Modeling epigenetic lesions that cause gliomas [Capture-Bis-seq]
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PROVIDER: PRJNA937635 | ENA |
REPOSITORIES: ENA
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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 | GSE225793 | GEO
Project description:Modeling epigenetic lesions that cause gliomas
| PRJNA937629 | ENA
Project description:Modeling epigenetic lesions that cause gliomas [ChIP-Seq]
| PRJNA937235 | ENA
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:This SuperSeries is composed of the SubSeries listed below.
2023-07-25 | GSE225794 | 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: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:Brachypodium distachyon cultivar:Bis-1 Genome sequencing
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Project description:This phase I trial studies the side effects and best dose of pembrolizumab and to see how well it works in treating younger patients with high-grade gliomas (brain tumors that are generally expected to be fast growing and aggressive), diffuse intrinsic pontine gliomas (brain stem tumors), brain tumors with a high number of genetic mutations, ependymoma or medulloblastoma that have come back (recurrent), progressed, or have not responded to previous treatment (refractory). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may induce changes in the body’s immune system, and may interfere with the ability of tumor cells to grow and spread.
| 2183538 | ecrin-mdr-crc
Project description:Gliomas are immunologically cold tumors that can be broken into several categories based on either RNA expression profiles or methylation profiles, with isocitrate dehydrogenase (IDH) mutations defining a major segregration between types. IDH mutant gliomas often exhibit defects in the retinoic acid pathway. We treated mice harboring IDH mutant gliomas with all-trans retinoic acid, and found that this treatment cause reductions in tumor growth and a swith in immune profiles in the tumor microenvironment.
2024-04-19 | GSE172387 | GEO