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Chromosome silencing in vitro reveals trisomy 21 causes cell-autonomous deficits in angiogenesis and early dysregulation in Notch signaling

ABSTRACT: Chromosome silencing in vitro reveals trisomy 21 causes cell-autonomous deficits in angiogenesis and early dysregulation in Notch signaling

PROVIDER: PRJNA702118 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13721900_1.fastq.gz	Fastqsanger.gz
	SRR13721900_2.fastq.gz	Fastqsanger.gz
	SRR13721901_1.fastq.gz	Fastqsanger.gz
	SRR13721901_2.fastq.gz	Fastqsanger.gz
	SRR13721902_1.fastq.gz	Fastqsanger.gz

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Chromosome silencing in vitro reveals trisomy 21 causes cell-autonomous deficits in angiogenesis and early dysregulation in Notch signaling

Project description:Despite the prevalence and clinical importance of Down syndrome, little is known as to the specific cell pathologies that underlie this multi-system disorder. To understand which cell types and pathways are more directly impacted by trisomy 21, we used an inducible-XIST system to silence the extra chromosome 21 in a panel of patient-derived iPSCs. Transcriptomic analysis showed significant dysregulation of potentially impacting programming of multiple cell-types as well as Notch. Analysis revealed prominent dysregulation in two major cell type processes: neurogenesis and angiogenesis. Angiogenesis is important for many systems impacted in Down syndrome but has been understudied. An in vitro assay for microvasculature formation used in a tightly controlled system reveals a novel cellular pathology that showed impairment in angiogenic response during tube formation. Results demonstrate that this is a cell-autonomous effect of trisomy 21 and transcriptomic analysis of differentiated endothelial cells shows deficits in known angiogenesis regulators. This study reveals a major unknown cell pathology caused by trisomy 21 and highlights the importance of endothelial cell function for Down syndrome pathologies, with wide reaching implications for development and disease progression.

2022-07-05 | GSE166849 | GEO

Chromosome silencing in vitro reveals trisomy 21 causes cell-autonomous deficits in angiogenesis and early dysregulation in Notch signaling.

Project description:Despite the prevalence of Down syndrome (DS), little is known regarding the specific cell pathologies that underlie this multi-system disorder. To understand which cell types and pathways are more directly affected by trisomy 21 (T21), we used an inducible-XIST system to silence one chromosome 21 in vitro. T21 caused the dysregulation of Notch signaling in iPSCs, potentially affecting cell-type programming. Further analyses identified dysregulation of pathways important for two cell types: neurogenesis and angiogenesis. Angiogenesis is essential to many bodily systems, yet is understudied in DS; therefore, we focused next on whether T21 affects endothelial cells. An in vitro assay for microvasculature formation revealed a cellular pathology involving delayed tube formation in response to angiogenic signals. Parallel transcriptomic analysis of endothelia further showed deficits in angiogenesis regulators. Results indicate a direct cell-autonomous impact of T21 on endothelial function, highlighting the importance of angiogenesis, with wide-reaching implications for development and disease progression.

| S-EPMC9505374 | biostudies-literature

Notch and VEGF pathways play distinct but complementary roles in tumor angiogenesis

Project description:We asked whether combining Notch and VEGF blockade would enhance suppression of tumor angiogenesis and growth, using the NGP neuroblastoma model. NGP tumors were engineered to express a Notch1 decoy construct (N1D), which restricts Notch signaling, and then treated with either the anti-VEGF antibody bevacizumab or vehicle. Combining Notch and VEGF blockade led to blood vessel regression, increasing endothelial cell apoptosis and disrupting pericyte coverage of endothelial cells. Combined Notch and VEGF blockade did not affect tumor weight, but did additively reduce tumor viability. Our results indicate that Notch and VEGF pathways play distinct but complementary roles in tumor angiogenesis, and show that concurrent blockade disrupts primary tumor vasculature and viability further than inhibition of either pathway alone. 6 neuroblastoma tumors were transfected with Notch1 decoy, 6 with Notch1 decoy and treated with bevacizumab, 6 tumors treated with bevacizumab, and 6 control tumors were profiled by human 133A 2.0 arrays

2013-12-01 | E-GEOD-48880 | biostudies-arrayexpress

Notch and VEGF pathways play distinct but complementary roles in tumor angiogenesis

2013-12-01 | GSE48880 | GEO

Angiogenesis gene expression upon Notch activation in human vascular smooth muscle cells

Project description:VSMCs were cultured on Jag1 or IgG-coated plates as described above. RNA was extracted using RNA isolation kit (Qiagen). Reverse-transcription PCR was done with RNA-to-cDNA kit (Applied Biosystems). cDNA was run on a TaqMan Low-Density Array, human angiogenesis panel (Applied Biosystems , Cat#4378725), amplified on a 7900 HT Fast Real Time PCR system (Applied Biosystems) according to manufacturer’s instructions. Angiogenesis gene expression was screened for human aortic vascular smooth muscle cells that were plated for 18 hours on either Notch ligands (Jag1 or Jag2) as compared to appropriate IgG controls (IgG1 or IgG2).

2011-12-01 | E-GEOD-34024 | biostudies-arrayexpress

NOTCH-mediated non-cell autonomous regulation of chromatin structure during senescence

Project description:NOTCH-mediated non-cell autonomous regulation of chromatin structure during senescence

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Rnf20 levels modulate the VEGF-Notch signaling circuits during sprouting angiogenesis

Project description:Rnf20 levels modulate the VEGF-Notch signaling circuits during sprouting angiogenesis

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Transcriptional Consequences of Trisomy 21 on Neural Induction

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

Rnf20 levels modulate the VEGF-Notch signaling circuits during sprouting angiogenesis [Rnf20_CD31_RNA_seq]

Project description:Rnf20 levels modulate the VEGF-Notch signaling circuits during sprouting angiogenesis [Rnf20_CD31_RNA_seq]

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Rnf20 levels modulate the VEGF-Notch signaling circuits during sprouting angiogenesis [02RNF20_Huvec]

Project description:Rnf20 levels modulate the VEGF-Notch signaling circuits during sprouting angiogenesis [02RNF20_Huvec]

| PRJNA875898 | ENA