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Transcriptomic analysis of Bmi1 overexpression in NSPC.

ABSTRACT: We have previously shown that conditional overexpression of Bmi1 in NSC increases their proliferation both in the developing neocortexand in the postnatal brain (Yadirgi et al. 2011). However, during embryonic development, increased and ectopic proliferation induced by overexpression of Bmi1 in progenitors committed toward a neuronal lineage triggered apoptosis, leading eventually to a reduced overall brain size (Yadirgi et al. 2011). These findings –increased proliferation of neural stem/progenitor cells (NSPC) and apoptosis of neuronal committed progenitors - could be faithfully reproduced in an in vitro assay where NSPC isolated from Nestin-Cre; STOP FloxBmi1 embryos are cultured in floating conditions in the presence of EGF and FGF2 (neurosphere assay). We isolated NSPC from Nestin-Cre;STOP FloxBmi1 E16.5 neocortices and cultured them briefly under neurosphere inducing conditions. We then analysed their transcriptome by whole-genome Illumina platform mouse v2 and compared it to the transcriptome of NSPC isolated from non-transgenic or single transgenic littermates. The objective of this analysis was to identify genes differentially expressed upon overexpression of the PcG gene Bmi1 in neural stem/progenitor cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE31607 | GEO | 2012/11/12

SECONDARY ACCESSION(S): PRJNA145589

REPOSITORIES: GEO

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Transcriptomic analysis of Bmi1 overexpression in NSPC.

Project description:We have previously shown that conditional overexpression of Bmi1 in NSC increases their proliferation both in the developing neocortexand in the postnatal brain (Yadirgi et al. 2011). However, during embryonic development, increased and ectopic proliferation induced by overexpression of Bmi1 in progenitors committed toward a neuronal lineage triggered apoptosis, leading eventually to a reduced overall brain size (Yadirgi et al. 2011). These findings M-bM-^@M-^Sincreased proliferation of neural stem/progenitor cells (NSPC) and apoptosis of neuronal committed progenitors - could be faithfully reproduced in an in vitro assay where NSPC isolated from Nestin-Cre; STOP FloxBmi1 embryos are cultured in floating conditions in the presence of EGF and FGF2 (neurosphere assay). We isolated NSPC from Nestin-Cre;STOP FloxBmi1 E16.5 neocortices and cultured them briefly under neurosphere inducing conditions. We then analysed their transcriptome by whole-genome Illumina platform mouse v2 and compared it to the transcriptome of NSPC isolated from non-transgenic or single transgenic littermates. The objective of this analysis was to identify genes differentially expressed upon overexpression of the PcG gene Bmi1 in neural stem/progenitor cells. 4 samples, 2 condition with 2 biological replicates per condition

2012-11-12 | E-GEOD-31607 | biostudies-arrayexpress

Mus musculus

Project description:Transcriptomic analysis of Bmi1 overexpression in NSPC.

| PRJNA145589 | ENA

Genes differentially expressed between Bmi1-overexpressing and empty vector control neural stem/progenitor cells

Project description:Neural stem/progenitor cells were isolated from the lateral ventricle wall of 4-6 week-old CD1 mice and grown as neurospheres under low density culture conditions. Test cells were transduced with bicistronic retroviral constructs for the over-expression of Bmi1 together with eGFP, and control cells were transduced with an empty vector construct expressing eGFP only. To identify genes, which are regulated by BMI1 in neural stem/progenitor cells, the gene expression profiles of neurosphere cells over-expressing Bmi1 were compared empty vector control cells using Affymetrix Gene mouse ST1.0 arrays 3 independent Bmi1-overexpressing neurosphere cultures (test samples) were compared to 3 independent empty vector neurosphere cultures (control samples).

2016-06-01 | E-GEOD-70451 | biostudies-arrayexpress

Genes differentially expressed between Bmi1-overexpressing and empty vector control neural stem/progenitor cells

2016-06-01 | GSE70451 | GEO

A fatty acid oxidation-dependent metabolic shift regulates adult neural stem cell quiescence

Project description:Adult hippocampal neurogenesis is important for certain forms of cognition and failing neurogenesis has been implicated in neuropsychiatric diseases. The neurogenic capacity of hippocampal neural stem/progenitor cells (NSPCs) depends on a balance between quiescent and proliferative states. However, how this balance is regulated remains poorly understood. Here we show that the rate of fatty acid oxidation (FAO) defines quiescence vs. proliferation in NSPCs. Quiescent NSPCs show high levels of carnitine palmitoyltransferase 1a (Cpt1a)-dependent FAO, which is downregulated in proliferating NSPCs. Pharmacological inhibition and conditional deletion of Cpt1a in vitro and in vivo leads to altered NSPC behavior, showing that Cpt1a-dependent FAO is required for stem cell maintenance and proper neurogenesis. Strikingly, experimental manipulation of malonyl-CoA, the metabolite that regulates levels of FAO, is sufficient to induce exit from quiescence and to enhance NSPC proliferation. Thus, the data presented here identify a shift in FAO metabolism that governs NSPC behavior and suggest an instructive role for fatty acid metabolism in regulating NSPC activity.

2019-11-15 | PXD005598 | Pride

Genomic Glucocorticoid Action in Embryonic Mouse Neural Stem Cells

Project description:The goal of this study was to measure genome-wide expression in primary mouse neural stem/progenitor cell (NSPC) cultures to determine if SOX2 ablation alters the transcriptomic response which occurs following glucocorticoid receptor activation by the synthetic glucocorticoid, Dexamethasone. Neurosphere cultures of SOX2 knock out (KO) NSPCs and control non-deleted wild-type (WT) NSPCs (C57BL/6) derived from the fetal telencephalon were established at postnatal day zero (P0).

2023-01-11 | GSE222392 | GEO

The role of nicotinamide phosphoribosyltransferase (Nampt) in hippocampal neural stem/progenitor cells

Project description:Neural stem/progenitor cell (NSPC) proliferation and self-renewal, as well as insult-induced differentiation, decrease markedly with age, but the molecular mechanisms responsible for these declines remain unclear. Here we show that levels of NAD+ and nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme in mammalian NAD+ biosynthesis, decrease with age in the hippocampus. Ablation of Nampt in adult NSPCs reduced their pool and proliferation in vivo. The decrease in the NSPC pool during aging can be rescued by enhancing hippocampal NAD+ levels. Nampt is the main source of NSPC NAD+ levels and required for G1/S progression of the NSPC cell cycle. Nampt is also critical for oligodendrocytic lineage fate decisions through a mechanism mediated redundantly by Sirt1 and Sirt2. Ablation of Nampt in the adult NSPCs in vivo reduced NSPC-mediated oligodendrogenesis upon injury. These phenotypes recapitulate defects in NSPCs during aging, implicating Nampt-mediated NAD+ biosynthesis as a mediator of these age-associated functional declines. Total RNA obtained from neurospheres derived from postnatal hippocampi subjected to 48 hours in vitro of incubation with Nampt-specific inhibitor FK866 (10 nM, 4 samples) or vehicle (DMSO, 1:1000, 4 samples).

2014-05-08 | E-GEOD-49784 | biostudies-arrayexpress

Transcriptomes of Neural Stem and Progenitor Cells from the subgranular zone (SGZ) of Wild Type (NTG) and 3xTg-AD mice at juvenile age

Project description:The goals of this study are to compare transcriptome profiling (RNA-seq) in wild-type (NTG) and 3xTg-AD mice, to determine the transcriptomal changes of neural stem and progenitor cells (NSPC) from the SGZ at early stages of Alzheimer's Disease in a mouse model. Methods: A tamoxifen (TAM)-inducible Nestin-CreERT2;ROSA26-EYFP reporter mouse line was cross-bred with NTG or 3xTG-AD mice to label NSPC upon TAM administration. YFP-positive NSPCs were sorted through FACS (Fluorescence-Activated Cell Sorting) 10 days after TAM from NTG; Nestin-CreERT2;ROSA26-EYFP and 3xTg-AD;Nestin-CreERT2;ROSA26-EYFP mice. RNA was extracted with RNeasy Micro Kit and deep-sequenced on the NovaSeq SP flowcell SR200 platform. The sequence reads of Fastq files that passed quality filters were aligned to the mouse genome (build mm10) using hisat2. Samtools was used to index the BAM files. DESeq2 was used to establish differential gene expression between NTG and 3xTg-AD samples. Results: We mapped about 48 million sequence reads per sample to the mouse genome (build mm10) and identified 1391 genes that were differentially expressed in the 3xTg-AD, with 720 down- and 671 up-regulated. Genes were considered significantly different between two genotypes if they meet the following criteria: 1) adjusted p-value < 0.05, and 2) log2 fold change > 0.5 or < -0.5. Conclusions: Gene ontology analysis of differentially expressed genes uncovered several pathways that may contribute to early neural stem cell decline in the 3xTg mice. Our results revealed very early perturbations in the SGZ neurogenic niche in the 3xTg mouse model of AD, manifested by intrinsic molecular changes in neural stem and progenitor cells (NSPC) at juvenile age, resulting in dysregulated neural stem cell homeostasis.

2023-02-15 | GSE218323 | GEO

The deubiquitinase USP22 stabilizes BMI1 polycomb ring finger oncoprotein to confer cancer stem cell traits and glioblastoma progression

Project description:Glioblastoma (GBM) is the most common and aggressive primary brain tumor with limited therapeutic options, possibly because of the highly tumorigenic subpopulations of stem cell-like cells. Mechanisms that sustain cancer stem cells are crucial to tumor progression. The polycomb group protein BMI1 (BMI1 proto-oncogene, polycomb ring finger) maintains cancer hallmarks including the glioblastoma stem-like cell (GSC) state. Ubiquitin-specific protease 22 (USP22) is highly expressed in and required for the maintenance of cancer stem cells (CSCs). Previously, we observed that forced expressed microRNA-218 in glioblastoma cells led to suppressed BMI1 expression. However, the pathways engaged by USP22 or driving BMI1 accumulation in GSCs remained elusive. Here, we found USP22 to be a novel deubiquitylase of BMI1. USP22 directly deubiquitylates and stabilizes BMI1. USP22 protein levels are elevated in tumor neurosphere. USP22 depletion induces BMI1 destabilization, and results in the inhibition of GSCs self-renewal by regulating a broad range of genes involved in glioma stemness and progression. Xenograft analyses using U87MG cells showed that both USP22 and BMI1 depletion attenuated tumor growth. Clinically, the expression levels of USP22 and BMI1 were positively correlated with those common targets like POSTN, HEY2, or PDGFRA and inversely correlated with ATF3 in human glioblastoma specimens. Taken together, our data reveals that USP22 functions as a novel deubiquitylase of BMI1 and inhibits self-renewal of GSCs by stabilizing BMI1. These findings also indicate that the USP22-BMI1 axis has a critical role in glioma tumorigenesis and that targeting the axis may provide a new therapeutic approach for human glioblastoma.

2017-01-01 | GSE89239 | GEO

The Polycomb protein BMI1 induces an invasive gene expression signature in melanoma that promotes metastasis and chemoresistance.

Project description:The epigenetic regulator BMI1 is upregulated in many human malignancies and has been implicated in cell migration, but the impact on autochthonous tumor progression is unexplored. Our analyses of human expression data show that BMI1 levels increase with progression in melanoma. We find that BMI1 expression in melanoma cells does not influence cell proliferation or primary tumor growth. In contrast, BMI1 levels are a key determinant of melanoma metastasis, whereby deletion impairs and overexpression enhances dissemination. Remarkably, BMI1’s pro-metastatic effect reflects enhancement of all stages of the metastatic cascade including invasion, migration, extravasation, adhesion and survival. Additionally, downregulation or upregulation of BMI1 induces sensitivity or resistance to BRAF inhibitor. Consistent with these pleiotropic effects, we find that BMI1 promotes widespread gene expression changes that encompass key hallmarks of the melanoma invasive signature, including activation of TGFβ, non-canonical Wnt, EMT and EGF/PDGF pathways. Importantly, for both primary and metastatic melanoma samples, this BMI1-induced signature identifies invasive subclasses of human melanoma and predicts poor patient outcome. Our data yield key insights into melanoma biology and establish BMI1 as a compelling drug target whose inhibition would suppress both metastasis and chemoresistance.

2016-02-03 | GSE71890 | GEO

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