PDF(Pubmed)
Abstract：
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.
摘要：
破坏调节元件的表观遗传病变代表了潜在的癌症驱动因素。然而,我们缺乏验证其致瘤影响的实验模型。这里,我们对异柠檬酸脱氢酶突变神经胶质瘤中产生的畸变进行建模，表现出DNA超甲基化。我们专注于PDGFRA癌基因附近的CTCF绝缘体，该绝缘体在这些肿瘤中被甲基化反复破坏。我们证明，在小鼠少突胶质祖细胞（OPC）中，同质绝缘体的破坏允许OPC特异性增强子接触并诱导Pdgfra，从而增加扩散。我们显示第二个病变，Cdkn2a肿瘤抑制因子的甲基化依赖性沉默，配合OPC中的绝缘子损耗。Pdgfra绝缘体和Cdkn2a的协调失活驱动了体内胶质细胞生成。尽管存在基因座同质性，这种绝缘体只在人类身上富含CpG，这一特征可能赋予人类神经胶质瘤风险，但使小鼠建模复杂化。我们的研究证明了复发性表观遗传病变在体外驱动OPC增殖和体内神经胶质增生的能力。
