Modeling epigenetic lesions that cause gliomas [ChIP-Seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA937235 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23571966_1.fastq.gz | Fastqsanger.gz | |||
| SRR23571966_2.fastq.gz | Fastqsanger.gz | |||
| SRR23571967_1.fastq.gz | Fastqsanger.gz | |||
| SRR23571967_2.fastq.gz | Fastqsanger.gz | |||
| SRR23571968_1.fastq.gz | Fastqsanger.gz |
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Project description:Modeling epigenetic lesions that cause gliomas
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Project description:Modeling epigenetic lesions that cause gliomas [Capture-Bis-seq]
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Project description:Epigenetic lesions that disrupt gene regulatory elements and expression are increasingly recognized as pervasive drivers of human cancers. However, we currently lack the in vitro and in vivo models required to functionally validate such lesions and their tumorigenic impact. Here we model aberrations that arise in Isocitrate Dehydrogenase mutant (IDHmut) lower-grade gliomas, which exhibit profound DNA hypermethylation. We initially focus on a CTCF insulator downstream of the PDGFRA oncogene that is recurrently disrupted in IDHmut gliomas. We demonstrate that disruption of the syntenic insulator in mouse oligodendrocyte-progenitor cells (OPCs) allows an OPC-specific enhancer to contact and induce PDGFRA, thereby increasing proliferation. In contrast, insulator disruption did not affect PDGFRA expression in neural progenitor cells (NPCs), which lack the enhancer. We also model a second recurrent epigenetic lesion in IDHmut gliomas, the methylation-dependent silencing of the CDKN2A tumor suppressor. We show that inactivation of CDKN2A/p19ARF by de novo promoter methylation or mutation drives OPC proliferation and synergizes with PDGFRA insulator loss. Finally, we use lentiviruses to coordinately inactivate the PDGFRA insulator and CDKN2A in mouse corpus callosum, resulting in low-grade gliomagenesis in vivo. Our study recapitulates recurrent epigenetic lesions in mouse models and demonstrates that combination of PDGFRA activation and CDKN2A silencing can transform OPCs in vitro and drive gliomagenesis in vivo.
2023-07-25 | GSE225732 | GEO
Project description:Epigenetic lesions that disrupt gene regulatory elements and expression are increasingly recognized as pervasive drivers of human cancers. However, we currently lack the in vitro and in vivo models required to functionally validate such lesions and their tumorigenic impact. Here we model aberrations that arise in Isocitrate Dehydrogenase mutant (IDHmut) lower-grade gliomas, which exhibit profound DNA hypermethylation. We initially focus on a CTCF insulator downstream of the PDGFRA oncogene that is recurrently disrupted in IDHmut gliomas. We demonstrate that disruption of the syntenic insulator in mouse oligodendrocyte-progenitor cells (OPCs) allows an OPC-specific enhancer to contact and induce PDGFRA, thereby increasing proliferation. In contrast, insulator disruption did not affect PDGFRA expression in neural progenitor cells (NPCs), which lack the enhancer. We also model a second recurrent epigenetic lesion in IDHmut gliomas, the methylation-dependent silencing of the CDKN2A tumor suppressor. We show that inactivation of CDKN2A/p19ARF by de novo promoter methylation or mutation drives OPC proliferation and synergizes with PDGFRA insulator loss. Finally, we use lentiviruses to coordinately inactivate the PDGFRA insulator and CDKN2A in mouse corpus callosum, resulting in low-grade gliomagenesis in vivo. Our study recapitulates recurrent epigenetic lesions in mouse models and demonstrates that combination of PDGFRA activation and CDKN2A silencing can transform OPCs in vitro and drive gliomagenesis in vivo.
2023-07-25 | GSE225793 | GEO
Project description:Epigenetic lesions that disrupt regulatory elements represent potential cancer drivers. However, we lack experimental models for validating their tumorigenic impact. Here, we model aberrations arising in isocitrate dehydrogenase-mutant gliomas, which exhibit DNA hypermethylation. We focus on a CTCF insulator near the PDGFRA oncogene that is recurrently disrupted by methylation in these tumors. We demonstrate that disruption of the syntenic insulator in mouse oligodendrocyte progenitor cells (OPCs) allows an OPC-specific enhancer to contact and induce Pdgfra, thereby increasing proliferation. We show that a second lesion, methylation-dependent silencing of the Cdkn2a tumor suppressor, cooperates with insulator loss in OPCs. Coordinate inactivation of the Pdgfra insulator and Cdkn2a drives gliomagenesis in vivo. Despite locus synteny, the insulator is CpG-rich only in humans, a feature that may confer human glioma risk but complicates mouse modeling. Our study demonstrates the capacity of recurrent epigenetic lesions to drive OPC proliferation in vitro and gliomagenesis in vivo.
| S-EPMC10530192 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-07-25 | GSE225794 | GEO
Project description:Human diffuse intrinsic pontine gliomas (DIPG) are an aggressive form of pediatric brain tumors that arise in the pons in young children thus resulting in significant morbidity and very poor survival. Recent data suggest that mutations in the histone H3.3 variant are often found in these tumors, though the mechanism of their contribution to oncogenesis remains to be elucidated. Here we report that the combination of constitutive PDGFRA activation and p53 suppression as well as expression of the K27M mutant form of the histone H3.3 variant leads to neoplastic transformation of hPSC-derived neural precursors. Our study demonstrates that human ES cells represent an excellent platform for the modeling of human tumors in vitro and in vivo, which could potentially lead to the elucidation of the molecular mechanisms underlying neoplastic transformation and the identification of novel therapeutic targets. Human ES cells were differentiated to NPCs and lentivirally transduced with a combination of constitutively active PDGFRA (D842V), sh-p53, and WT or K27M mutant form of histone H3.3 variant.
2014-11-21 | E-GEOD-55541 | biostudies-arrayexpress
Project description:Human diffuse intrinsic pontine gliomas (DIPG) are an aggressive form of pediatric brain tumors that arise in the pons in young children thus resulting in significant morbidity and very poor survival. Recent data suggest that mutations in the histone H3.3 variant are often found in these tumors, though the mechanism of their contribution to oncogenesis remains to be elucidated. Here we report that the combination of constitutive PDGFRA activation and p53 suppression as well as expression of the K27M mutant form of the histone H3.3 variant leads to neoplastic transformation of hPSC-derived neural precursors. Our study demonstrates that human ES cells represent an excellent platform for the modeling of human tumors in vitro and in vivo, which could potentially lead to the elucidation of the molecular mechanisms underlying neoplastic transformation and the identification of novel therapeutic targets.
2014-11-21 | GSE55541 | GEO
Project description:Primary brain tumors are the fourth leading cause of cancer mortality in adults under the age of 54 years and the leading cause of cancer mortality in children in the United States. Therapy for the most common type of primary brain tumors, gliomas, remains suboptimal. The development of new and more effective treatments will likely require a better understanding of the biology of these tumors. Here, we show that use of the high-density 100K single-nucleotide polymorphism arrays in a large number of primary tumor samples allows for a much higher resolution survey of the glioma genome than has been previously reported in any tumor type. We not only confirmed alterations in genomic areas previously reported to be affected in gliomas, but we also refined the location of those sites and uncovered multiple, previously unknown regions that are affected by copy number alterations (amplifications, homozygous and heterozygous deletions) as well as allelic imbalances (loss of heterozygosity/gene conversions). The wealth of genomic data produced may allow for the development of a more rational molecular classification of gliomas and serve as an important starting point in the search for new molecular therapeutic targets. (Cancer Res 2006; 66(19): 9428-36) Experiment Overall Design: 178 glioma samples including 82 glioblastomas, 33 astrocytomas, 52 oligodendrogliomas and 11 mixed gliomas were hybridized to 100K mapping arrays (Hind and Xba) to detect and summarize chromosomal aberations in those samples.
2008-06-15 | E-GEOD-6109 | biostudies-arrayexpress
Project description:Gliomas arising in the brainstem and thalamus are devastating tumors that are difficult to surgically resect due to their proximity to eloquent brain structures. Here, we performed a comprehesive genomic and epigenomic study, using gene expression and methylation microarrays, to research on th different genomic and epigenetic signatures between brainstem, thalamic, and supratentorial gliomas. Comparison of brainstem, thalamic and supratentorial gliomas
2014-05-27 | E-GEOD-50774 | biostudies-arrayexpress