TY  - JOUR
AU  - Costa, Ana Luisa
AU  - Doncevic, Daria
AU  - Wu, Yonghe
AU  - Yang, Lin
AU  - Man, Ka Hou
AU  - Spreng, Anna-Sophie
AU  - Winter, Hannah
AU  - Fletcher, Michael
AU  - Radlwimmer, Bernhard
AU  - Herrmann, Carl
TI  - A new IDH-independent hypermethylation phenotype is associated with astrocyte-like cell state in glioblastoma.
JO  - Genome biology
VL  - 26
IS  - 1
SN  - 1465-6906
CY  - London
PB  - BioMed Central
M1  - DKFZ-2025-01418
SP  - 192
PY  - 2025
AB  - 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.
KW  - Glioblastoma: genetics
KW  - Glioblastoma: pathology
KW  - Glioblastoma: metabolism
KW  - Humans
KW  - DNA Methylation
KW  - Isocitrate Dehydrogenase: genetics
KW  - Isocitrate Dehydrogenase: metabolism
KW  - Astrocytes: metabolism
KW  - Astrocytes: pathology
KW  - Phenotype
KW  - Cell Line, Tumor
KW  - CpG Islands
KW  - Epigenesis, Genetic
KW  - Gene Expression Regulation, Neoplastic
KW  - Brain Neoplasms: genetics
KW  - Brain Neoplasms: pathology
KW  - Isocitrate Dehydrogenase (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40611337
C2  - pmc:PMC12225510
DO  - DOI:10.1186/s13059-025-03670-y
UR  - https://inrepo02.dkfz.de/record/302878
ER  -