Transcriptomic changes induced by Gsk-3-deletion in cerebellar progenitors
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE135463 | GEO | 2019/08/07
REPOSITORIES: GEO
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Project description:Microcephaly and medulloblastoma result from mutations that compromise genomic stability. We report that Atr, which is mutated in the microcephalic disorder Seckel syndrome, is required to maintain chromosomal integrity during postnatal cerebellar neurogenesis. Atr deletion in cerebellar granule neuron progenitors (CGNPs) induced proliferation-associated DNA damage, p53 activation, apoptosis, and cerebellar hypoplasia. Co-deletions of either Bax and Bak or p53 prevented apoptosis in Atr-deleted CGNPs, but failed to fully rescue cerebellar growth. Atr-deficient CGNPs showed impaired cell cycle checkpoint function and continued to proliferate, accumulating chromosomal abnormalities. RNA-Seq demonstrated that the transcriptional response to Atr-deficient proliferation was p53-driven. Acute Atr inhibition in vivo by nanoparticle-formulated VE-822 reproduced the disruptions seen with Atr deletion. Our data show that p53-driven apoptosis and senescence, and non-apoptotic cell death redundantly limit growth in Atr-deficient progenitors. These overlapping mechanisms that suppress growth in Atr-disrupted CGNPs may be exploited for treatment of CGNP-derived medulloblastoma using Atr inhibition.
2016-09-01 | GSE85393 | GEO
Project description:Microcephaly and medulloblastoma result from mutations that compromise genomic stability. We report that Atr, which is mutated in the microcephalic disorder Seckel syndrome, is required to maintain chromosomal integrity during postnatal cerebellar neurogenesis. Atr deletion in cerebellar granule neuron progenitors (CGNPs) induced proliferation-associated DNA damage, p53 activation, apoptosis, and cerebellar hypoplasia. Co-deletions of either Bax and Bak or p53 prevented apoptosis in Atr-deleted CGNPs, but failed to fully rescue cerebellar growth. Atr-deficient CGNPs showed impaired cell cycle checkpoint function and continued to proliferate, accumulating chromosomal abnormalities. RNA-Seq demonstrated that the transcriptional response to Atr-deficient proliferation was p53-driven. Acute Atr inhibition in vivo by nanoparticle-formulated VE-822 reproduced the disruptions seen with Atr deletion. Our data show that p53-driven apoptosis and senescence, and non-apoptotic cell death redundantly limit growth in Atr-deficient progenitors. These overlapping mechanisms that suppress growth in Atr-disrupted CGNPs may be exploited for treatment of CGNP-derived medulloblastoma using Atr inhibition.
2016-09-01 | GSE83720 | GEO
Project description:Medulloblastoma is the most common malignant pediatric brain tumor, and mechanisms underlying its development are poorly understood. We identified recurrent amplification of the miR-17/92 polycistron proto-oncogene in 6% of pediatric medulloblastomas by high-resolution single-nucleotide polymorphism genotyping arrays and subsequent interphase fluorescence in situ hybridization on a human medulloblastoma tissue microarray. Profiling the expression of 427 mature microRNAs (miRNA) in a series of 90 primary human medulloblastomas revealed that components of the miR-17/92 polycistron are the most highly up-regulated miRNAs in medulloblastoma. Expression of miR-17/92 was highest in the subgroup of medulloblastomas associated with activation of the sonic hedgehog (Shh) signaling pathway compared with other subgroups of medulloblastoma. Medulloblastomas in which miR-17/92 was up-regulated also had elevated levels of MYC/MYCN expression. Consistent with its regulation by Shh, we observed that Shh treatment of primary cerebellar granule neuron precursors (CGNP), proposed cells of origin for the Shh-associated medulloblastomas, resulted in increased miR-17/92 expression. In CGNPs, the Shh effector N-myc, but not Gli1, induced miR-17/92 expression. Ectopic miR-17/92 expression in CGNPs synergized with exogenous Shh to increase proliferation and also enabled them to proliferate in the absence of Shh. We conclude that miR-17/92 is a positive effector of Shh-mediated proliferation and that aberrant expression/amplification of this miR confers a growth advantage to medulloblastomas. A total of 90 primary medulloblastoma specimens were profiled by Affymetrix exon array and gene-level analysis was performed.
2010-04-14 | E-GEOD-21166 | biostudies-arrayexpress
Project description:Medulloblastoma is the most common malignant pediatric brain tumor, and mechanisms underlying its development are poorly understood. We identified recurrent amplification of the miR-17/92 polycistron proto-oncogene in 6% of pediatric medulloblastomas by high-resolution single-nucleotide polymorphism genotyping arrays and subsequent interphase fluorescence in situ hybridization on a human medulloblastoma tissue microarray. Profiling the expression of 427 mature microRNAs (miRNA) in a series of 90 primary human medulloblastomas revealed that components of the miR-17/92 polycistron are the most highly up-regulated miRNAs in medulloblastoma. Expression of miR-17/92 was highest in the subgroup of medulloblastomas associated with activation of the sonic hedgehog (Shh) signaling pathway compared with other subgroups of medulloblastoma. Medulloblastomas in which miR-17/92 was up-regulated also had elevated levels of MYC/MYCN expression. Consistent with its regulation by Shh, we observed that Shh treatment of primary cerebellar granule neuron precursors (CGNP), proposed cells of origin for the Shh-associated medulloblastomas, resulted in increased miR-17/92 expression. In CGNPs, the Shh effector N-myc, but not Gli1, induced miR-17/92 expression. Ectopic miR-17/92 expression in CGNPs synergized with exogenous Shh to increase proliferation and also enabled them to proliferate in the absence of Shh. We conclude that miR-17/92 is a positive effector of Shh-mediated proliferation and that aberrant expression/amplification of this miR confers a growth advantage to medulloblastomas.
2010-04-02 | GSE21166 | GEO
Project description:Medulloblastoma (MB) is the most common malignant brain tumor. MB is a cerebellar tumor that occurs mostly in children between the ages of 3-7 years but also in adults. Human MBs are classified into four subgroups: Wingless (WNT), Sonic Hedgehog (SHH), Group 3 (G3) and G4, each of which with distinct molecular signatures. SHH MBs with MYCN amplification and TP53 mutations and G3 MBs characterized by C-MYC (MYC) overexpression in ~17% of cases from gene amplification with stem like properties, are the most aggressive and least curable with current therapeutic regimen. Using an orthotopic transplant approach, we found that enforced expression of MYCN in cerebellar granule neural progenitors (CGNPs) from 5-7 days old Trp53-null mice induced SHH MBs after transfer in the cortices or cerebella of naive recipient mice. In contrast, overexpression of MYC induced G3 MBs. Because MYCN and MYC bind to the same E-box DNA sequences, we hypothesized that the difference between MYC and MYCN-induced gene expression and tumor identity might be due to their interaction with different partners in CGNPs. In this study, we investigated the role of the Myc interacting zinc finger protein 1 (MIZ1). We found that MIZ1 binds with higher affinity to MYC than to MYCN and that MIZ1 and MYC co-occupy thousands of promoters in G3 MB. Remarkably, enforced expression of a MYC mutant (MYCV394D) that no longer binds to MIZ1 in Trp53-null CGNPs or expression of wild type MYC in CGNPs that lack functional Miz1 resulted in massive changes of the resulting tumorâ??s transcriptional program. Tumors differed from both SHH and G3 medulloblastoma and had a later time of onset compared to MYC-driven G3 medulloblastoma. Our data demonstrate that interaction of MYC with MIZ1 is required for the development of G3 medulloblastoma. ChIP-Seq experiments for Miz1, c-Myc and NMyc from murine medulloblastoma material. Either sorted tumor cells (Miz1 and c-Myc) or spheres from tumor cells (Miz1 and NMyc) were used. Input-samples were sequenced as controls. RNA-Seq from G3 medulloblastomas after restoration of Atoh1 expression.
2016-01-21 | E-GEOD-64425 | biostudies-arrayexpress
Project description:Medulloblastoma (MB) is the most common malignant brain tumor. MB is a cerebellar tumor that occurs mostly in children between the ages of 3-7 years but also in adults. Human MBs are classified into four subgroups: Wingless (WNT), Sonic Hedgehog (SHH), Group 3 (G3) and G4, each of which with distinct molecular signatures. SHH MBs with MYCN amplification and TP53 mutations and G3 MBs characterized by C-MYC (MYC) overexpression in ~17% of cases from gene amplification with stem like properties, are the most aggressive and least curable with current therapeutic regimen. Using an orthotopic transplant approach, we found that enforced expression of MYCN in cerebellar granule neural progenitors (CGNPs) from 5-7 days old Trp53-null mice induced SHH MBs after transfer in the cortices or cerebella of naive recipient mice. In contrast, overexpression of MYC induced G3 MBs. Because MYCN and MYC bind to the same E-box DNA sequences, we hypothesized that the difference between MYC and MYCN-induced gene expression and tumor identity might be due to their interaction with different partners in CGNPs. In this study, we investigated the role of the Myc interacting zinc finger protein 1 (MIZ1). We found that MIZ1 binds with higher affinity to MYC than to MYCN and that MIZ1 and MYC co-occupy thousands of promoters in G3 MB. Remarkably, enforced expression of a MYC mutant (MYCV394D) that no longer binds to MIZ1 in Trp53-null CGNPs or expression of wild type MYC in CGNPs that lack functional Miz1 resulted in massive changes of the resulting tumor’s transcriptional program. Tumors differed from both SHH and G3 medulloblastoma and had a later time of onset compared to MYC-driven G3 medulloblastoma. Our data demonstrate that interaction of MYC with MIZ1 is required for the development of G3 medulloblastoma.
2016-01-21 | GSE64425 | GEO
Project description:Medulloblastoma (MB) is a highly malignant primary brain tumor that originates from the cerebellar granule neuron precursors (CGNPs) in the cerebellum or posterior fossa. The overactivation of the Sonic Hedgehog (Shh) signal pathway accounts for the occurrence of 30% clinical cases of MB. Shh engagement with the inhibitory receptor Patched 1 derepresses the second receptor, Smoothened (Smo), and thereby activates the Gli transcriptional factors, allowing for the expression of a cohort of genes involved in cell growth and differentiation. Nevertheless, the mechanisms of Shh signaling-driven carcinogenesis, e.g. the Gli target genes that play pivotal roles in the transformation of CGNPs, remain largely unknown. To screen for the genes involved in the development of Shh subtype MB, we attempt to analyze genes differentially expressed between CGNPs and MB cells, which will hopefully provide clues for the elucidation of key molecular events that mediate the onset of this specific type of nervous system malignancy.
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Project description:Intratumor epigenetic heterogeneity is emerging as a key mechanism underlying tumor evolution and drug resistance. Epigenetic abnormalities frequently occur in medulloblastoma, the most common childhood malignant brain tumor. Medulloblastoma is classified into four subtypes including SHH medulloblastoma, which is characterized by elevated SHH signaling and a cerebellum granule neuron precursor (CGNP) cell-of-origin. Here we report that the histone H3K27 methyltransferase polycomb repressor complex 2 (PRC2) is often heterogeneous within individual SHH medulloblastoma tumors. In mouse models, complete deletion of the PRC2 core subunit EED inhibited medulloblastoma growth, while a mosaic deletion of EED significantly enhanced tumor growth. EED is intrinsically required for CGNP maintenance by inhibiting both neural differentiation and cell death. Complete deletion of EED led to CGNP depletion and reduced occurrence of medulloblastoma. Surprisingly, medulloblastomas with mosaic EED levels grew faster than control wildtype tumors and expressed increased levels of oncogenes such as Igf2, which is directly repressed by PRC2 and has been demonstrated to be both necessary and sufficient for SHH medulloblastoma progression. IGF2 mediated the oncogenic effects of PRC2 heterogeneity in tumor growth. Assessing clones of a human medulloblastoma cell line with different EED levels confirmed that EEDlow cells can stimulate the growth of EEDhigh cells through paracrine IGF2 signaling. Thus, PRC2 heterogeneity plays an oncogenic role in medulloblastoma through both intrinsic growth competence and non-cell autonomous mechanisms in distinct tumor subclones.
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Project description:The expression of circular RNAs in cerebellar cancer versus medulloblastoma subgroups SHH, WNT, Group3 and Group4 has been interrogated. Fusion RNAs containing exons from distinct genes joined at canonical splice sites were also identified.
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