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Effect of Network-Correcting Molecules on NOTCH1 (N1)-Haploinsufficient Human Induced Pluripotent Stem Cell (iPSC)-Derived Endothelial Cells (ECs)

ABSTRACT: Effect of Network-Correcting Molecules on NOTCH1 (N1)-Haploinsufficient Human Induced Pluripotent Stem Cell (iPSC)-Derived Endothelial Cells (ECs)

PROVIDER: PRJNA515762 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8453500_1.fastq.gz	Fastqsanger.gz
	SRR8453500_2.fastq.gz	Fastqsanger.gz
	SRR8453510_1.fastq.gz	Fastqsanger.gz
	SRR8453510_2.fastq.gz	Fastqsanger.gz
	SRR8453520_1.fastq.gz	Fastqsanger.gz

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Effect of Network-Correcting Molecules on NOTCH1 (N1)-Haploinsufficient Human Induced Pluripotent Stem Cell (iPSC)-Derived Endothelial Cells (ECs)

Project description:Discovery of small molecules that correct gene networks dysregulated in human disease may allow identification of therapies that treat disease at its fundamental basis by leveraging mechanism-based data. Here, we report the first broad gene network-based drug screen, which led to discovery of a drug candidate that effectively treats aortic valve disease in an animal model. We previously reported haploinsufficiency of NOTCH1 (N1) as a genetic cause of human aortic valve thickening and calcification, the third most common form of heart disease, and described the resulting gene network dysregulation in human induced pluripotent stem cell (iPSC)-derived endothelial cells (ECs). We exposed isogenic N1+/+ or N1+/– iPSC-derived ECs to each of 1595 small molecules or control and developed a machine learning approach that accurately distinguished WT or N1-haploinsufficient cells based on expression of 119 genes assayed by targeted RNA-sequencing. 9 small molecules corrected the gene network of N1+/– ECs sufficiently to be classified as WT. Among hits tested in vivo, the estrogen receptor-related alpha inverse agonist XCT790 significantly reduced aortic valve thickening, calcification, and stenosis in N1-haploinsufficient mice with shortened telomeres, which model the range of age-dependent cardiac disease observed in humans. This strategy, made feasible by human iPSC technology, next generation sequencing approaches, and machine learning, may represent a more effective path for drug discovery compared to conventional screening approaches.

2021-01-01 | GSE125299 | GEO

Effect of XCT790 on Aortic Valves (AV) in NOTCH1 (N1)-Haploinsufficient Mice

Project description:RNA-seq on aortic valves from WT vs N1-haploinsufficient telomere-shortened (generation 2 Terc-/-) mice with either healthy AVs or AV stenosis treated with control solvent or XCT790

2021-01-01 | GSE152061 | GEO

Effect of XCT790 on Aortic Valves (AV) in NOTCH1 (N1)-Haploinsufficient Mice

Project description:Effect of XCT790 on Aortic Valves (AV) in NOTCH1 (N1)-Haploinsufficient Mice

| PRJNA638168 | ENA

Effect of Network-Correcting Molecules

Project description:Effect of Network-Correcting Molecules

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HEK NICD AP-MS - Notch signaling is a core patterning module for vascular morphogenesis, which co-determines the sprouting behaviour of endothelial cells (ECs)

Project description:Notch signaling is a core patterning module for vascular morphogenesis, which co-determines the sprouting behaviour of endothelial cells (ECs). Tight quantitative and temporal control of Notch activity is essential for vascular development, yet the details of Notch regulation in ECs are incompletely understood. We found that ubiquitin-specific peptidase 10 (USP10) interacted with the NOTCH1 intracellular domain (NICD1) to slow the ubiquitin-dependent turnover of this short-lived form of the activated NOTCH1 receptor. Accordingly, inactivation of USP10 reduced NICD1 abundance and stability, and diminished Notch-induced target gene expression in ECs. In mice, loss of endothelial Usp10 increased vessel sprouting and partially restored the patterning defects caused by ectopic expression of NICD1. Thus, USP10 functions as an NICD1 deubiquitinase, which fine-tunes endothelial Notch responses during angiogenic sprouting.

2019-04-11 | PXD013192 | Pride

Transcriptional profiling of human cardiomyocytes and endothelial cells derived from NOTCH1 knockout induced pluripotent stem cells (iPSCs)

Project description:Pathogenic NOTCH1 mutations are linked to congenital heart defects. To pinpoint how NOTCH1 deficiency affects cardiac development, we generated homozygous NOTCH1 knockout (N1KO) human induced pluripotent stem cells (iPSCs). We then performed high-throughput RNA-seq to profile differential gene expression in cardiomyocytes (iPSC-CMs) and endothelial cells (iPSC-ECs) derived from wild type (WT) and N1KO iPSCs.

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Cyclin C is a haploinsufficient tumour suppressor

Project description:Cyclin C was cloned as a growth-promoting G1 cyclin, and was also shown to regulate gene transcription. Here we report that in vivo cyclin C acts as a haploinsufficient tumour suppressor, by controlling Notch1 oncogene levels. Cyclin C activates an 'orphan' CDK19 kinase, as well as CDK8 and CDK3. These cyclin-C-CDK complexes phosphorylate the Notch1 intracellular domain (ICN1) and promote ICN1 degradation. Genetic ablation of cyclin C blocks ICN1 phosphorylation in vivo, thereby elevating ICN1 levels in cyclin-C-knockout mice. Cyclin C ablation or heterozygosity collaborates with other oncogenic lesions and accelerates development of T-cell acute lymphoblastic leukaemia (T-ALL). Furthermore, the cyclin C encoding gene CCNC is heterozygously deleted in a significant fraction of human T-ALLs, and these tumours express reduced cyclin C levels. We also describe point mutations in human T-ALL that render cyclin-C-CDK unable to phosphorylate ICN1. Hence, tumour cells may develop different strategies to evade inhibition by cyclin C.

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Project description:In this study we mutated the ecsAB operon in two different Staphylococcus aureus strains, Newman and LS-1, and performed a wide characterization of phenotypic effects of the mutations. A growth defect, increased autolysis and lysostaphin sensitivity, decreased levels of cell wall proteins and altered cell surface texture indicate that Ecs deficiency causes significant changes in the cell wall. The precursor form of staphylokinase was released into the wall in an Ecs-dependent manner. Pathogenicity of the ecs mutants was studied with a mouse arthritis model. Mice inoculated with ecs mutants developed markedly milder infections than when inoculated with the wild-type strains, as was illustrated by a lower mortality, less weight loss, decreased persistence of staphylococci in the kidneys and a milder arthritis. DNA microarray analysis revealed that inactivation of Ecs in S. aureus Newman caused either up-regulation or down-regulation of genes encoding various membrane transport proteins, particularly ABC transporters and phosphate-specific transport (PST) systems. Differentially expressed were also several genes encoding proteins involved in virulence, including the virulence factor regulator protein Rot, protein A, adhesins and capsular polysaccharide biosynthesis proteins. Furthermore, the susceptibility of ecs mutant to ribosomal antibiotics as well as the chelerythrine and sanguinarine plant alkaloids was increased. WT and ecsA mutant strains were hybridized at 3 and 6 hours of growth in rich medium (4-replicates)

2011-01-01 | E-GEOD-22353 | biostudies-arrayexpress

Study of ecs mutation

Project description:Ecs is an ATP-binding cassette (ABC) transporter present in aerobic and facultative anaerobic gram-positive Firmicutes. Inactivation of Bacillus subtilis Ecs causes pleiotropic changes in the bacterial phenotype including inhibition of intramembrane proteolysis. The molecule(s) transported by Ecs is (are) still unknown. In this study we mutated the ecsAB operon in two Staphylococcus aureus strains, Newman and LS-1. Phenotypic and functional characterization of these Ecs deficient mutants revealed a defect in growth, increased autolysis and lysostaphin sensitivity, altered composition of cell wall proteins including the precursor form of staphylokinase and an altered bacterial surface texture. DNA microarray analysis indicated that the Ecs deficiency changed expression of the virulence factor regulator protein Rot accompanied by differential expression of membrane transport proteins, particularly ABC transporters and phosphate-specific transport systems, protein A, adhesins and capsular polysaccharide biosynthesis proteins. Virulence of the ecs mutants was studied in a mouse model of hematogenous S. aureus infection. Mice inoculated with the ecs mutant strains developed markedly milder infections than those inoculated with the wild-type strains and had consequently lower mortality, less weight loss, milder arthritis and decreased persistence of staphylococci in the kidneys. The ecs mutants had higher susceptibility to ribosomal antibiotics and plant alkaloids chelerythrine and sanguinarine. Our results show that Ecs is essential for staphylococcal virulence and antimicrobial resistance probably since the transport function of Ecs is essential for the normal structure and function of the cell wall. Thus targeting Ecs may be a new approach in combating staphylococcal infection.

2011-01-01 | GSE22353 | GEO

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2016-09-01 | GSE85576 | GEO

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