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  • AMPLIFICATION  (3)
  • moss
  • orobol
  • 1
    Keywords: CANCER ; EXPRESSION ; LINES ; AMPLIFICATION ; CHROMATIN ; SPECIFICATION ; STEM-CELLS ; expression profiling ; RETINOIC ACID ; PATTERN ; medulloblastoma ; MIDBRAIN ; Immunoprecipitation ; CEREBELLAR DEVELOPMENT ; AURORA KINASE ; OTX2
    Abstract: The transcription factor OTX2 has been implicated as an oncogene in medulloblastoma, which is the most common malignant brain tumor in children. It is highly expressed in most medulloblastomas and amplified in a subset of them. To study the role OTX2 has in medulloblastoma we investigated the downstream pathway of OTX2. We generated D425 medulloblastoma cells in which endogenous OTX2 can be silenced by inducible shRNA. Silencing of OTX2 strongly inhibited cell proliferation and resulted in a neuronal-like differentiation. Expression profiling of time courses after silencing showed a progressive change in gene expression for many cellular processes. Downregulated genes were highly enriched for cell cycle and visual perception genes, while upregulated genes were enriched for genes involved in development and differentiation. This shift is reminiscent of expression changes described during normal cerebellum development where proliferating granule progenitor cells have high OTX2 expression, which diminishes when these cells exit the cell cycle and start to differentiate. ChIP-on-chip analyses of OTX2 in D425 cells identified cell cycle and perception genes as direct OTX2 targets, while regulation of most differentiation genes appeared to be indirect. The expression of many directly regulated genes correlated to OTX2 expression in primary tumors, suggesting the in vivo relevance of these genes and their potential as targets for therapeutic intervention. These analyses provide more insight in the molecular network of OTX2, demonstrating that OTX2 is essential in medulloblastoma and directly drives proliferation by regulation of cell cycle genes
    Type of Publication: Journal article published
    PubMed ID: 21964830
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  • 2
    Keywords: SURVIVAL ; AMPLIFICATION ; MUTATIONS ; CNS ; BRAIN-TUMORS ; medulloblastoma ; HIGH EXPRESSION ; ABUNDANT NEUROPIL ; TRUE ROSETTES ; GENETIC PROFILES
    Abstract: Embryonal tumor with multilayered rosettes (ETMR, previously known as ETANTR) is a highly aggressive embryonal CNS tumor, which almost exclusively affects infants and is associated with a dismal prognosis. Accurate diagnosis is of critical clinical importance because of its poor response to current treatment protocols and its distinct biology. Amplification of the miRNA cluster at 19q13.42 has been identified previously as a genetic hallmark for ETMR, but an immunohistochemistry-based assay for clinical routine diagnostics [such as INI-1 for atypical teratoid rhabdoid tumor (AT/RT)] is still lacking. In this study, we screened for an ETMR-specific marker using a gene-expression profiling dataset of more than 1,400 brain tumors and identified LIN28A as a highly specific marker for ETMR. The encoded protein binds small RNA and has been implicated in stem cell pluripotency, metabolism and tumorigenesis. Using an LIN28A specific antibody, we carried out immunohistochemical analysis of LIN28A in more than 800 childhood brain-tumor samples and confirmed its high specificity for ETMR. Strong LIN28A immunoexpression was found in all 37 ETMR samples tested, whereas focal reactivity was only present in a small (6/50) proportion of AT/RT samples. All other pediatric brain tumors were completely LIN28A-negative. In summary, we established LIN28A immunohistochemistry as a highly sensitive and specific, rapid, inexpensive diagnostic tool for routine pathological verification of ETMR.
    Type of Publication: Journal article published
    PubMed ID: 23161096
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  • 3
    Keywords: GENE ; CELL-LINES ; IDENTIFICATION ; AMPLIFICATION ; COMPARATIVE GENOMIC HYBRIDIZATION ; RETINOIC ACID ; SUBTYPES ; PROFILES ; LANDSCAPE
    Abstract: Recent studies showed frequent mutations in histone H3 lysine 27 (H3K27) demethylases in medulloblastomas of Group 3 and Group 4, suggesting a role for H3K27 methylation in these tumors. Indeed, trimethylated H3K27 (H3K27me3) levels were shown to be higher in Group 3 and 4 tumors compared to WNT and SHH medulloblastomas, also in tumors without detectable mutations in demethylases. Here, we report that polycomb genes, required for H3K27 methylation, are consistently upregulated in Group 3 and 4 tumors. These tumors show high expression of the homeobox transcription factor OTX2. Silencing of OTX2 in D425 medulloblastoma cells resulted in downregulation of polycomb genes such as EZH2, EED, SUZ12 and RBBP4 and upregulation of H3K27 demethylases KDM6A, KDM6B, JARID2 and KDM7A. This was accompanied by decreased H3K27me3 and increased H3K27me1 levels in promoter regions. Strikingly, the decrease of H3K27me3 was most prominent in promoters that bind OTX2. OTX2-bound promoters showed high levels of the H3K4me3 and H3K9ac activation marks and intermediate levels of the H3K27me3 inactivation mark, reminiscent of a bivalent modification. After silencing of OTX2, H3K27me3 levels strongly dropped, but H3K4me3 and H3K9ac levels remained high. OTX2-bound bivalent genes showed high expression levels in D425, but the expression of most of these genes did not change after OTX2 silencing and loss of the H3K27me3 mark. Maintaining promoters in a bivalent state by sustaining H3K27 trimethylation therefore seems to be an important function of OTX2 in medulloblastoma, while other transcription factors might regulate the actual expression levels of these genes.
    Type of Publication: Journal article published
    PubMed ID: 23179372
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  • 4
    ISSN: 0031-9422
    Keywords: 6''-malonyl glucosides ; 7-O-glucosides ; Bryales ; Bryum capillare ; Musci ; NMR spectra. ; isoflavones ; moss ; orobol ; pratensein
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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