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Mus musculus
8 Downloadable Samples
Affymetrix Mouse Genome 430A 2.0 Array (mouse430a2)
Description
FTY720/Fingolimod, an FDA-approved drug for treatment of multiple sclerosis, has beneficial effects in the CNS that are not yet well understood, independent of its effects on immune cell trafficking. Here we show that FTY720 enters the nucleus where it is phosphorylated by sphingosine kinase 2 (SphK2) and nuclear FTY720-P that accumulates there, binds and inhibits class I histone deacetylases (HDACs) enhancing specific histone acetylations. FTY720 is also phosphorylated in mice and accumulates in various brain regions, including hippocampus, inhibits HDACs and enhances histone acetylation and gene expression programs associated with memory and learning leading to improvement of memory impairment independently of its immunosuppressive actions. Our data suggest that sphingosine-1-phosphate and SphK2 play specific roles in memory functions and that FTY720 may be a useful adjuvant therapy to facilitate extinction of aversive memories.
Publication Title
Active, phosphorylated fingolimod inhibits histone deacetylases and facilitates fear extinction memory.
Sample Metadata Fields
Sex, Age, Specimen part, Treatment
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
ERα-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples- Homo sapiens
- 12 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
A significant fraction of breast cancers exhibit de novo or acquired resistance to estrogen deprivation. To model resistance to aromatase inhibitor (AI) therapy, long-term estrogen-deprived (LTED) derivatives of MCF-7 and HCC-1428 cells were generated through culture for 3 and 7 months under hormone-depleted conditions, respectively. These LTED cells showed sensitivity to the ER downregulator fulvestrant under hormone-depleted conditions, suggesting continued dependence upon ER signaling for hormone-independent growth. To evaluate the role of ER in hormone-independent growth, LTED cells were treated +/- 1 uM fulvestrant x 48 h before RNA was harvested for gene expression analysis.
Publication Title
ERα-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
RNA from circulating blood reticulocytes was utilized to provide a robust description of genes transcribed at the final stages of erythroblast maturation. After depletion of leukocytes and platelets, Affymetrix HG-U133Plus 2.0 arrays were hybridized with probe from total RNA isolated from blood sampled from 6 umbilical cords and 6 healthy adult humans.
Publication Title
Let-7 microRNAs are developmentally regulated in circulating human erythroid cells.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 22 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Hyperactivation of phosphatidylinositol-3 kinase (PI3K) promotes escape from hormone dependence in estrogen receptor-positive breast cancer.
Publication Title
Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Mus musculus
- 22 Downloadable Samples
Illumina HiSeq 2500
Description
Multiple sclerosis involves an aberrant autoimmune response and progressive failure of remyelination in the central nervous system. Prevention of neural degeneration and subsequent disability requires remyelination through the generation of new oligodendrocytes, but current treatments exclusively target the immune system. Oligodendrocyte progenitor cells are stem cells in the central nervous system and the principal source of myelinating oligodendrocytes. These cells are abundant in demyelinated regions of patients with multiple sclerosis, yet fail to differentiate, thereby representing a cellular target for pharmacological intervention. To discover therapeutic compounds for enhancing myelination from endogenous oligodendrocyte progenitor cells, we screened a library of bioactive small molecules on mouse pluripotent epiblast stem-cell-derived oligodendrocyte progenitor cells. Here we show seven drugs function at nanomolar doses selectively to enhance the generation of mature oligodendrocytes from progenitor cells in vitro. Two drugs, miconazole and clobetasol, are effective in promoting precocious myelination in organotypic cerebellar slice cultures, and in vivo in early postnatal mouse pups. Systemic delivery of each of the two drugs significantly increases the number of new oligodendrocytes and enhances remyelination in a lysolecithin-induced mouse model of focal demyelination. Administering each of the two drugs at the peak of disease in an experimental autoimmune encephalomyelitis mouse model of chronic progressive multiple sclerosis results in striking reversal of disease severity. Immune response assays show that miconazole functions directly as a remyelinating drug with no effect on the immune system, whereas clobetasol is a potent immunosuppressant as well as a remyelinating agent. Mechanistic studies show that miconazole and clobetasol function in oligodendrocyte progenitor cells through mitogen-activated protein kinase and glucocorticoid receptor signalling, respectively. Furthermore, both drugs enhance the generation of human oligodendrocytes from human oligodendrocyte progenitor cells in vitro. Collectively, our results provide a rationale for testing miconazole and clobetasol, or structurally modified derivatives, to enhance remyelination in patients. Overall design: RNA sequencing of oligodendrocyte progenitor cells treated with vehicle, miconazole or clobetasol for 0, 2, 6, or 12 hours. Cells were plated 1.5 hours prior to addition of drug.
Publication Title
Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo.
Sample Metadata Fields
No sample metadata fields
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GSE2189- Homo sapiens
- 18 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
Human lung cancer (A549) cells were treated 50uM of the metal cation-containing chemotherapeutic drug motexafin gadolinium (MGd) for 4, 12, and 24 hrs and expression compared to control cells (treated with 5% mannitol for the same length of time)
Publication Title
Motexafin gadolinium disrupts zinc metabolism in human cancer cell lines.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 10 Downloadable Samples
- Affymetrix Mouse Gene 1.1 ST Array (mogene11st)
Description
Nuclear receptors (NRs) are ligand-activated transcription factors regulating a large variety of processes involved in reproduction, development, and metabolism. NRs are ideal drug targets. Immortalized cell lines recapitulate NR biology very poorly and primary cultures are laborious and require a constant need for donor material. There is a clear need for development of novel preclinical model systems that better resemble human physiology since technical uncertainty early in drug development is the cause of many preclinical drugs not reaching the clinic. Here, we studied whether organoids, mini-organs derived from the respective tissues stem cells, can serve as a novel (preclinical) model system to study NR biology and targeteability. We characterized mRNA expression profiles of the NR superfamily in mouse liver, ileum, and colon organoids. NR mRNA expression patterns were similar to the respective tissues, indicating their suitability for NR research. Metabolic NRs Fxr, Lxr, Lxr, Ppar, and Ppar were responsive to ligands in an NR-dependent fashion, as demonstrated by regulation of expression and binding to endogenous target genes. Transcriptome analyses of wildtype colonic organoids stimulated with Rosiglitazone showed that lipid metabolism was the highest significant changed function, greatly mimicking the known function of PPARs and Rosiglitazone in vivo. In conclusion, our results demonstrate that organoids constitutes a versatile and promising in vitro system to study NR biology and targeteability.
Publication Title
Characterization of stem cell-derived liver and intestinal organoids as a model system to study nuclear receptor biology.
Sample Metadata Fields
Treatment
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Methylation of histone H3 lysine 4 (H3K4me) at actively expressed, cell type-specific genes is established during development by the Trithorax group of epigenetic regulators. In mammals, the Trithorax family includes KMT2A-D (MLL1-4), a family of SET domain proteins that function in large complexes to impart mono-, di-, and trimethylation at H3K4. Individual KMT2s and their co-factors are essential for embryonic development and the establishment of correct gene expression patterns, presumably by demarcating the active and accessible regions of the genome in a cell specific and heritable manner. Despite the importance of H3K4me marks in development, little is known about the importance of histone methylation in maintaining gene expression patterns in fully differentiated and non-dividing cell types. In this report, we utilized an inducible cardiac-specific Cre driver to delete the PTIP protein, a key component of a H3K4me complex, and ask whether this activity is still required to maintain the phenotype of terminally differentiated cardiomyocytes. Our results demonstrate that reducing the H3K4me3 marks is sufficient to alter gene expression patterns and significantly augment systolic heart function. These results clearly show that maintenance of H3K4me3 marks is necessary for the stability of the transcriptional program in differentiated cells. The array we performed allowed us to identify genes that are regulated by PTIP and histone methylation.
Publication Title
Loss of H3K4 methylation destabilizes gene expression patterns and physiological functions in adult murine cardiomyocytes.
Sample Metadata Fields
Sex, Specimen part
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Direct cell fate conversion allows the generation of somatic cells that are otherwise difficult to obtain directly from patients. The clinical applicability of this approach depends on obtaining an initial source of somatic cells from adult patients that is easy to harvest, store, and manipulate for reprogramming. Here we have generated induced neural progenitor cells (iNPCs) from neonatal as well as peripheral blood from human adults using single factor OCT4 based reprogramming. Unlike fibroblasts that share molecular hallmarks of neural crest, direct OCT4 reprogramming of human blood could be facilitated by SMAD+GSK-3 inhibition to overcome restrictions on neural fate conversion. Blood derived (BD)-iNPCs functionally differentiate in vivo, and respond to guided differentiation in vitro to produce both glia (astrocytes and oligodendrocytes) and multiple neuronal subtypes including dopamine releasing DA neurons (CNS related) and nociceptive neurons (PNS). Furthermore, BD nociceptive neurons phenocopy chemotherapy induced neurotoxicity in a system suitable for high throughput drug screening. Our findings provide an easily accessible approach to generate human NPCs that harbor extensive developmental potential, enabling the study of clinically relevant neural diseases directly from patient cohorts.
Publication Title
Single Transcription Factor Conversion of Human Blood Fate to NPCs with CNS and PNS Developmental Capacity.
Sample Metadata Fields
Specimen part
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