Gene expression data from zebrafish SHH medulloblastoma brains and normal brains.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1015242 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26034368_1.fastq.gz | Fastqsanger.gz | |||
| SRR26034368_2.fastq.gz | Fastqsanger.gz | |||
| SRR26034369_1.fastq.gz | Fastqsanger.gz | |||
| SRR26034369_2.fastq.gz | Fastqsanger.gz | |||
| SRR26034370_1.fastq.gz | Fastqsanger.gz |
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Project description:Sonic hedgehog (Shh) signaling plays a critical role in regulating cerebellum development by maintaining the physiological proliferation of granule neuron precursors (GNPs), and its dysregulation leads to the oncogenesis of medulloblastoma. O-GlcNAcylation (O-GlcNAc) of proteins is an emerging regulator of brain function that maintains normal development and neuronal circuitry. Here, we demonstrate that O-GlcNAc transferase (OGT) in GNPs mediate the cerebellum development, and the progression of the Shh-subgroup of medulloblastoma. Specifically, OGT regulates the proliferation of GNPs by activating the Shh signaling pathway via O-GlcNAcylation at S355 of GLI family zinc finger 2 (Gli2), which in turn promotes its deacetylation and transcriptional activity via dissociation from p300, a histone acetyltransferases (HATs). Inhibition of OGT via genetic ablation or chemical inhibition improves survival in a medulloblastoma mouse model. These data uncover a critical role for O-GlcNAc signaling in cerebellar development, and pinpoint a potential therapeutic target for Shh-associated medulloblastoma.
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Project description:The childhood brain tumour medulloblastoma includes four subtypes with very different prognoses. Here, we show that paracrine signals driven by mutant Beta-Catenin in WNT-medulloblastoma â an essentially curable form of the disease â induce an aberrant fenestrated vasculature that permits the accumulation of high levels of intra-tumoural chemotherapy and a robust therapeutic response. In contrast, SHH-medulloblastoma â a less curable disease subtype â contains an intact blood brain barrier, rendering this tumour impermeable and resistant to chemotherapy. Remarkably, the medulloblastoma-endothelial cell paracrine axis can be manipulated in vivo, altering chemotherapy permeability and clinical response. Thus, medulloblastoma genotype dictates tumour vessel phenotype, explaining in part the disparate prognoses among medulloblastoma subtypes and suggesting an approach to enhance the chemoresponsiveness of other brain tumours. We used microarrays to detail the global program of gene expression within endothelial cells from normal mouse hindbrain and genetic mouse models of different medulloblastoma subtypes to identify and verify up-regulated and down-regulated genes Endothelial cells were isolated from adult mouse hindbrain and genetic mouse models of Wnt and Shh-medulloblastoma using Cd-144 and Cd-105 antibodies based magnetic sorting. RNA was extracted and used for hybridization on Affymetrix microarrays. We sought to identify changes in endothelial gene expression patterns based on the surrounding microenvironment, so we purified endothelial cells from normal mouse brain or tumors from genetic mouse models. These include the Shh-medulloblastoma model (Ptch+/-; Ink4c -/-) and Wnt-medulloblastoma model (Blbp-Cre; mutant Ctnnb1+/-; p53-/-; mutant Pik3ca +/-)
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Project description:Sequencing data of human SHH medulloblastoma samples
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Project description:Germline loss-of-function (LOF) variants in Elongator complex protein 1 (ELP1) are the most prevalent predisposing genetic events in childhood medulloblastoma (MB), accounting for ~30% of the Sonic Hedgehog (SHH) 3 subtype. The underlying mechanism(s) by which germline ELP1 deficiency provokes SHH-MB pathogenesis remain unknown. Genetically engineered mice mimicking heterozygous germline Elp1 LOF (Elp1HET) seen in affected germline carriers exhibit hallmark features of cancer predisposition in cerebellar granule neuron progenitors (GNPs), including increased DNA replication stress, genomic instability, accelerated cell cycle, and stalled differentiation. Orthotopic transplantation of Elp1HET GNPs harboring somatic Ptch1 inactivation yielded SHH-MB-like tumors with compromised p53 signaling, providing an explanation for the exclusivity of ELP1-associated MBs in SHH-3 subtype. Preclinical treatment of ELP1-mutant patient-derived xenografts with an FDA-approved HDM2 inhibitor reactivated p53-dependent apoptosis and extended survival. Our findings functionally substantiate the role of ELP1 deficiency in SHH-MB predisposition and nominate therapeutics that overcome p53 inhibition as a rational treatment option.
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Project description:Medulloblastoma could be classified into four subtypes: Wnt, Shh, Group 3, and Group 4. Subtypes of medulloblastoma have distinct epigenetic properties. We report that a chromatin regulator SMARCA4/Brg1 controls a transcriptional program that specifically required for Shh-type medulloblastoma identity and proliferation. We show that Brg1 deletion significantly inhibited tumor formation and progression in a mouse medulloblastoma model. Genomic experiments indicate that Brg1 specifically coordinates with key transcription factors including Gli1, Atoh1, and REST to regulate the expression of both oncogenes and tumor suppressors. Shh-type medulloblastoma displays distinct H3K27me3 properties. We demonstrate that Brg1 modulates activities of H3K27me3 modifiers to regulate expression of medulloblastoma genes. Brg1 is important for the growth of a human medulloblastoma cell line and Brg1-regulated pathways are conserved in human Shh-type medulloblastoma. This study reveals a novel epigenetic mechanism that controls medulloblastoma development and provides a rationale for developing subtype-specific treatment strategies.
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