一种新的不依赖异柠檬酸脱氢酶的高甲基化表型与胶质母细胞瘤中的星形胶质细胞样细胞状态相关。

A new IDH-independent hypermethylation phenotype is associated with astrocyte-like cell state in glioblastoma.

作者信息

Costa Ana Luisa, Doncevic Daria, Wu Yonghe, Yang Lin, Man Ka Hou, Spreng Anna-Sophie, Winter Hannah, Fletcher Michael Nai Chung, Radlwimmer Bernhard, Herrmann Carl

机构信息

Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, Heidelberg University, Heidelberg, 69120, Germany.

Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany.

出版信息

Genome Biol. 2025 Jul 3;26(1):192. doi: 10.1186/s13059-025-03670-y.

DOI:10.1186/s13059-025-03670-y

PMID:40611337

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12225510/

Abstract

BACKGROUND

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.

RESULTS

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.

CONCLUSIONS

Our results suggest that RTK2-CIMP is a key contributor to cell-state plasticity in glioblastoma.

摘要

背景

DNA甲基化在癌症发生和发展中起关键作用，并与遗传和临床特征各异的肿瘤类型相关，包括异柠檬酸脱氢酶（IDH）突变型和IDH野生型成人型弥漫性胶质瘤。在此，我们鉴定出一种CpG岛甲基化表型（CIMP），其可表征IDH野生型胶质母细胞瘤的受体酪氨酸激酶2（RTK2）亚型。

结果

这种RTK2-CIMP影响的基因组位置和细胞功能不同于IDH突变相关的IDH-CIMP，并抑制其靶基因的表达。RTK2-CIMP区域的染色质具有抑制性和激活性标记的组合特征，包括多梳蛋白相关的H3K27me3和增强子相关的H3K4me1，这与神经祖细胞中具有双价态启动子的基因的DNA甲基化介导的沉默一致。在功能上，RTK2-CIMP影响神经谱系基因，并与星形胶质细胞样胶质母细胞瘤显著相关，提示RTK2-CIMP是星形胶质细胞样细胞状态的一种表观遗传特征。此外，我们证明RTK2-CIMP可在胶质母细胞瘤细胞中通过基因操作诱导产生。