%0 Journal Article
%A Costa, Ana Luisa
%A Doncevic, Daria
%A Wu, Yonghe
%A Yang, Lin
%A Man, Ka Hou
%A Spreng, Anna-Sophie
%A Winter, Hannah
%A Fletcher, Michael
%A Radlwimmer, Bernhard
%A Herrmann, Carl
%T A new IDH-independent hypermethylation phenotype is associated with astrocyte-like cell state in glioblastoma.
%J Genome biology
%V 26
%N 1
%@ 1465-6906
%C London
%I BioMed Central
%M DKFZ-2025-01418
%P 192
%D 2025
%X 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.
%K Glioblastoma: genetics
%K Glioblastoma: pathology
%K Glioblastoma: metabolism
%K Humans
%K DNA Methylation
%K Isocitrate Dehydrogenase: genetics
%K Isocitrate Dehydrogenase: metabolism
%K Astrocytes: metabolism
%K Astrocytes: pathology
%K Phenotype
%K Cell Line, Tumor
%K CpG Islands
%K Epigenesis, Genetic
%K Gene Expression Regulation, Neoplastic
%K Brain Neoplasms: genetics
%K Brain Neoplasms: pathology
%K Isocitrate Dehydrogenase (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40611337
%2 pmc:PMC12225510
%R 10.1186/s13059-025-03670-y
%U https://inrepo02.dkfz.de/record/302878