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Expression data comparing transformed or neoplastic human neural precursors following OTX2 knockdown to transformed human neural precursor cells

ABSTRACT: Medulloblastoma (MB) is the most common malignant primary pediatric brain tumor and is currently divided into 4 subtypes based on different genomic alterations, gene expression profiles and response to treatment: WNT, Sonic Hedgehog (SHH), Group 3 and Group 4. The extensive heterogeneity has made it difficult to assess the relevance of genes to malignant progression. For example, expression of the transcription factor, OTX2, is frequently dysregulated in multiple MB variants; however, it's role may be subtype specific. Here, we utilized human embryonic stem cell-derived neural precursors to determine the role of OTX2 in MB tumor progression using gain and loss of function studies. We used global gene expression profiling to determine what transcripts and pathways were differentially expressed following knockdown of OTX2 in transformed or neoplastic human embryonic neural precursor cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE66671 | GEO | 2015/08/25

SECONDARY ACCESSION(S): PRJNA277714

REPOSITORIES: GEO

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Expression data comparing transformed or neoplastic human neural precursors following OTX2 knockdown to transformed human neural precursor cells

Project description:Medulloblastoma (MB) is the most common malignant primary pediatric brain tumor and is currently divided into 4 subtypes based on different genomic alterations, gene expression profiles and response to treatment: WNT, Sonic Hedgehog (SHH), Group 3 and Group 4. The extensive heterogeneity has made it difficult to assess the relevance of genes to malignant progression. For example, expression of the transcription factor, OTX2, is frequently dysregulated in multiple MB variants; however, it's role may be subtype specific. Here, we utilized human embryonic stem cell-derived neural precursors to determine the role of OTX2 in MB tumor progression using gain and loss of function studies. We used global gene expression profiling to determine what transcripts and pathways were differentially expressed following knockdown of OTX2 in transformed or neoplastic human embryonic neural precursor cells. OTX2 was knocked down in transformed human embyronic neural precursors (trans-hEN) using Silencer select siRNAs. trans-hEN OTX2 KD and scrambled control trans-hENs were then grown as neurospheres in defined medium and collected at passage 1. RNA was extracted using the Norgen All-in-One kit.

2015-08-25 | E-GEOD-66671 | biostudies-arrayexpress

Expression data comparing OTX2-overexpressing human neural precursors to human neural precursor cells

Project description:Medulloblastoma (MB) is the most common malignant primary pediatric brain tumor and is currently divided into 4 subtypes based on different genomic alterations, gene expression profiles and response to treatment: WNT, Sonic Hedgehog (SHH), Group 3 and Group 4. The extensive heterogeneity has made it difficult to assess the relevance of genes to malignant progression. For example, expression of the transcription factor, OTX2, is frequently dysregulated in multiple MB variants; however, it's role may be subtype specific. Here, we utilized human embryonic stem cell-derived neural precursors to determine the role of OTX2 in MB tumor progression using gain and loss of function studies. We used global gene expression profiling to determine what transcripts and pathways were differentially expressed following overexpression of OTX2 in human embryonic neural precursor cells. OTX2 was stably overexpressed in human embyronic neural precursors (hEN) by lentiviral transduction. OTX2-hENs and control hENs were then grown as neurospheres in defined medium and collected at passage 2. RNA was extracted using the Norgen All-in-One kit.

2015-08-25 | E-GEOD-66670 | biostudies-arrayexpress

Expression data comparing OTX2-overexpressing human neural precursors to human neural precursor cells

Project description:Medulloblastoma (MB) is the most common malignant primary pediatric brain tumor and is currently divided into 4 subtypes based on different genomic alterations, gene expression profiles and response to treatment: WNT, Sonic Hedgehog (SHH), Group 3 and Group 4. The extensive heterogeneity has made it difficult to assess the relevance of genes to malignant progression. For example, expression of the transcription factor, OTX2, is frequently dysregulated in multiple MB variants; however, it's role may be subtype specific. Here, we utilized human embryonic stem cell-derived neural precursors to determine the role of OTX2 in MB tumor progression using gain and loss of function studies. We used global gene expression profiling to determine what transcripts and pathways were differentially expressed following overexpression of OTX2 in human embryonic neural precursor cells.

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Characterization of a novel OTX2-driven self-renewal program in Group 3 and Group 4 medulloblastoma [expression]

Project description:Medulloblastoma (MB) is the most common malignant primary pediatric brain cancer. Among the most aggressive subtypes, Group 3 and Group 4 originate from stem/progenitor cells, frequently metastasize, and often display the worst prognosis, yet, as the names imply, we know the least about the molecular mechanisms driving their progression. Here, we show that the transcription factor orthodenticle homeobox 2 (OTX2) promotes self-renewal while inhibiting differentiation in vitro and increases tumor-initiating capacity from MB stem cell populations in vivo. Characterization of the OTX2 regulatory network revealed a novel relationship between OTX2 and genes associated with multiple axon guidance signaling pathways in Group 3 and Group 4 MB stem/progenitor cells. In particular, OTX2 levels were negatively correlated with semaphorin (SEMA) signaling, as expression of 9 SEMA pathway genes is upregulated following OTX2 knockdown with some being potential direct OTX2 targets. Importantly, this negative correlation between OTX2 and SEMA pathway genes was also observed in patient samples, with lower expression of SEMA4D associated with poor outcome in Group 3 and 4 tumors. Functional studies using established and newly derived MB cell lines demonstrated that increased levels of SEMA pathway genes are associated with decreased self-renewal and growth, and that RHO signaling, known to mediate the effects of SEMA genes, is contributing to the OTX2 KD phenotype. Our study provides critical mechanistic insight into the networks controlled by OTX2 in self-renewing MB cells and reveals novel roles for axon guidance genes and their downstream effectors as putative tumor suppressors and therapeutic targets in Group 3 and Group 4 MB.

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Project description:Otx2 has been shown to be non cell autonomously required for photoreceptor cell survival in the adult mouse RPE. This study aims to identify Otx2 DNA binding profile in both RPE and neural retina to i) identify direct targets of Otx2 in the RPE ii) compare Otx2 binding profile in neural retina and RPE to unveil hidden functions in the neural retina. WT and GFP antibodies were used to perform two independent ChIP-seq experiments using Illumina GAIIx.

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Otx2 ChIP-seq in the adult mouse Retinal Pigmented Epithelium (RPE) and neural retina

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An OTX2-PAX3 signaling axis regulates Group 3 medulloblastoma cell fate [scRNA-seq]

Project description:scRNA-seq was performed to evaluate the OTX2-PAX3-mTOR signalling axis at the single cell level in heterogeneous Group 3 MB tumorspheres

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OTX2 activity at distal regulatory elements shapes the chromatin landscape of Group 3 medulloblastoma [RNA-seq]

Project description:Medulloblastoma is the most frequent malignant pediatric brain tumor and is divided into at least four subgroups known as Wnt, SHH, Group 3 and Group 4. Here we characterized gene regulation mechanisms in the most aggressive subtype, Group 3 tumors, through genome-wide chromatin and expression profiling. Our results show that most active distal sites in these tumors are occupied by the transcription factor OTX2. Highly active OTX2 bound enhancers are often arranged as clusters of adjacent peaks and are also bound by the transcription factor NEUROD1. These sites are responsive to OTX2 and NEUROD1 knockdown and could also be generated de novo upon ectopic OTX2 expression in primary cells, showing that OTX2 cooperates with NEUROD1 and plays a major role in maintaining and possibly establishing regulatory elements as a pioneer factor. Among OTX2 target genes we identified the kinase NEK2, whose knockdown and pharmacological inhibition decreased cell viability. Our studies thus show that OTX2 controls the regulatory landscape of Group 3 medulloblastoma through cooperative activity at enhancer elements and contributes to the expression of critical target genes.

2017-02-21 | GSE92583 | GEO

OTX2 activity at distal regulatory elements shapes the chromatin landscape of Group 3 medulloblastoma [ChIP-seq]

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