A new IDH-independent hypermethylation phenotype is associated with astrocyte-like cell state in glioblastoma
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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 identified 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 (AC)-like glioblastoma, suggesting that RTK2-CIMP is an epigenetic signature of the AC-like cell state. Furthermore, we demonstrated that RTK2-CIMP can be induced by genetic manipulation in glioblastoma cells, suggesting that RTK2-CIMP is a key contributor to cell-state plasticity in glioblastoma.
ORGANISM(S): Mus musculus
PROVIDER: GSE296674 | GEO | 2025/05/13
REPOSITORIES: GEO
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