Characterization of a novel OTX2-driven self-renewal program in Group 3 and Group 4 medulloblastoma
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ABSTRACT:
PROVIDER: PRJNA384960 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5486930_1.fastq.gz | Fastqsanger.gz | |||
| SRR5486930_2.fastq.gz | Fastqsanger.gz | |||
| SRR5486929_1.fastq.gz | Fastqsanger.gz | |||
| SRR5486929_2.fastq.gz | Fastqsanger.gz |
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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.
2019-01-01 | GSE98279 | GEO
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.
2019-01-01 | GSE98354 | GEO
Project description:We evaluated changes in active and repressive histone modifications following the silencing of OTX2 in Group 3 medulloblastoma tumorspheres
2020-06-11 | GSE132269 | GEO
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
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 | GSE92582 | GEO
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 | GSE92584 | GEO
Project description: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. The role of OTX2 in medulloblastoma and its downstream targets are unclear. Therefore, we generated D425 medulloblastoma cells in which we can silence endogenous OTX2 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. Down regulated genes were highly enriched for cell cycle and visual perception genes, while up regulated genes were enriched for genes involved in development and differentiation. This shift in expression profiles is reminiscent to changes described to occur during normal cerebellum development. OTX2 is expressed in proliferating granular progenitor cells, but the expression diminishes when these cells exit the cell cycle and start differentiating. ChIP-on-chip analyses of OTX2 in D425 cells showed that cell cycle and perception genes were direct OTX2 targets, while regulation of most differentiation genes appears to be indirect. These analyses provide the first insight in the molecular network of OTX2, demonstrating that OTX2 is essential in medulloblastoma and directly drives proliferation by regulating the expression of cell cycle genes. Since many of these genes also correlate in expression with OTX2 in primary tumors, they might be potential targets for therapy in medulloblastoma patients. Keywords: OTX2, medulloblastoma, mRNA profiling *** This Series represents the gene expression component of the study. Three independent time course experiments of OTX2 silencing, and 1 control experiment in D425 medulloblastoma cells.
2012-07-03 | E-GEOD-22875 | biostudies-arrayexpress
Project description:An OTX2-PAX3 signaling axis regulates Group 3 medulloblastoma cell fate
| PRJNA548355 | ENA
Project description: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. The role of OTX2 in medulloblastoma and its downstream targets are unclear. Therefore, we generated D425 medulloblastoma cells in which we can silence endogenous OTX2 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. Down regulated genes were highly enriched for cell cycle and visual perception genes, while up regulated genes were enriched for genes involved in development and differentiation. This shift in expression profiles is reminiscent to changes described to occur during normal cerebellum development. OTX2 is expressed in proliferating granular progenitor cells, but the expression diminishes when these cells exit the cell cycle and start differentiating. ChIP-on-chip analyses of OTX2 in D425 cells showed that cell cycle and perception genes were direct OTX2 targets, while regulation of most differentiation genes appears to be indirect. These analyses provide the first insight in the molecular network of OTX2, demonstrating that OTX2 is essential in medulloblastoma and directly drives proliferation by regulating the expression of cell cycle genes. Since many of these genes also correlate in expression with OTX2 in primary tumors, they might be potential targets for therapy in medulloblastoma patients. Keywords: OTX2, medulloblastoma, mRNA profiling
2012-07-04 | GSE22875 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2019-01-01 | GSE98384 | GEO