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Cell competition regulates the fate decision of neural stem cells

ABSTRACT: Cell competition is a new notion of old theory Darwinian theory in cell level. It is notorious as its function on cancer promotion, actually, cell competition is a critical checkpoint machinery in development, its proper operation roles out suboptimal cells and makes sure the high quality of basic materials make up organism. Although its function has been revealed on other organs, it remains mysterious in brain development. In this paper, we get a compromised cell competitional model by knocking out endothelial Brd4, the lack of Brd4 in endothelial cell induces less neural stem cells deaths and compromised cell competition, endothelial Brd4 regulates cell competition is Testican2 dependent, Testican2 can deposit Sparc. We find a noncanonical role of the canonical negative cell competitional regulator Sparc in the fate decision of neural stem cells, neural stem cells highly expressing Sparc steps forward differentiation. We also find a compromised cell competition in AD patients, by cloning a point mutant of Brd4 found in a group of AD, we reveals that the mutant lose the potential of cell competition promotion. We put forward a new strategy for the treatment of aging related diseases by enhancing cell competitional state.

ORGANISM(S): Mus musculus

PROVIDER: GSE223131 | GEO | 2023/01/25

REPOSITORIES: GEO

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BRD4 orchestrates genome folding to promote neural crest progenitor differentiation

Project description:Higher-order chromatin structure is critical for proper gene regulation, but the relationship between genome folding and cellular identity remains elusive. Here, we show that genetic deletion of the Bromodomain-containing protein 4 (BRD4) in murine neural crest cells recapitulates features of cohesinopathies. We demonstrate that BRD4 interacts with NIPBL, a positive cohesin regulator, and acute depletion of BRD4 or loss of the BRD4-NIPBL interaction reduces NIPBL-occupancy, elucidating the importance of BRD4 in stabilizing NIPBL on chromatin. Genome-wide chromatin interaction mapping and quantitative imaging studies demonstrate that BRD4-depletion results in aberrant genome folding, specifically loss of a subset of chromatin loops, weakening of TADs, and compromised loop extrusion. Finally, loss of BRD4 or the interaction with NIPBL impedes neural crest differentiation which, remarkably, is rescued by WAPL depletion, a negative cohesin regulator. Our data reveal that BRD4 choreographs genome folding, illustrating the importance of balancing cohesin activity on progenitor differentiation.

2021-07-16 | GSE169516 | GEO

A 9-kDa matricellular SPARC fragment released by cathepsin D exhibits pro-tumor activity in cancer

Project description:The remodeling of the extracellular matrix (ECM) by proteases releases fragments that promote tumor progression and metastasis. The protease cathepsin D (cath-D), a marker of poor prognosis in triple-negative breast cancer (TNBC), is aberrantly secreted in the ECM. Using degradomics, we discovered that the matricellular protein SPARC is a substrate of extracellular cath-D. In vitro, cath-D induced limited proteolysis of SPARC C-terminal extracellular Ca2+ binding domain at acidic pH, leading to the production of SPARC fragments (34-, 27-, 16-, 9-, and 6-kDa). Cath-D secreted by TNBC cells cleaved fibroblast- and cancer cell-derived SPARC at the tumor pericellular pH. SPARC cleavage also occurred in TNBC tumors. Among these fragments, the 9-kDa SPARC fragment inhibited TNBC cell adhesion and spreading, and stimulated their migration, endothelial transmigration and invasion more potently than full-length SPARC. Our study establishes a novel crosstalk between proteases and matricellular proteins in the ECM through limited proteolysis of SPARC, revealing a novel targetable 9-kDa bioactive SPARC fragment for TNBC.

2021-09-09 | PXD022826 | Pride

Transcriptional profile of genes affected by the loss of Brd4 in the embryonic stem cells

Project description:BRD4 is an important epigenetic reader implicated in the pathogenesis of a number of different cancers and other diseases. Brd4-null mouse embryos die shortly after implantation and are compromised in their ability to maintain the inner cell mass (ICM), which gives rise to embryonic stem cells (ESCs). We investigated the functions of Brd4 in the ESCs in the present study. To determine the Brd4 target genes in embryonic stem cells. TL1 ESCs were transfected with control siRNA, or Brd4 siRNA. At 48 h post-transfection, total RNAs were isolated using the RNeasy minikit (Qiagen). Expression microarray analyses were performed on mRNA samples isolated from three independent experiments using a mouse Gene 2.0ST array (Affymetrix) at the University of Pennsylvania Microarray Core Facility. RMA from Affymetrix package was applied to the data for preprocessing and normalization. Limma was used for detection of differentially expressed genes. Benjamini & Hochberg correction was applied for the multiple comparisons.

2014-10-01 | E-GEOD-59142 | biostudies-arrayexpress

Transcriptional profile of genes affected by the loss of Brd4 in the embryonic stem cells

2014-10-01 | GSE59142 | GEO

DNA-binding pluripotency factors and DNA demethylases can cooperate to maintain pluripotent stem cell identity even in the absence of Brd4 [ATAC-seq]

Project description:The relative contributions of sequence-specific transcription factors and DNA/histone modifications to stem cell maintenance remains controversial. For example, the acetyllysine reader Brd4 has been implicated in stem cell maintenance, but how absolute the role of Brd4 is in maintaining pluripotency remains unclear. Here we show that Brd4 is dispensable for the proliferation, self-renewal and pluripotency of embryonic stem cells. In naive, ground state pluripotent stem cells, Mediator recruitment and transcription factor binding to stem cell-specific genes are maintained in the absence of Brd4 function or expression. Even in metastable embryonic stem cells poised for differentiation, Brd4 independence can be maintained by overexpression of pluripotency transcription factors so long as the DNA methylcytosine oxidases, Tet1 and Tet2, are present to facilitate chromatin accessibility. These data reveal that Brd4 is not essential for self-renewal of embryonic stem cells. Rather, Brd4 contributes to stem cell maintenance only under conditions where the expression of pluripotency transcription factors and/or DNA demethylation machinery is compromised.

2018-04-09 | GSE95641 | GEO

Transcription profiling of mouse SPARC-null vs. wild-type lens epithelium

Project description:SPARC is a matricellular glycoprotein involved in regulation of the extracellular matrix, growth factors, adhesion, and migration. SPARC-null mice have altered basement membranes and develop posterior sub-capsular cataracts with cell swelling and equatorial vacuoles. Exchange of fluid, nutrients, and waste products in the avascular lens is driven by a unique circulating ion current. Here we demonstrate that SPARC-null mouse lenses exhibit abnormal circulation of fluid, ion, and small molecules which leads to altered fluorescein distribution in vivo, loss of resting membrane polarization, and altered distribution of small molecules. Microarray analysis of SPARC-null lenses showed changes in gene expression of ion channels and receptors, matrix and adhesion genes, cytoskeleton, immune response genes, and cell signaling molecules. Our results demonstrate that the regulation of SPARC on cell-capsular matrix interactions can influence the circulation of fluid and ions in the lens, and the phenotype in the SPARC-null mouse lens is the result of multiple intersecting pathways. Experiment Overall Design: Lens epithelial cells from 7 lenses of littermate mice were isolated by laser capture microdissection. 3 wild-type lenses from 3 different mice and 4 knock-out lenses from 3 different mice were used as biological replicates.

2009-05-11 | E-GEOD-13402 | biostudies-arrayexpress

Social status and ejaculate investment in the house mouse c4pr_liv

Project description:Sperm competition theory predicts that males should tailor ejaculates according to their social status. Here we test this in a model vertebrate, the house mouse (Mus musculus domesticus), combining experimental data with a quantitative proteomics analysis of seminal fluid composition. Our analyses reveal that both sperm production and the relative production of proteins found in seminal fluid differ according to social dominance. Notably, whereas dominant males produce and ejaculate more sperm, subordinate males produce greater relative amounts of key proteins used in the formation of copulatory plugs. These findings have important implications for understanding the dynamics and outcome of sperm competition.

2021-09-09 | PXD019727 | Pride

Genome-wide analysis of SPARC(secreted protein acidic and rich in cysteine)-responsive gene expression in HTR-8/SVneo cells

Project description:SPARC is a matricellular glycoprotein that plays critical roles in the pathologies associated with obesity and diabetes, as well as tumorigenesis. The objective of this study was to investigate the role of SPARC in the process of trophoblast invasion which shares many similarities with tumor cells invasion. Our results reveals that hormones, cell adhesion molecules, ECM molecules, growth factors and cytokines all are mediated by SPARC in EVT invasion. HTR-8/SVneo cells were transfected with SPARC siRNA or a 25-nucleotide universal negative control siRNA using Lipofectamine 2000 according to the manufacturer’s protocol. Seventy-two hours after transfection, cells were harvested and RNA was isolated using standard procedures.

2012-04-27 | E-GEOD-37639 | biostudies-arrayexpress

Chromatin-associated protein interactions drive megadomain formation in NUT midline carcinoma

Project description:To investigate the mechanism that drives dramatic mistargeting of active chromatin in NUT-midline carcinoma, we have identified protein interactions unique to the BRD4-NUT fusion oncoprotein compared to wild type BRD4. Using crosslinking, affinity purification, and mass spectrometry, we identify the p300 acetyltransferase as ectopically associated with BRD4 through the NUT fusion in both NMC and non-NMC cell types. We also identify ZNF532 among a number of candidates uniquely associated with BRD4-NUT in NMC patient cells but not present in 293T cells. p300 and ZNF532 are both implicated in feed-forward regulatory loops leading to propagation of the oncogenic regulatory complex in BRD4-NUT patient cells. Extending our biochemical findings, we independently identified a novel ZNF532-NUT translocation fusion in a newly diagnosed NMC patient. ChIP-seq of key players: NUT, ZNF532, BRD4, p300, and anti-H3K27ac, reveals the formation of ZNF532-NUT-associated hyperacetylated megadomains, distinctly localized, but otherwise analogous to those found in BRD4-NUT patient cells. Our results support a model in which NMC is caused by a cascade of misregulation that is initiated by ectopic protein-protein interactions on chromatin between NUT and several distinct, but interacting, components of BRD4 regulatory complexes.

2017-08-22 | GSE96775 | GEO

A phenotypic screening platform for chronic pain therapeutics using all-optical electrophysiology

Project description:Chronic pain associated with osteoarthritis (OA) remains an intractable problem with few effective treatment options. New approaches are needed to model the disease biology and to drive discovery of therapeutics. Here, we present an in vitro model of OA pain, where dorsal root ganglion (DRG) sensory neurons were sensitized by a defined mixture of disease-relevant inflammatory mediators, here called Sensitizing PAin Reagent Composition or SPARC. OA-SPARC components showed synergistic or additive effects when applied in combination and induced pain phenotypes in vivo. To measure the effect of OA-SPARC on neural firing in a scalable format for drug discovery, we used a custom system for high throughput all-optical electrophysiology. This system enabled light-based membrane voltage recordings from hundreds of neurons in parallel with single cell resolution and a throughput of up to 500,000 neurons per day, with patch clamp-like single action potential resolution. A computational framework was developed to construct a multiparameter OA-SPARC neuronal phenotype and to quantitatively assess phenotype reversal by candidate pharmacology with different mechanisms of action. We screened ~3000 approved drugs and mechanistically focused compounds, yielding data from over 1.2 million individual neurons with detailed assessment of both functional OA-SPARC phenotype rescue and orthogonal “off-target” effects. Analysis of confirmed hits revealed diverse potential analgesic mechanisms including well-known ion channel modulators as well as less characterized mechanisms including MEK inhibitors and tyrosine kinase modulators, providing validation of the platform for pain drug discovery.

2023-08-02 | GSE237797 | GEO

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