Filters
Technology
Platform
GSE24628
Mus musculus
16 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Medulloblastoma encompasses a collection of clinically and molecularly diverse tumor subtypes that together comprise the most common malignant childhood brain tumor. These tumors are thought to arise within the cerebellum, with approximately 25% originating from granule neuron precursor cells (GNPCs) following aberrant activation of the Sonic Hedgehog pathway (hereafter, SHH-subtype). The pathological processes that drive heterogeneity among the other medulloblastoma subtypes are not known, hindering the development of much needed new therapies. Here, we provide evidence that a discrete subtype of medulloblastoma that contains activating mutations in the WNT pathway effector CTNNB1 (hereafter, WNT-subtype), arises outside the cerebellum from cells of the dorsal brainstem. We found that genes marking human WNT-subtype medulloblastomas are more frequently expressed in the lower rhombic lip (LRL) and embryonic dorsal brainstem than in the upper rhombic lip (URL) and developing cerebellum. Magnetic resonance imaging (MRI) and intra-operative reports showed that human WNT-subtype tumors infiltrate the dorsal brainstem, while SHH-subtype tumors are located within the cerebellar hemispheres. Activating mutations in Ctnnb1 had little impact on progenitor cell populations in the cerebellum, but caused the abnormal accumulation of cells on the embryonic dorsal brainstem that included aberrantly proliferating Zic1+ precursor cells. These lesions persisted in all mutant adult mice and in 15% of cases in which Tp53 was concurrently deleted, progressed to form medulloblastomas that recapitulated the anatomy and gene expression profiles of human WNT-subtype medulloblastoma. We provide the first evidence that subtypes of medulloblastoma have distinct cellular origins. Our data provide an explanation for the marked molecular and clinical differences between SHH and WNT-subtype medulloblastomas and have profound implications for future research and treatment of this important childhood cancer.
Publication Title
Subtypes of medulloblastoma have distinct developmental origins.
Sample Metadata Fields
Specimen part
View Samples- Rattus norvegicus
- 3 Downloadable Samples
- Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
The LH surge triggers dramatic transcriptional changes in genes associated with ovulation and luteinization. The present study investigated the spatiotemporal expression of nuclear factor interleukin-3 (NFIL3), a transcriptional regulator of the bZIP transcription factor superfamily, and its potential role in the ovary during the periovulatory period. NFIL3, also known as E4-binding protein 4 or NFIL3/E4BP4, was originally identified as a transcriptional repressor based on its DNA-binding activity at the promoter of the gene encoding the adenovirus E4 protein. Immature female rats were injected with PMSG, treated with hCG, and ovaries or granulosa cells were collected at various times after hCG. Nfil3 mRNA was highly induced both in intact ovaries and granulosa cells after hCG treatment. In situ hybridization demonstrated that Nfil3 mRNA was highly induced in theca-interstitial cells at 4-8 h after hCG, localized to granulosa cells at 12 h, and decreased at 24 h. Over-expression of NFIL3 in granulosa cells inhibited the induction of prostaglandin-endoperoxide synthase 2 (Ptgs2), progesterone receptor (Pgr), epiregulin (Ereg), and amphiregulin (Areg) and down regulated levels of prostaglandin E2. The inhibitory effect on Ptgs2 induction was reversed by NFIL3 siRNA treatment. In theca-interstitial cells the expression of hydroxyprostaglandin dehydrogenase 15-(NAD) (Hpgd) was also inhibited by NFIL3 over-expression. Data from luciferase assays demonstrated that NFIL3 over-expression decreased the induction of the Ptgs2 and Areg promoter activity. EMSA and ChIP analyses indicated that NFIL3 binds to the promoter region containing the DNA binding sites of CREB and C/EBP?. In summary, hCG induction of NFIL3 expression may modulate the process of ovulation and theca-interstitial and granulosa cell differentiation by regulating expression of PTGS2, PGR, AREG, EREG, and HPGD, potentially through interactions with CREB and C/EBP? on their target gene promoters.
Publication Title
A role for nuclear factor interleukin-3 (NFIL3), a critical transcriptional repressor, in down-regulation of periovulatory gene expression.
Sample Metadata Fields
Sex
View Samples- Homo sapiens
- 23 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Determining mechanism-based biomarkers that distinguish adaptive and adverse cellular processes is critical to understanding the health effects of environmental exposures. Shifting from in vivo, low-throughput toxicity studies to high-throughput screening (HTS) paradigms and risk assessment based on in vitro and in silico testing requires utilizing toxicity pathway information to distinguish adverse outcomes from recoverable adaptive events. Little work has focused on oxidative stresses in human airway for the purposes of predicting adverse responses. We hypothesize that early gene expression-mediated molecular changes could be used to delineate adaptive and adverse responses to environmentally-based perturbations. Here, we examined cellular responses of the tracheobronchial airway to zinc (Zn) exposure, a model oxidant. Airway derived BEAS-2B cells exposed to 210 M Zn2+ elicited concentration- and time-dependent cytotoxicity. Normal, adaptive, and cytotoxic Zn2+ exposure conditions were determined with traditional apical endpoints, and differences in global gene expression around the tipping point of the responses were used to delineate underlying molecular mechanisms. Bioinformatic analyses of differentially expressed genes indicate early enrichment of stress signaling pathways, including those mediated by the transcription factors p53 and NRF2. After 4 h, 154 genes were differentially expressed (p <0.01) between the adaptive and cytotoxic Zn2+ concentrations. Nearly 40% of the biomarker genes were related to the p53 signaling pathway with 30 genes identified as likely direct targets using a database of p53 ChIP-seq studies. Despite similar p53 activation profiles, these data revealed widespread dampening of p53 and NRF2-related genes as early as 4 h after exposure at higher, unrecoverable Zn2+ exposures. Thus, in our model early increased activation of stress response pathways indicated a recoverable adaptive event. Overall, this study highlights the importance of characterizing molecular mechanisms around the tipping point of adverse responses to better inform HTS paradigms.
Publication Title
Developing a Gene Biomarker at the Tipping Point of Adaptive and Adverse Responses in Human Bronchial Epithelial Cells.
Sample Metadata Fields
Cell line, Time
View Samples- Mus musculus
- 10 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Human medulloblastoma (MB) can be segregated into four major categories based on gene expression patterns: Hedgehog (HH) subtype, Wnt subtype, Group 3, and Group 4. However, they all exhibit strikingly different gene expression profiles from Atypical Teratoid/Rhabdoid Tumor (AT/RT). We re-analyzed published gene expression microarray dataset of pediatric brain tumors to identify a gene expression profile that clearly distinguished human AT/RT from human MB. We used this profile, choosing only genes that have clear murine orthologs, to compare tumors from Snf5F/Fp53L/LGFAP-Cre mice (in C57Bl/6 strain background) with MB from Ptc1+/- mice (in mixed C57Bl/6 and 129Sv strain background). Snf5F/Fp53L/LGFAP-Cre tumors are clearly very different from mouse MB and the markers that distinguish human AT/RT from human MB also distinguish the mouse tumors.
Publication Title
Generation of a mouse model of atypical teratoid/rhabdoid tumor of the central nervous system through combined deletion of Snf5 and p53.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 4 Downloadable Samples
- Affymetrix Murine 11K SubB Array (mu11ksubb), Affymetrix Murine 11K SubA Array (mu11ksuba)
Description
PKR is an interferon induced serine/threonine protein kinase, that is activated by double stranded RNA. PKR plays an important role in the antiviral defense by interferon. In addition to its role in translation, PKR participates in several signaling pathways to transcription. The goal of this experiment is to study the role of PKR in regulating gene expression in our NIH 3T3 inducible cell line, which could overexpress PKR wt protein after the removal of tetracycline (Donze O, Dostie J, Sonenberg N. (1999) Virology 256: 322-9).
Publication Title
The protein kinase PKR: a molecular clock that sequentially activates survival and death programs.
Sample Metadata Fields
Cell line
View Samples- Rattus norvegicus
- 48 Downloadable Samples
- Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
To investigate the molecular mechanisms associated with initial dose-related events that are linked to the development of liver tumours: liver growth; cell proliferation; changes in histopathology such as hypertrophy
Publication Title
An integrated functional genomic study of acute phenobarbital exposure in the rat.
Sample Metadata Fields
Specimen part, Time
View Samples- Rattus norvegicus
- 4 Downloadable Samples
- Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
LH-indced RUNX2 expression is important for luteal gene expression.
Publication Title
RUNX2 transcription factor regulates gene expression in luteinizing granulosa cells of rat ovaries.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Homo sapiens
- 376 Downloadable Samples
- Affymetrix HT HG-U133+ PM Array Plate (hthgu133pluspm)
Description
Whole blood (paxgene) gene expression was measured using Affymetrix microarray from 377 individuals with rheumatoid arthritis.
Publication Title
Integrative genomic deconvolution of rheumatoid arthritis GWAS loci into gene and cell type associations.
Sample Metadata Fields
Sex, Age, Specimen part, Disease
View Samples- Rattus norvegicus
- 39 Downloadable Samples
- Affymetrix Rat Genome U34 Array (rgu34a)
Description
Although glucocorticoids (GCs) are known to exert numerous effects in the hippocampus, their chronic regulatory functions remain poorly understood. Moreover, evidence is inconsistent regarding the longstanding hypothesis that chronic GC exposure promotes brain aging/Alzheimer's disease. Here, we adrenalectomized male F344 rats at 15-months-of-age, maintained them for 3 months with implanted corticosterone (CORT) pellets producing low or intermediate (glucocorticoid-receptor (GR)-activating) blood levels of CORT, and performed microarray/pathway analyses in hippocampal CA1. We defined the chronic GC-dependent transcriptome as 393 genes that exhibited differential expression between Intermediate- and Low-CORT groups. Short-term CORT (4 days) did not recapitulate this transcriptome. Functional processes/pathways overrepresented by chronic CORT-upregulated genes included learning/plasticity, differentiation, glucose metabolism and cholesterol biosynthesis, whereas processes overrepresented by CORT-downregulated genes included inflammatory/immune/glial responses and extracellular structure. These profiles indicate that GCs chronically activate neuronal/metabolic processes while coordinately repressing a glial axis of reactivity/inflammation. We then compared the GC-transcriptome with a previously-defined hippocampal aging transcriptome, revealing a high proportion of common genes. Although CORT and aging moved expression of some common genes in the same-direction, the majority were shifted in opposite directions by CORT and aging (e.g., glial inflammatory genes downregulated by CORT are upregulated with aging). These results contradict the hypothesis that GCs simply promote brain aging, and also suggest that the opposite-direction shifts during aging reflect resistance to CORT regulation. Therefore, we propose a new model in which aging-related GC resistance develops in some target pathways while GC overstimulation develops in others, together generating much of the brain aging phenotype.
Publication Title
Glucocorticoid-dependent hippocampal transcriptome in male rats: pathway-specific alterations with aging.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Homo sapiens
- 18 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Recent data suggests that common genetic risk for metabolic disorders such as obesity may be human-specific and exert effects through the central nervous system. To overcome the limitation of human tissue access for study, we have generated induced human pluripotent stem cell (hiPSC)- derived neuronal cultures which recapture many features of hypothalamic neurons within the arcuate nucleus. Here we have comprehensively characterized this model across development and benchmarked these neurons to in vivo events. We also demonstrate their utility in study of obesity risk variants. The dynamic transcriptome across neuronal maturation was examined using microarray and RNAseq methods at 9 time points. K-means clustering of the longitudinal data was conducted to identify co-regulation and miRNA control of biological processes. The transcriptomes were compared to those of 103 samples from 13 brain regions reported in the Genotype-Tissue Expression database (GTEx) using principal components analysis. Genes with proximity to body mass index (BMI)-associated genetic variants were mapped to the developmentally expressed genesets, and enrichment significance was assessed with Fishers exact test. The human neuronal cultures have a transcriptional and physiological profile of NPY/AgRP hypothalamic neurons. The neuronal transcriptomes were highly correlated with adult hypothalamus as compared to any other brain region from the GTEx. Also, roughly 25% of the transcripts showed changes in expression across maturation stages and potential co-regulation of biological processes that mirror neuronal development in vivo. These developmentally expressed genes were significantly enriched for genes in proximity to BMI-associated variants.
Publication Title
Molecular Profiling of Human Induced Pluripotent Stem Cell-Derived Hypothalamic Neurones Provides Developmental Insights into Genetic Loci for Body Weight Regulation.
Sample Metadata Fields
Specimen part
View Samples