生物
癌症研究
DNA甲基化
表观遗传学
CTCF公司
PDGFRA公司
CDKN2A
胶质瘤
癌变
遗传学
增强子
癌症
间质细胞
转录因子
基因表达
主旨
基因
作者
Gilbert J. Rahme,Nauman Javed,Kaitlyn L. Puorro,Shouhui Xin,Volker Hovestadt,Sarah E. Johnstone,B Bernstein
出处
期刊:Cell
[Elsevier]
日期:2023-08-01
卷期号:186 (17): 3674-3685.e14
被引量:10
标识
DOI:10.1016/j.cell.2023.06.022
摘要
Epigenetic lesions that disrupt regulatory elements represent potential cancer drivers. However, we lack experimental models for validating their tumorigenic impact. Here, we model aberrations arising in isocitrate dehydrogenase-mutant gliomas, which exhibit DNA hypermethylation. We focus on a CTCF insulator near the PDGFRA oncogene that is recurrently disrupted by methylation in these tumors. We demonstrate that disruption of the syntenic insulator in mouse oligodendrocyte progenitor cells (OPCs) allows an OPC-specific enhancer to contact and induce Pdgfra, thereby increasing proliferation. We show that a second lesion, methylation-dependent silencing of the Cdkn2a tumor suppressor, cooperates with insulator loss in OPCs. Coordinate inactivation of the Pdgfra insulator and Cdkn2a drives gliomagenesis in vivo. Despite locus synteny, the insulator is CpG-rich only in humans, a feature that may confer human glioma risk but complicates mouse modeling. Our study demonstrates the capacity of recurrent epigenetic lesions to drive OPC proliferation in vitro and gliomagenesis in vivo.
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