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Notch3 ChIP-sequencing of brain mural cells differentiated from human pluripotent stem cell-derived neural crest via Notch3 activation

ABSTRACT: Molecular mechanisms underlying the differentiation of brain mural cells from neural crest are poorly understood. We found that activation of Notch3 signaling in human pluripotent stem cell-derived neural crest (using lentiviral overexpression of the human Notch3 intracellular domain, N3ICD) was sufficient to direct the differentiation of mural cells. We used Notch3 ChIP-sequencing to identify cis-regulatory elements directly bound by the Notch3 transcriptional activation complex in this system.

ORGANISM(S): Homo sapiens

PROVIDER: GSE205212 | GEO | 2024/02/02

REPOSITORIES: GEO

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RNA-sequencing of brain mural cells differentiated from human pluripotent stem cell-derived neural crest via Notch3 activation

Project description:Molecular mechanisms underlying the differentiation of brain mural cells from neural crest are poorly understood. We found that activation of Notch3 signaling in human pluripotent stem cell-derived neural crest (using lentiviral overexpression of the human Notch3 intracellular domain, N3ICD) was sufficient to direct the differentiation of mural cells.

2024-02-02 | GSE205213 | GEO

Cigarette Smoke Activates NOTCH3 to Promote Goblet Cell Differentiation in Human Airway Epithelial Cells

Project description:Chronic obstructive pulmonary disease (COPD) is the 3rd leading cause of death in the United States and is caused primarily by cigarette smoking. Increased numbers of mucus-producing secretory (“goblet”) cells defined as goblet cell metaplasia or hyperplasia (GCMH), contributes significantly to COPD pathophysiology. The objective of this study was to determine whether NOTCH signaling regulates goblet cell differentiation in response to cigarette smoke. To this end, primary human bronchial epithelial cells (HBECs) from nonsmokers and COPD smokers were differentiated in vitro on air-liquid interface and exposed to cigarette smoke extract (CSE) for 7 days. NOTCH signaling activity was modulated using (1) the NOTCH/γ-secretase inhibitor Dibenzazepine (DBZ), (2) lentiviral over-expression of the NOTCH3-intracellular domain (NICD3) or (3) NOTCH3-specific siRNA. Cell differentiation and response to CSE were evaluated by qPCR, Western blotting, immunostaining and RNA-Seq. Our data demonstrate that CSE exposure of nonsmoker airway epithelium induced goblet cell differentiation characteristic of GCMH. Treatment with DBZ suppressed CSE-dependent induction of goblet cell differentiation. Furthermore, CSE induced NOTCH3 activation, as revealed by increased NOTCH3 nuclear localization and elevated NICD3 protein levels. Over-expression of NICD3 increased expression of the goblet cell associated genes SPDEF and MUC5AC, whereas NOTCH3 knockdown suppressed CSE-mediated induction of SPDEF and MUC5AC. Finally, CSE exposure of COPD airway epithelium induced goblet cell differentiation in a NOTCH3-dependent manner. These results identify NOTCH3 activation as one of the important mechanisms by which cigarette smoke induces goblet cell differentiation, thus providing a potential strategy to control GCMH-related pathologies in smokers and patients with COPD.

2020-06-16 | GSE152446 | GEO

Notch signaling regulates neural crest differentiation from human pluripotent stem cells

Project description:The aim of the dataset was to study on genome-wide level the effect of Notch inhibition in gene expression on neural crest differentiation of human embryonic stem cells under chemically defined conditions. Total RNA from hESCs, hESC-derived neural crest, hESC-derived neural crest+DAPT, and hESC-derived neural stem cells was collected and compared at their global gene expression level. Samples from 3 biological replicates were analysed.

2014-03-03 | E-GEOD-53203 | biostudies-arrayexpress

Norepinephrine transporter-deficient neural crest cells

Project description:Background: The goal of this study was to determine the transcriptional consequences of norepinephrine transporter (NET) gene deletion in noradrenergic neuron differentiation. The norepinephrine transporter (NET) is the target of powerful mind-altering substances, such as tricyclic antidepressants and the drug of abuse, cocaine. NET function in adult noradrenergic neurons of the peripheral and central nervous systems is that of a scavenger that internalizes norepinephrine from the synaptic cleft. By contrast, norepinephrine (NE) transport has a different role in embryogenesis. It promotes differentiation of neural crest cells and locus ceruleus progenitors into noradrenergic neurons, whereas NET inhibitors, such as the tricyclic antidepressant desipramine and the drug of abuse, cocaine, inhibit noradrenergic differentiation. While NET structure und regulation of NET function is well described, little is known about downstream targets of NE transport. Results: We have determined by long serial analysis of gene expression (LongSAGE) the gene expression profiles of in vitro differentiating wild type and norepinephrine transporter-deficient (NETKO) neural crest derivatives. Comparison analyses with the wild type library (GSM 105765) have identified a number of important differentially expressed genes, including genes relevant to noradrenergic neuron differentiation and to the phenotype of NETKO mice. Furthermore we have identified novel differentially expressed genes. Conclusions: Loss of NET function during embryonic development deregulates signaling pathways that are critically involved in neural crest formation and noradrenergic neuron differentiation. The library was constructed from total RNA of 60 neural crest culture at culture day 7. The neural tubes were dissected from E9.5 embryos that lack the norepinephrine transporter gene.

2008-06-23 | E-GEOD-11788 | biostudies-arrayexpress

Genome-wide analysis of differential gene expression in human embryonic stem cell-derived central nervous system, neural crest, and progenitor populations over time

Project description:Melanocytes are pigment-producing cells of neural crest origin responsible for protecting the skin against UV-irradiation. Melanocyte dysfunction leads to pigmentation defects including albinism, vitiligo, and piebaldism and is a key feature of systemic pathologies such as Hermansky-Pudlak (HP) and Chediak-Higashi (CH) Syndromes. Pluripotent stem cell technology offers a novel approach for studying human melanocyte development and disease. Here we report that timed exposure to activators of WNT, BMP and EDN3 signaling triggers the sequential induction of neural crest and melanocyte precursor fates under dual-SMAD inhibition conditions. Using a SOX10::GFP hESC reporter line, we demonstrate that the temporal onset of WNT activation is particularly critical for human neural crest induction. Surprisingly, suppression of BMP signaling does reduce neural crest yield. Subsequent differentiation of hESC-derived melanocyte precursors under defined conditions yields pure populations of pigmented cells matching the molecular and functional properties of adult melanocytes. Melanocytes from patient-specific iPSCs faithfully reproduce the ultrastructural features of the HP- and CH-specific pigmentation defects with minimal variability across lines. Our data define a highly specific requirement for WNT signaling during neural crest induction and enable the generation of pure populations of hiPSC-derived melanocytes for faithful modeling of human pigmentation disorders. Total RNA obtained from a timecourse of Dual SMAD Inhibition (DSi), Neural Crest (NC), and Melanocyte (BE) differentiation of human embryonic stem cells in triplicate.

2013-06-01 | E-GEOD-45223 | biostudies-arrayexpress

Global ubiquitinome profiling identify Nedd4 as aregulator of Profilin 1 and actin remodeling in neural crest cells

Project description:We utilized quantitative analyses of the proteome, transcriptome, and ubiquitinome to study how ubiquitination and NEDD4 control neural crest cell survival and stem-cell-like properties. We report 276 novel NEDD4 targets in neural crest cells and show that loss of NEDD4 leads to a striking global reduction in specific ubiquitin lysine linkages.

2022-02-08 | PXD024103 | Pride

NOTCH3 missense variants cause familial partial lipodystrophy

Project description:Molecular defects in some ultra-rare subtypes of familial lipodystrophies remain unidentified. We identified novel NOTCH3 heterozygous variants in familial partial lipodystrophy (FPL) pedigrees. All variants were clustered in the heterodimerization domain of the negative regulatory region of NOTCH3. Proteomics of skin fibroblasts revealed significantly higher RNA expression of NOTCH3 and activation of widespread senescence pathways in the FPL patients versus controls.

2024-10-28 | MSV000096235 | MassIVE

NOTCH3-IC

Project description:NOTCH3-IC

| PRJNA480489 | ENA

RNA Sequencing of default, melanocyte biased and enteric human neural crest populations (NC) and neuroectoderm (CNS)

Project description:We have generated expression profiles of three different neural crest populations from human embryonic stem cells. These profiles were compared to a neuroectoderm population. We find that the neural crest populations are separable and distinct. All cell types were differentiated from human embryonic stem cells. Neural crest populations were sorted on day 12 for CD49. The neuroectoderm cells were unsorted and harvested on day 12 of differentiation.

2016-02-12 | E-GEOD-66148 | biostudies-arrayexpress

The NOTCH3 Downstream Target HEYL Is Required for Efficient Human Airway Basal Cell Differentiation [RNA-Seq]

Project description:Basal cells (BC) are the resident stem/progenitor cells of the adult pseudostratified airway epithelium, whose differentiation program is orchestrated by the NOTCH signaling pathway. NOTCH3 receptor mediated signaling regulates BC to club cell differentiation; however, the downstream responses that regulate this process are largely unknown. In the present study we utilized an in vitro air-liquid interface model of the human pseudostratified airway epithelium to identify the NOTCH3-dependent downstream genes/pathways that regulate human BC to club cell differentiation. Activation of NOTCH3 signaling in BC via lentivirus-mediated over-expression of the active NOTCH3 intracellular domain (NICD3) promoted club cell differentiation. Bulk RNA-seq analysis of control vs NICD3 -transduced cells, identified 692 NICD3 responsive genes enriched for pathways linked to airway epithelial biology and differentiation including Wnt/β-catenin Signaling. Expression of the classical NOTCH target HEYL increased in response to NOTCH3 activation and positively correlated with the club cell marker SCGB1A1. Further, using single-cell RNA-seq, we report that HEYL+ cells primarily clustered with SCGB1A1+ and NOTCH3+ cells. Moreover, HEYL protein co-localized with SCGB1A1 in ALI cultures in vitro and in the human and mouse airway epithelium in vivo. siRNA-mediated knockdown of HEYL in BC led to changes in epithelial structure including altered morphology and significant reductions in transepithelial electrical resistance and expression of tight junction related genes. Finally, HEYL knockdown significantly reduced the number of SCGB1A1+ club cells, along with a corresponding increase in KRT8+ BC-intermediate cells. Overall, our data identifies NOTCH3-HEYL signaling as a key regulator of BC to club cell differentiation.

2021-03-04 | GSE168126 | GEO

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