-07 | GSE222365 | GEO
Project description:Human trisomies can alter cellular phenotypes and produce congenital abnormalities such as Down Syndrome (DS). Here we have generated induced pluripotent stem cells (iPSCs) from DS fibroblasts, and introduced a TKNEO transgene into one copy of chromosome 21 by gene targeting. When selecting against TKNEO, spontaneous chromosome loss was the most common cause for survival, with a frequency of ~10-4, while point mutations, epigenetic silencing, and TKNEO deletions occurred at lower frequencies in this unbiased comparison of inactivating mutations. Mitotic recombination events resulting in extended loss of heterozygosity were not observed in DS iPSCs. The disomic cells that we derived proliferated faster and produced more endothelia in vivo than their otherwise isogenic trisomic counterparts, but hematopoietic differentiation, pluripotency and survival were statistically unchanged. Our study describes the first targeted removal of a human trisomy, which could prove useful in both clinical and research applications. RNA samples were from two trisomic iPSC clone (C2-4, C3-5) and four derived disomic subclones (C2-4-3, C2-4-4 and C3-5-11, C3-5-13). Duplicate RNA samples from human embyonic stem cells (H1) were included as control.
2012-10-23 | E-GEOD-38931 | biostudies-arrayexpress
Project description:Down syndrome (trisomy 21) is the most common genetic cause of intellectual disability, but the precise molecular mechanisms underlying impaired cognition remain unclear. Elucidation of these mechanisms has been hindered by the lack of a model system that contains full trisomy of chromosome 21 (Ts21) in a human genome that enables normal gene regulation. To overcome this limitation,we created Ts21-induced pluripotent stem cells (iPSCs) from two sets of Ts21 human fibroblasts. One of the fibroblast lines had low level mosaicism for Ts21 and yielded Ts21 iPSCs and an isogenic control that is disomic for human chromosome 21 (HSA21). Differentiation of all Ts21 iPSCs yielded similar numbers of neurons expressingmarkers characteristic of dorsal forebrain neurons that were functionally similar to controls. Expression profiling of Ts21 iPSCs and their neuronal derivatives revealed changes in HSA21 genes consistent with the presence of 50% more genetic material as well as changes in non- HSA21 genes that suggested compensatory responses to oxidative stress. Ts21 neurons displayed reduced synaptic activity, affecting excitatory and inhibitory synapses equally. Thus, Ts21 iPSCs and neurons display unique developmental defects that are consistent with cognitive deficits in individuals with Down syndrome and may enable discovery of the underlying causes of and treatments for this disorder. Three independent RNA samples were collected from Down syndrome (DS) and control iPSCs between passages 24 and 48. Three independent RNA samples were collected from 30 day old neurons differentiated from Down syndrome (DS) and control iPSCs.
2013-07-09 | E-GEOD-48611 | biostudies-arrayexpress