Transcriptional Consequences of Trisomy 21 on Neural Induction
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1041371 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26852700.fastq.gz | Fastqsanger.gz | |||
| SRR26852701.fastq.gz | Fastqsanger.gz | |||
| SRR26852702.fastq.gz | Fastqsanger.gz | |||
| SRR26852703.fastq.gz | Fastqsanger.gz | |||
| SRR26852704.fastq.gz | Fastqsanger.gz |
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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:Consequences of aneuploidy in human fibroblasts with trisomy 21
| PRJNA646219 | ENA
Project description:IntroductionDown 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, and, relevant to the hallmark intellectual disability in Down syndrome, how trisomy 21 affects neural development. We tested the hypothesis that trisomy 21 exerts effects on human neural development as early as neural induction.MethodsBulk 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.ResultsGene 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 oxidative stress), and extracellular matrix were altered in trisomy 21 cells. Further analysis uncovered heterochronic expression of genes.ConclusionTrisomy 21 impacts discrete developmental pathways at the earliest stages of neural development. The results suggest that metabolic dysfunction arises early in embryogenesis in trisomy 21 and may affect development and function more broadly.
| S-EPMC10865501 | biostudies-literature
Project description:Molecular consequences of trisomy in lymphoblastoid cell lines from patients with Down syndrome. This project analyses differentially expressed genes between humans with trisomy 21 and humans without trisomy 21.
2012-08-15 | GSE34458 | 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:Although Down Syndrome (DS) is the leading genetic cause of intellectual disability in children, the developmental pathogenesis remains largely unknown, and better strategies are needed to investigate this. We previously showed that one copy of chromosome 21 can be epigenetically silenced in DS iPSCs by insertion of an XIST transgene, which produces a non-coding RNA that normally silences one X chromosome in female cells. XIST was shown to induce heterochromatin and silence transcription across chromosome 21 in pluripotent stem cells, the natural developmental context of XIST function. Prior literature indicated that initiation of chromosome silencing is only possible within 48 hours of mES cell differentiation, however it would be highly advantageous experimentally if trisomy silencing could be initiated in differentiated cells, and this is critical for any therapeutic potential of XIST. Here we use RNAseq and molecular cytology to investigate the effectiveness of XIST for trisomy silencing in cells undergoing in vitro neural differentiation and examine the potential cell phenotypic effects of chromosomal silencing. Induction of XIST from the onset of differentiation resulted in comprehensive silencing of chromosome 21 genes, providing a powerful approach to examine effects of trisomy on neurogenesis. To determine whether human neural stem cells can initiate XIST-mediated silencing, we induced XIST at several times during neural differentiation. We demonstrate for the first time that differentiated normal human cells can initiate chromosome silencing in response to XIST expression. While this process only takes a few days in pluripotent cells, we show that it takes 2-3 weeks in differentiated cells. Importantly, single-cell RNAseq revealed that cells which express XIST preferentially differentiate into neurons, providing evidence of phenotypic improvement with trisomy silencing, which is seen even when XIST is initiated weeks into differentiation. We are currently investigating whether silenced neurons show other non-chromosome 21 transcriptional changes suggestive of potentially improved function. These studies have important implications for the understanding of XIST biology and DS neurobiology, and also further open the possibility of a chromosomal therapy for DS using a single gene: XIST.
2020-01-23 | GSE125837 | GEO
Project description:Molecular consequences of trisomy in lymphoblastoid cell lines from patients with Down syndrome. This project analyses differentially expressed genes between humans with trisomy 21 and humans without trisomy 21. Total RNA obtained from human lymphoblastoid cell lines without trisomy 21 compared to cell lines from human with trisomy 21.
2012-08-14 | E-GEOD-34458 | biostudies-arrayexpress
Project description:Although Down Syndrome (DS) is the leading genetic cause of intellectual disability in children, the developmental pathogenesis remains largely unknown, and better strategies are needed to investigate this. We previously showed that one copy of chromosome 21 can be epigenetically silenced in DS iPSCs by insertion of an XIST transgene, which produces a non-coding RNA that normally silences one X chromosome in female cells. XIST was shown to induce heterochromatin and silence transcription across chromosome 21 in pluripotent stem cells, the natural developmental context of XIST function. Prior literature indicated that initiation of chromosome silencing is only possible within 48 hours of mES cell differentiation, however it would be highly advantageous experimentally if trisomy silencing could be initiated in differentiated cells, and this is critical for any therapeutic potential of XIST. Here we use RNAseq and molecular cytology to investigate the effectiveness of XIST for trisomy silencing in cells undergoing in vitro neural differentiation and examine the potential cell phenotypic effects of chromosomal silencing. Induction of XIST from the onset of differentiation resulted in comprehensive silencing of chromosome 21 genes, providing a powerful approach to examine effects of trisomy on neurogenesis. To determine whether human neural stem cells can initiate XIST-mediated silencing, we induced XIST at several times during neural differentiation. We demonstrate for the first time that differentiated normal human cells can initiate chromosome silencing in response to XIST expression. While this process only takes a few days in pluripotent cells, we show that it takes 2-3 weeks in differentiated cells. Importantly, single-cell RNAseq revealed that cells which express XIST preferentially differentiate into neurons, providing evidence of phenotypic improvement with trisomy silencing, which is seen even when XIST is initiated weeks into differentiation. We are currently investigating whether silenced neurons show other non-chromosome 21 transcriptional changes suggestive of potentially improved function. These studies have important implications for the understanding of XIST biology and DS neurobiology, and also further open the possibility of a chromosomal therapy for DS using a single gene: XIST.
2020-01-23 | GSE125838 | GEO
Project description:RNA-seq of lymphoblastoid cells from a family of individuals (one of which has Trisomy 21) was used to determine the molecular origin of dosage compensation in Trisomy 21.
2023-04-29 | GSE230995 | GEO
Project description:GRO-seq of lymphoblastoid cells from a family of individuals (one of which has Trisomy 21) was used to determine the molecular origin of dosage compensation in Trisomy 21.
2023-04-29 | GSE230994 | GEO