The morphogen and mitogen, Sonic Hedgehog, activates a Gli1-dependent transcription program that drives proliferation of granule neuron progenitors (GNPs) within the external germinal layer of the postnatally developing cerebellum. Medulloblastomas with mutations activating the Sonic Hedgehog signaling pathway preferentially arise within the external germinal layer, and the tumor cells closely resemble GNPs. Atoh1/Math1, a basic helix-loop-helix transcription factor essential for GNP histogenesis, does not induce medulloblastomas when expressed in primary mouse GNPs that are explanted from the early postnatal cerebellum and transplanted back into the brains of nave mice. However, enforced expression of Atoh1 in primary GNPs enhances the oncogenicity of cells overexpressing Gli1 by almost three orders of magnitude. Unlike Gli1, Atoh1 cannot support GNP proliferation in the absence of Sonic Hedgehog signaling and does not govern expression of canonical cell cycle genes. Instead, Atoh1 maintains GNPs in a Sonic Hedgehog-responsive state by regulating genes that trigger neuronal differentiation, including many expressed in response to bone morphogenic protein-4. Therefore, by targeting multiple genes regulating the differentiation state of GNPs, Atoh1 collaborates with the pro-proliferative Gli1-dependent transcriptional program to influence medulloblastoma development.
Atoh1 inhibits neuronal differentiation and collaborates with Gli1 to generate medulloblastoma-initiating cells.
Age, Specimen part, Treatment
View SamplesMice lacking p53 and one or two alleles of the cyclin D-dependent kinase inhibitor p18Ink4c are prone to medulloblastoma development. The tumor frequency is increased by exposing postnatal animals to ionizing radiation at a time when their cerebella are developing. In irradiated mice engineered to express a floxed p53 allele and a Nestin-Cre transgene, tumor development can be restricted to the brain. Analysis of these animals indicated that inactivation of one or both Ink4c alleles did not affect the time of medulloblastoma onset but increased tumor invasiveness. All such tumors exhibited complete loss of function of the Patched 1 (Ptc1) gene encoding the receptor for sonic hedgehog, and many exhibited other recurrent genetic alterations, including trisomy of chromosome 6, amplification of N-Myc, modest increases in copy number of the Ccnd1 gene encoding cyclin D1, and other complex chromosomal rearrangements. In contrast, medulloblastomas arising in Ptc1+/- mice lacking one or both Ink4c alleles retained p53 function and exhibited only limited genomic instability. Nonetheless, complete inactivation of the wild type Ptc1 allele was a universal event, and trisomy of chromosome 6 was again frequent. The enforced expression of N-Myc or cyclin D1 in primary cerebellar granule neuron precursors isolated from Ink4c-/-, p53-/- mice enabled the cells to initiate medulloblastomas when injected back into the brains of immunocompromised recipient animals. These engineered tumors exhibited gene expression profiles indistinguishable from those of medulloblastomas that arose spontaneously. These results underscore the functional interplay between a network of specific genes that recurrently contribute to medulloblastoma formation.
Genetic alterations in mouse medulloblastomas and generation of tumors de novo from primary cerebellar granule neuron precursors.
No sample metadata fields
View SamplesTransfer RNA (tRNA) modifications enhance the efficiency, specificity and fidelity of translation in all organisms. The anticodon modification mcm5s2U34 is required for normal growth and stress resistance in yeast; mutants lacking this modification have numerous phenotypes. Mutations in the homologous human genes are linked to neurological disease. The yeast phenotypes can be ameliorated by overexpression of specific tRNAs, suggesting that the modifications are necessary for efficient translation of specific codons. We determined the in vivo ribosome distributions at single codon resolution in yeast strains lacking mcm5s2U. We found accumulations at AAA, CAA, and GAA codons, suggesting that translation is slow when these codons are in the ribosomal A site, but these changes appeared too small to affect protein output. Instead, we observed activation of the GCN4-mediated stress response by a non- canonical pathway. Thus, loss of mcm5s2U causes global effects on gene expression due to perturbation of cellular signaling. Overall design: WT yeast and mutants lacking anticodon tRNA modifications were grown in YPD, and subjected to ribosome footprint profiling (ribo-seq) and RNA-seq of poly-A selected RNA. Dataset contains biological replicates for WT, ?ncs6 and ?uba4. Technical replicates were also performed for all RNA-seq datasets (using a different poly-A selection method).
Loss of a conserved tRNA anticodon modification perturbs cellular signaling.
Cell line, Subject
View SamplesRON WT and RON KO at 5, 6, 7 week virgin mammary glands
The Ron receptor tyrosine kinase negatively regulates mammary gland branching morphogenesis.
Age
View SamplesWe examined the role of TREM2 on microglia responses to amyloid-beta deposition in a mouse model of Alzheimer's disease
TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model.
Age, Specimen part
View SamplesBackground: MYC is a transcription factor encoded by the c-MYC gene (thereafter termed MYC). MYC is key transcription factor involved in many central cellular processes including ribosomal biogenesis. MYC is overexpressed in the majority of human tumours including aggressive B-cell lymphoma especially Burkitt's lymphoma. Although Burkitt's lymphoma is a highlight example for MYC overexpression due to a chromosomal translocation, no global analysis of MYC binding sites by chromatin immunoprecipitation (ChIP) followed by global next generation sequencing (ChIP-Seq) has been conducted so far in Burkitt's lymphoma.
Deep sequencing of MYC DNA-binding sites in Burkitt lymphoma.
Specimen part, Cell line
View SamplesMedulloblastoma 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.
Subtypes of medulloblastoma have distinct developmental origins.
Specimen part
View Samples10 adult participants of dose group 3x10^6 pfu, and 10 participants of dose group 20x10^6 pfu. Reads were aligned to the human reference assembly (GRCh38.p7) using STAR software (v2.4.2a; option ''--quantMode GeneCounts''). Gene annotation was obtained from Ensembl (release 79, ensemble.org). VOOM+Limma analysis (R software, version 3.2.2) was used to assess differential gene expression at each post-vaccination day (d1, d3 and d7) against baseline (d0). Next, we intergreted gene expression data and antibody response using an sPLS algorithm, in order to down-select genes correlating with multivariate antibody responses at days 28, 54, 84,180. Overall design: 56 samples from D0, D1, D3 and D7 were analysed. Data from samples with low RIN (RIN <8, 17 samples), low RNA or library concentration (2 samples), missing samples (5 samples) were set to missing.
Systems Vaccinology Identifies an Early Innate Immune Signature as a Correlate of Antibody Responses to the Ebola Vaccine rVSV-ZEBOV.
Specimen part, Subject
View SamplesIL-2 production defines precursors fated to become T Follicular Helper cells Overall design: Sorted naïve IL-2.eGFP CD4 T cells were activvated in vitro or in vivo. Total RNA was isolated from CD69+ IL-2.eGFP+ and CD69+ IL-2.eGFP– CD4 T cells 18-24 hours after activation.
Differential IL-2 expression defines developmental fates of follicular versus nonfollicular helper T cells.
Specimen part, Cell line, Subject
View SamplesFCHL is a common, complex genetic lipid disorder with a largely unknown aetiology. Altered adipose tissue metabolism has been implicated as contributing to FCHL.
CDKN2B expression in adipose tissue of familial combined hyperlipidemia patients.
No sample metadata fields
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