Trisomy 21 human iPSC derived interneuron progenitors
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE201523 | GEO | 2022/07/18
REPOSITORIES: GEO
Similar Datasets
Project description:Trisomy 21 human iPSC derived interneuron progenitors
| PRJNA832126 | ENA
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
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.
2013-07-09 | GSE48611 | GEO
Project description:Gene expression was measured in trisomy 21 and trisomy 13 human fetal samples. For TS21, regions assayed were cerebrum, cerebellum, heart, and cerebrum-derived astrocyte cell lines. Keywords = trisomy 21 Keywords = Down syndrome Keywords = aneuploidy Keywords = brain Keywords = heart Keywords = trisomy 13 Keywords: other
2005-05-10 | GSE1397 | GEO
Project description:To date, a universal biomarker panel with a potential to predict high-risk pregnancies or adverse pregnancy outcome does not exist. Transcriptomic approach, a measure of gene expression levels across the genome, is a powerful tool to capture differentially expressed genes (DEG) in various conditions, including human trisomy of chromosome 21 (Ts21). DEG can be used to design a biomarker set as a diagnostic-predictive tool for various conditions of heterogeneous aetiology in a prenatal setting. In the search of novel biomarker set to predict high-risk pregnancies, we performed global expression profiling to find DEG in Ts21 used as a model. Subsequently we performed targeted validation and diagnostic performance evaluation on a larger group of case and control samples. Initially, transcriptomic profiles of 10 cultivated amniocyte samples with Ts21 and 9 with normal euploid constitution were determined using Agilent 4x44K expression microarrays. DEG were discovered using linear regression modelling implemented in limma package. Datasets from Ts21 transcriptomic studies available at GEO repository were incorporated to select our preliminary top DEG. Subsequently, selected top DEG were validated using RT-PCR quantification on independent sample of 16 cases with Ts21 and 32 controls, as well as new datasets from previously performed expression studies in Ts21. The classification was performed using support vector machine classification kernel and evaluated using leave-one-out cross validation approach.
2013-06-19 | GSE48051 | GEO
Project description:To date, a universal biomarker panel with a potential to predict high-risk pregnancies or adverse pregnancy outcome does not exist. Transcriptomic approach, a measure of gene expression levels across the genome, is a powerful tool to capture differentially expressed genes (DEG) in various conditions, including human trisomy of chromosome 21 (Ts21). DEG can be used to design a biomarker set as a diagnostic-predictive tool for various conditions of heterogeneous aetiology in a prenatal setting. In the search of novel biomarker set to predict high-risk pregnancies, we performed global expression profiling to find DEG in Ts21 used as a model. Subsequently we performed targeted validation and diagnostic performance evaluation on a larger group of case and control samples. Initially, transcriptomic profiles of 10 cultivated amniocyte samples with Ts21 and 9 with normal euploid constitution were determined using Agilent 4x44K expression microarrays. DEG were discovered using linear regression modelling implemented in limma package. Datasets from Ts21 transcriptomic studies available at GEO repository were incorporated to select our preliminary top DEG. Subsequently, selected top DEG were validated using RT-PCR quantification on independent sample of 16 cases with Ts21 and 32 controls, as well as new datasets from previously performed expression studies in Ts21. The classification was performed using support vector machine classification kernel and evaluated using leave-one-out cross validation approach. Transcriptomic profiles of 10 cultivated amniocyte samples with Ts21 and 9 with normal euploid constitution were determined using Agilent 4x44K expression microarrays.
2013-06-19 | E-GEOD-48051 | biostudies-arrayexpress
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.
2012-10-23 | GSE38931 | GEO
Project description:Patients with Down syndrome (DS, trisomy 21, T21) are at increased risk of transient abnormal myelopoiesis (TAM) and acute megakaryoblastic leukemia (ML-DS). Both TAM and ML-DS require prenatal somatic mutations in GATA1, resulting in the truncated isoform GATA1s. The mechanism by which individual chromosome 21 (HSA21) genes synergize with GATA1s for leukemic transformation is challenging to study, in part due to limited human cell models with wild type GATA1 or GATA1s. HSA21-encoded DYRK1A is overexpressed in ML-DS and may be a therapeutic target. To determine how DYRK1A influences hematopoiesis in concert with GATA1s, we used gene editing to disrupt all 3 alleles of DYRK1A in isogenic T21 induced pluripotent stem cells (iPSCs) with and without the GATA1s mutation. Unexpectedly, hematopoietic differentiation revealed that DYRK1A loss combined with GATA1s leads to increased megakaryocyte proliferation and decreased maturation. This proliferative phenotype was associated with upregulation of D-type cyclins and hyperphosphorylation of Rb to allow E2F release and de-repression of its downstream targets. Notably, DYRK1A loss had no effect in T21/wtGATA1 megakaryocytes. These surprising results suggest that increased DYRK1A expression may be protective against TAM and ML-DS and that DYRK1A inhibition would not be a therapeutic option for GATA1s-associated leukemias.
2023-11-04 | GSE243702 | 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 (DS) is caused by an extra copy of chromosome 21. We are characterizing protein changes in human skin fibroblasts. We propose to study corresponding changes at the DNA level (by SNP analysis) and the RNA level (using Affymetrix chips). These studies will detail transcriptional and translational regulation in trisomy. The Specific Aim is to obtain data on RNA transcript levels using Affymetrix expression arrays in a group of trisomy 21 and euploid fibroblast cell lines. In parallel, we will acquire SNP data to determine both genotype (call) and copy number changes for trisomic samples. The results will allow us to identify the patterns of change in a trisomic chromosome (relative to control). [1] We hypothesize that in genomic DNA samples derived from trisomy 21 (TS21) fibroblasts there will be an increased copy number on chr21 with additional microdeletions and microdeletions. [2] We hypothesize that the RNA transcripts derived from chr21 will be elevated relative to euploid controls. [3] We hypothesize that altered RNA transcript levels will be significantly correlated with altered protein levels from these same fibroblast cell lines. The experimental design is as follows. All samples are from deidentified individuals and were obtained from the Brain and Tissue Bank for Developmental Disorders at the University of Maryland, with Johns Hopkins IRB approval.[1] There are five trisomy 21 samples and five euploid samples (total n=10). Fibroblasts were grown in culture to comparable confluency and passage number. Cells were harvested. Total RNA was isolated with a Qiagen kit. The quantity and purity of the RNA was confirmed by spectrophotometry and by electrophoresing an aliquot on a 1% agarose gel. Approximately 10 micrograms of total RNA will be sent to TGen on dry ice for analysis on Affymetrix U133 PlusTwo arrays. Data analysis will be with Affymetrix and Partek software.
2008-06-16 | E-GEOD-9762 | biostudies-arrayexpress