Homo sapiens
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PROVIDER: PRJNA183939 | ENA |
REPOSITORIES: ENA
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Project description:Down syndrome (trisomy 21) is the most common viable chromosomal disorder with intellectual impairment and several other developmental abnormalities. Here, we report the generation and characterization of induced pluripotent stem cells (iPSCs) derived from monozygotic twins discordant for trisomy 21 in order to eliminate the effects of the variability of genomic background. The alterations observed by genetic analysis at the iPSC level and at first approximation in early development illustrate the developmental disease transcriptional signature of Down syndrome. Moreover, we observed an abnormal neural differentiation of Down syndrome iPSCs in vivo when formed teratoma in NOD-SCID mice, and in vitro when differentiated into neuroprogenitors and neurons. These defects were associated with changes in the architecture and density of neurons, astroglial and oligodendroglial cells together with misexpression of genes involved in neurogenesis, lineage specification and differentiation. Furthermore, we provide novel evidence that dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) on chromosome 21 likely contribute to these defects. Importantly, we found that targeting DYRK1A pharmacologically or by shRNA results in a considerable correction of these defects. mRNA-seq profiling of iPS cells (4 euploid and 3 trisomy 21) derived from fibroblasts of monozygotic twins discordant for trisomy 21
2013-12-01 | E-GEOD-52249 | biostudies-arrayexpress
Project description:Down syndrome (trisomy 21) is the most common viable chromosomal disorder with intellectual impairment and several other developmental abnormalities. Here, we report the generation and characterization of induced pluripotent stem cells (iPSCs) derived from monozygotic twins discordant for trisomy 21 in order to eliminate the effects of the variability of genomic background. The alterations observed by genetic analysis at the iPSC level and at first approximation in early development illustrate the developmental disease transcriptional signature of Down syndrome. Moreover, we observed an abnormal neural differentiation of Down syndrome iPSCs in vivo when formed teratoma in NOD-SCID mice, and in vitro when differentiated into neuroprogenitors and neurons. These defects were associated with changes in the architecture and density of neurons, astroglial and oligodendroglial cells together with misexpression of genes involved in neurogenesis, lineage specification and differentiation. Furthermore, we provide novel evidence that dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) on chromosome 21 likely contribute to these defects. Importantly, we found that targeting DYRK1A pharmacologically or by shRNA results in a considerable correction of these defects. aCGH profiling of iPS cells derived from fibroblasts of monozygotic twins discordant for trisomy 21
2013-12-01 | E-GEOD-52250 | biostudies-arrayexpress
Project description:Down syndrome (trisomy 21) is the most common viable chromosomal disorder with intellectual impairment and several other developmental abnormalities. Here, we report the generation and characterization of induced pluripotent stem cells (iPSCs) derived from monozygotic twins discordant for trisomy 21 in order to eliminate the effects of the variability of genomic background. The alterations observed by genetic analysis at the iPSC level and at first approximation in early development illustrate the developmental disease transcriptional signature of Down syndrome. Moreover, we observed an abnormal neural differentiation of Down syndrome iPSCs in vivo when formed teratoma in NOD-SCID mice, and in vitro when differentiated into neuroprogenitors and neurons. These defects were associated with changes in the architecture and density of neurons, astroglial and oligodendroglial cells together with misexpression of genes involved in neurogenesis, lineage specification and differentiation. Furthermore, we provide novel evidence that dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) on chromosome 21 likely contribute to these defects. Importantly, we found that targeting DYRK1A pharmacologically or by shRNA results in a considerable correction of these defects.
2013-12-01 | GSE52250 | GEO
Project description:Down syndrome (trisomy 21) is the most common viable chromosomal disorder with intellectual impairment and several other developmental abnormalities. Here, we report the generation and characterization of induced pluripotent stem cells (iPSCs) derived from monozygotic twins discordant for trisomy 21 in order to eliminate the effects of the variability of genomic background. The alterations observed by genetic analysis at the iPSC level and at first approximation in early development illustrate the developmental disease transcriptional signature of Down syndrome. Moreover, we observed an abnormal neural differentiation of Down syndrome iPSCs in vivo when formed teratoma in NOD-SCID mice, and in vitro when differentiated into neuroprogenitors and neurons. These defects were associated with changes in the architecture and density of neurons, astroglial and oligodendroglial cells together with misexpression of genes involved in neurogenesis, lineage specification and differentiation. Furthermore, we provide novel evidence that dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) on chromosome 21 likely contribute to these defects. Importantly, we found that targeting DYRK1A pharmacologically or by shRNA results in a considerable correction of these defects.
2013-12-01 | GSE52249 | GEO
Project description:Background: Pathogenic variants of zinc finger C4H2-type containing (ZC4H2) on the X chromosome caused a group of genetic diseases called ZC4H2-associated rare disorders (ZARD), including Wieacker-Wolff Syndrome (WRWF) and Female-restricted Wieacker-Wolff Syndrome (WRWFFR). Patients displayed arthrogryposis multiplex congenita (AMC), central and peripheral nervous system involvement, as well as multiple dysmorphic features. The underlying mechanisms of the complex syndrome remain to be elucidated. Methods: Expression levels of ZC4H2 were knockdown in neural stem cells (NSCs) derived from induced pluripotent stem cells (iPSCs) by lentiviral-expressed shRNAs against ZC4H2. RNA sequencing (RNA seq) was subsequently applied to study the effects on gene expression profiles. The expression levels of differentially expressed genes were then verified by PCR array and RT-qPCR. Results: neural stem cell-like cells were induced from human induced pluripotent stem cells (hiPSCs), which were confirmed to express biomarkers of Neural stem cells (NSCs) by immunofluorescence. The viability of NSCs were affected through inhibition of ZC4H2 expression after they were infected with lentivirus containing siRNA targeting to ZC4H2 gene. The RNA-seq results showed that the gene expression pattern in NSCs was changed after inhibition of ZC4H2. DEGs were significantly enriched in oxidative phosphorylation and neurodegenerative diseases signaling pathways. Down-regulation of ZC4H2 might affect neural development by affecting the expression of genes related to oxidative phosphorylation signaling pathway. Conclusions: Down-regulation of genes related to the oxidative phosphorylation pathway might be involved in the pathogenity of the disease. Keywords: Female-restricted Wieacker-Wolff Syndrome (WRWF), Wieacker-Wolff Syndrome (WRWFFR), ZC4H2, Arthrogryposis multiplex congenita (AMC), nonsense mutation
2022-07-17 | GSE208171 | GEO
Project description:Down syndrome (DS) is the most frequent cause of human congenital mental retardation. Cognitive deficits in DS result from perturbations of normal cellular processes both during development and in adult tissues, but the mechanisms underlying DS etiology remain poorly understood. To assess the ability of iPSCs to model DS phenotypes, as a prototypical complex human disease, we generated bona-fide DS and wild-type (WT) non-viral iPSCs by episomal reprogramming. DS iPSCs selectively overexpressed chromosome 21 genes, consistent with gene dosage, which was associated with deregulation of thousands of genes throughout the genome. DS and WT iPSCs were neurally converted at >95% efficiency, and had remarkably similar lineage potency, differentiation kinetics, proliferation and axon extension at early time points. However, at later time points DS cultures showed a two-fold bias towards glial lineages. Moreover, DS neural cultures were up to two times more sensitive to oxidative stress induced apoptosis, and this could be prevented by the anti-oxidant N-acetylcysteine. Our results reveal a striking complexity in the genetic alterations caused by trisomy-21 that are likely to underlie DS developmental phenotypes, and indicate a central role for defective early glial development in establishing developmental defects in DS brains. Furthermore, oxidative stress sensitivity is likely to contribute to the accelerated neurodegeneration seen in DS, and we provide proof of concept for screening corrective therapeutics using DS iPSCs and their derivatives. Non-viral DS iPSCs can therefore recapitulate features of complex human disease in vitro, and provide a renewable and ethically unencumbered discovery platform. Control (WT) and Down Syndrome iPSC lines were generated via episomal reprogramming of human donor fibroblasts. Two iPSC clones conforming to iPS criteria (determined by immunocytochemistry detection of pluripotency markers) were developed from each fibroblast donor. Two control (WT) and DS lines each were further characterized and underwent neural differentiation. Multiple biological replicates of donor fibroblast and iPSC from both control (WT) and DS lines, including 3 euploid DS samples and 3 MEL1 hESC controls (total 54 samples) were hybridized to Illumina HT-12 v4 microarray for gene expression analysis.
2012-12-17 | E-GEOD-42956 | biostudies-arrayexpress
Project description:Background: A genetic variant MED12 c.3423C>T,p.Arg1138Trp, classified as a variant of uncertain significance, was identified in a female patient with multiple congenital anomalies and developmental delay. MED12, located on the X chromosome, is a subunit of the Mediator complex which is involved in regulation of transcription and RNA polymerase II activity. The functional consequence of these MED12 genetic variants in disease is undetermined, and insight into disease mechanism is required. Method: We compare disease in seven female MED12 p.Arg1138Trp patients with a disease phenotype including Blepharophimosis – intellectual disability syndrome, Maat-Kievet-Brunner MKB type, Choleostasis-pigmentary retinopathy-cleft palate syndrome, and non-syndromic MED12-related condition. Inducible pluripotent stem cells were derived from patient PBMCs, followed by neural disease modelling for transcriptomics and functional protein analysis. Results: The phenotype for female patients with the MED12 c.3423C>T, p.Arg1138Trp genetic variant, indicated overlapping and divergent clinical features. In comparison of MED12 genetic variant neural cells, derived from patient induced pluripotent stem cells (iPSCs), identified altered expression levels for genes that regulate RNA polymerase II activity (ZNF558, ZIM2, ZFP3, TBR1, PEG3, EMX1, DMRTA2), transcription and pre-mRNA processing (ZIM2, and SNRPN) and neural development (BMP3, CNP, EBF2, EMX1, EOMES, LXH5, NHLH1, UNCX). Transcriptomics analysis further revealed a reduction in pathways related to axon development, forebrain differentiation, and cell specification (neural cell specification); and significant upregulation of pathway gene sets related to pre-ribosome complex (nucleolus) in the MED12 genetic variant cells. Comparison of MED12 wild-type and MED12 p.Arg1138Trp neural progenitor cells indicated similar MED12 transcript and protein expression. However, there was a decrease in MED12L expression, at the transcript and protein level, and significantly reduced MED12L localisation to the nucleolus in the MED12 p.Arg1138Trp cells. Conclusion: Patient iPSC derived stimulated for neural cell differentiation indicate delayed neural development in MED112 p.Arg1138Trp expressing cells providing functional evidence of disease aetiology. Disease mechanism in genetic variant neural cells was linked to decreased localisation of MED12L to the nucleolus and dysregulation of the pre-ribosome complex.
2025-10-01 | GSE288303 | GEO
Project description:Background: A genetic variant MED12 c.3423C>T,p.Arg1138Trp, classified as a variant of uncertain significance, was identified in a female patient with multiple congenital anomalies and developmental delay. MED12, located on the X chromosome, is a subunit of the Mediator complex which is involved in regulation of transcription and RNA polymerase II activity. The functional consequence of these MED12 genetic variants in disease is undetermined, and insight into disease mechanism is required. Method: We compare disease in seven female MED12 p.Arg1138Trp patients with a disease phenotype including Blepharophimosis – intellectual disability syndrome, Maat-Kievet-Brunner MKB type, Choleostasis-pigmentary retinopathy-cleft palate syndrome, and non-syndromic MED12-related condition. Inducible pluripotent stem cells were derived from patient PBMCs, followed by neural disease modelling for transcriptomics and functional protein analysis. Results: The phenotype for female patients with the MED12 c.3423C>T, p.Arg1138Trp genetic variant, indicated overlapping and divergent clinical features. In comparison of MED12 genetic variant neural cells, derived from patient induced pluripotent stem cells (iPSCs), identified altered expression levels for genes that regulate RNA polymerase II activity (ZNF558, ZIM2, ZFP3, TBR1, PEG3, EMX1, DMRTA2), transcription and pre-mRNA processing (ZIM2, and SNRPN) and neural development (BMP3, CNP, EBF2, EMX1, EOMES, LXH5, NHLH1, UNCX). Transcriptomics analysis further revealed a reduction in pathways related to axon development, forebrain differentiation, and cell specification (neural cell specification); and significant upregulation of pathway gene sets related to pre-ribosome complex (nucleolus) in the MED12 genetic variant cells. Comparison of MED12 wild-type and MED12 p.Arg1138Trp neural progenitor cells indicated similar MED12 transcript and protein expression. However, there was a decrease in MED12L expression, at the transcript and protein level, and significantly reduced MED12L localisation to the nucleolus in the MED12 p.Arg1138Trp cells. Conclusion: Patient iPSC derived stimulated for neural cell differentiation indicate delayed neural development in MED112 p.Arg1138Trp expressing cells providing functional evidence of disease aetiology. Disease mechanism in genetic variant neural cells was linked to decreased localisation of MED12L to the nucleolus and dysregulation of the pre-ribosome complex.
2025-10-01 | GSE288302 | GEO
Project description:Down syndrome, caused by trisomy 21, is a complex developmental disorder associated with intellectual disability and reduced growth of multiple organs. Structural pathologies are present at birth, reflecting embryonic origins. A fundamental unanswered question is how an extra copy of human chromosome 21 contributes to organ-specific pathologies that characterize individuals with Down syndrome. Relevant to the hallmark intellectual disability in Down syndrome, how does trisomy 21 affect neural development? We tested the hypothesis that trisomy 21 exerts effects on human neural development as early as neural induction. Bulk RNA sequencing was performed on isogenic trisomy 21 and euploid human induced pluripotent stem cells (iPSCs) at successive stages of neural induction: embryoid bodies at Day 6, early neuroectoderm at Day 10, and differentiated neuroectoderm at Day 17. Gene expression analysis revealed over 1,300 differentially expressed genes in trisomy 21 cells along the differentiation pathway compared to euploid controls. Less than 5% of the gene expression changes included upregulated chromosome 21 encoded genes at every timepoint. Genes involved in specific growth factor signaling pathways (Wnt and Notch), metabolism (including interferon response and oxidative stress), and extracellular matrix were altered in trisomy 21 cells. Further analysis revealed heterochronic expression of genes. This comprehensive analysis reveals that trisomy 21 impacts discrete developmental pathways at the earliest stages of neural development. Further, the results suggest that metabolic dysfunction arises early in embryogenesis in trisomy 21 and may thus affect development and function more broadly.
2024-01-31 | GSE247990 | GEO
Project description:Down syndrome (DS) is the leading genetic cause of mental retardation and is caused by a third copy of human chromosome 21. The different pathologies of DS involve many tissues with a distinct array of neural phenotypes. Here we characterize new embryonic stem cell lines with DS (DS-ESCs), and focus on the neural aspects of the diease. Our results show that neural progenitor cells (NPCs) differentiated from five independent DS-ESC lines display increased apoptosis and down-regulation of forehead developmental genes. Analysis of differentially expressed genes suggested RUNX1 as a key transcription regulator in DS-NPCs. Using genome editing we were able to disrupt all three copies of RUNX1 in DS-ESCs, leading to down-regulation of several RUNX1 target developmental genes accompanied by reduced apoptosis and neuron migration. Our work sheds new light on the role of RUNX1 and the importance of dosage balance in the development of neural phenotypes in DS.
2016-09-24 | GSE84887 | GEO