Induced-pluripotent stem-derived vascular endothelial cells in Down syndrome
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE203257 | GEO | 2022/05/20
REPOSITORIES: GEO
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Project description:Congenital heart defects (CHDs) are very frequent in children with Down syndrome (DS), the genetic condition caused by trisomy of chromosome 21 (T21). However, the mechanisms by which T21 causes susceptibility to CHDs are poorly understood. Here, using a combination of human induced pluripotent stem cell (iPSC)-based model and Dp(16)1Yey/+ (Dp16) a mouse model of DS, we identified downregulation of canonical Wnt signaling that is caused by increased dosage of interferon (IFN) receptors encoded on chromosome 21 (HSA21) as a causative factor of CHDs in DS. We differentiated human iPSCs derived from individuals with DS as well as CHDs (DS/CHD iPSCs), and controls (control iPSCs) into cardiac cells. We observed that T21 upregulates IFN signaling, downregulates the canonical WNT pathway, and impairs cardiac differentiation. Furthermore, genetic and pharmacological normalization of IFN pathways restored canonical WNT signaling and rescued defects during cardiac differentiation of DS/CHD iPSCs. Strikingly, treatment with an inhibitor of Janus kinase, which is activated by IFN receptor engagement normalized the canonical Wnt pathway and ameliorated CHDs in Dp16 embryos. Our findings provide new mechanisms underlying CHDs in DS, ultimately aiding the development of novel therapeutic strategies.
2023-06-28 | GSE217557 | GEO
Project description:Trisomy of human chromosome 21 (T21) gives rise to Down syndrome, the most frequent life-born autosomal aneuploidy. To enable in vitro analyses of the cellular and moelcular mechanisms leading to the neurological alterations associated with T21, we created and characterized a panel of genomically diverse T21 and euploid induced pluripotent stem cells (iPSCs) from fibroblasts obtained from the Coriell Institute for Biomedical Research, and we then differentiated these iPSCs into neural progenitor cells (NPCs). Microarray transcriptomic analyses were performed on this panel of fibroblasts, iPSCs, and NPCs, identifying genes and pathways that were altered in T21 lines relative to euploid as well as genes and pathways in NPCs that showed inter-individual variability.
2024-11-06 | GSE273850 | GEO
Project description:Genome-wide comparison of trisomy 21 iPSCs and derived isogenic disomy 21 iPSCs.
| PRJNA169328 | ENA
Project description:We generated human induced pluripotent stem cells (iPSCs) from trisomy 21 (T21) and euploid patient tissues with and without GATA1 mutations causing exclusive expression of truncated GATA1, termed GATA1short (GATA1s). Transcriptome analysis comparing expression levels of genes in GATA1s vs. wtGATA1-expressing progenitors demonstrated that GATA1s impairs erythropoiesis and enhances megakaryopoiesis and myelopoiesis in both T21 and euploid contexts in the iPSC-model system.
2015-01-26 | GSE36787 | GEO
Project description:We utilized human derived induced pluripotent stem cells (iPSCs) and iPSC derived neural progenitor cells (NPCs) from individuals with Down syndrome and sex matched controls to interrogate the cell type consequences of trisomy 21 (T21). We report the consequences of T21 on the spatial chromatin organization (Hi-C), lamina-associated domains (ChIP-seq), chromatin state (ATAC-seq), and transcriptome (RNA-seq) in an isogenic pair (euploid: Iso-E and trisomic: Iso-T cells derived from the same individual), pair of male individuals with euploid (Ma-E) and trisomic (Ma-T), pair of female individuals with euploid (Fe-E) and trisomic (Fe-T). Our findings show that T21 induces chromosomal introversion, disrupts lamina-associated domains (LADs) and alters the genome-wide chromatin-accessibility of NPCs but not iPSCs. While the overall organization of A/B compartments and location of TAD-boundaries are conserved in NPCs harboring T21, we observe loss of chromatin-accessibility within the A-compartment that is associated with transcriptional downregulation, and increased long-range chromatin interactions in the B-compartment that is associated with transcriptional upregulation. We find that these architectural changes are similar to those observed in senescent cells, and our transcriptional analysis confirms that differentially expressed genes (DEGs) identified in NPCs harboring T21 are highly correlated with DEGs identified in oxidative stress induced senescent cells. Finally, we demonstrate that the senolytic drug combination of dasatinib and quercetin alleviates the genome-wide transcriptional disruption, as well as deficits in cellular migration and proliferation observed in NPCs harboring T21.
2021-10-11 | GSE185192 | GEO
Project description:Human Trisomy 21 (T21), which causes Down Syndrome (DS), is the most common known cause of intellectual disability. However, the molecular basis for DS phenotypic variability remains poorly understood. Here we used SWATH mass spectrometry (SWATH-MS) to quantify protein abundance and protein turnover in fibroblasts from a monozygotic twin pair discordant for T21, and to profile protein expression in 11 unrelated DS individuals and age-matched controls. The integration of the steady state and turnover proteomic data sets with transcript profiles indicated that protein-specific degradation of members of stoichiometric complexes presents a major determinant of T21 gene dosage outcome, a primary effect that was not apparent from genomic data. The data also reveal that T21 results in extensive proteome remodeling similarly affecting proteins encoded by all chromosomes. Finally, we found broad, organelle-specific posttranscriptional effects such as significant down-regulation of the mitochondrial proteome contributing DS hallmarks and variability.
2017-11-01 | PXD004880 | Pride
Project description:We generated human induced pluripotent stem cells (iPSCs) from trisomy 21 (T21) and euploid patient tissues with and without GATA1 mutations causing exclusive expression of truncated GATA1, termed GATA1short (GATA1s). Transcriptome analysis comparing expression levels of genes in GATA1s vs. wtGATA1-expressing progenitors demonstrated that GATA1s impairs erythropoiesis and enhances megakaryopoiesis and myelopoiesis in both T21 and euploid contexts in the iPSC-model system. We analyzed the transcriptome of (i) T21 iPSC-derived heamtopoietic progenitors expressing wtGATA1 (6 replicates) or GATA1s (3 replicates), as well as of (ii) euploid iPSC-derived progenitors expressing wtGATA1 (2 replicates) or GATA1s (2 replicates).
2015-01-26 | E-GEOD-36787 | biostudies-arrayexpress
Project description:Children with trisomy 21 (T21) are highly predisposed to acute myeloid leukemia, which is preceded by a pre-leukemic transient abnormal myelopoiesis driven by truncating mutations in GATA1 (GATA1s). We investigated gene expression profiles in T21 and isogenic euploid hematopoietic progenitor cells (HPCs) derived from human induced pluripotent stem cells (iPSCs), in combination GATA1s and STAG2 mutations associated with T21 myeloid leukemia. We identified upregulation of interferon alpha/gamma responses and ribosome subunit pathways in gene set enrichment analysis in T21 versus euploid CD45+ hematopoietic cells, whereas pathways regulating genome integrity including mitotic spindle and G2/M checkpoint were downregulated. GATA1s in T21 cells led to downregulation of heme metabolism and apoptosis pathways as well as a further significant increase in the average expression of genes on chromosome 21. These results suggest that T21 and GATA1s mutations cooperate to disrupt normal HPC functions and cause myeloid lineage skewing.
2024-01-29 | GSE238115 | GEO
Project description:Trisomy 21 (T21) is the most frequent genetic cause of cognitive impairment. To assess the perturbations of gene expression in T21, and to eliminate the noise of the genomic variability, we studied the transcriptome of fetal fibroblasts from a pair of monozygotic twins discordant for T21. Here we show that the differential expression between the twins is organized in domains along all chromosomes that are either up- or downregulated. These gene expression dysregulation domains (GEDDs) can be defined by the expression level of their gene content, and are well conserved in induced pluripotent stem cells derived from the twins’ fibroblasts. Comparison of the transcriptome of the Ts65Dn mouse model of DS and wild-type, also showed GEDDs along the mouse chromosomes that were syntenic in human. The GEDDs correlate with the lamina-associated (LADs) and replication domains of mammalian cells. The overall LADs position was not altered in trisomic cells. However, the H3K4me3 profile of the trisomic fibroblasts was modified and accurately followed the GEDD pattern. These results suggest that the nuclear compartments of trisomic cells undergo modifications of the chromatin environment influencing the overall transcriptome and that GEDDs may therefore contribute to some T21 phenotypes. Reduced representation bisulfite sequencing in monozygotic twins discordant for trisomy 21
2014-04-08 | E-GEOD-55505 | biostudies-arrayexpress
Project description:Trisomy 21 (T21) is the most frequent genetic cause of cognitive impairment. To assess the perturbations of gene expression in T21, and to eliminate the noise of the genomic variability, we studied the transcriptome of fetal fibroblasts from a pair of monozygotic twins discordant for T21. Here we show that the differential expression between the twins is organized in domains along all chromosomes that are either up- or downregulated. These gene expression dysregulation domains (GEDDs) can be defined by the expression level of their gene content, and are well conserved in induced pluripotent stem cells derived from the twins’ fibroblasts. Comparison of the transcriptome of the Ts65Dn mouse model of DS and wild-type, also showed GEDDs along the mouse chromosomes that were syntenic in human. The GEDDs correlate with the lamina-associated (LADs) and replication domains of mammalian cells. The overall LADs position was not altered in trisomic cells. However, the H3K4me3 profile of the trisomic fibroblasts was modified and accurately followed the GEDD pattern. These results suggest that the nuclear compartments of trisomic cells undergo modifications of the chromatin environment influencing the overall transcriptome and that GEDDs may therefore contribute to some T21 phenotypes. H3K4me3 ChIP-Seq profiling of monozygotic twins discordant for trisomy 21.
2014-04-08 | E-GEOD-55506 | biostudies-arrayexpress