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| Home > Publications database > A new IDH-independent hypermethylation phenotype is associated with astrocyte-like cell state in glioblastoma. |
| Home > Publications database > A new IDH-independent hypermethylation phenotype is associated with astrocyte-like cell state in glioblastoma. |
| Journal Article | DKFZ-2025-01418 |
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2025
BioMed Central
London
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Please use a persistent id in citations: doi:10.1186/s13059-025-03670-y
Abstract: DNA methylation plays a crucial role in cancer development and progression and has been linked to genetically and clinically distinct tumor classes, including IDH-mutated and IDH-wildtype adult-type diffuse gliomas. Here, we identify a CpG-island methylator phenotype (CIMP) that characterizes the receptor tyrosine kinase 2 (RTK2) subtype of IDH-wildtype glioblastoma.This RTK2-CIMP affects genomic locations and cell functions distinct from those of IDH mutation-associated IDH-CIMP and suppresses the expression of its target genes. The RTK2-CIMP-region chromatin is characterized by a combination of repressive and activating marks, including polycomb-associated H3K27me3 and enhancer-associated H3K4me1, consistent with DNA methylation-mediated silencing of genes with bivalent-state promoters in neural progenitor cells. Functionally, RTK2-CIMP affects neuronal lineage genes and is significantly associated with astrocyte-like glioblastoma, suggesting that RTK2-CIMP is an epigenetic signature of the astrocyte-like cell state. Furthermore, we demonstrate that RTK2-CIMP can be induced by genetic manipulation in glioblastoma cells.Our results suggest that RTK2-CIMP is a key contributor to cell-state plasticity in glioblastoma.
Keyword(s): Glioblastoma: genetics (MeSH) ; Glioblastoma: pathology (MeSH) ; Glioblastoma: metabolism (MeSH) ; Humans (MeSH) ; DNA Methylation (MeSH) ; Isocitrate Dehydrogenase: genetics (MeSH) ; Isocitrate Dehydrogenase: metabolism (MeSH) ; Astrocytes: metabolism (MeSH) ; Astrocytes: pathology (MeSH) ; Phenotype (MeSH) ; Cell Line, Tumor (MeSH) ; CpG Islands (MeSH) ; Epigenesis, Genetic (MeSH) ; Gene Expression Regulation, Neoplastic (MeSH) ; Brain Neoplasms: genetics (MeSH) ; Brain Neoplasms: pathology (MeSH) ; Isocitrate Dehydrogenase
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