小柯机器人

美国丹娜-法伯癌症研究所Bradley E. Bernstein团队近期取得重要工作进展。他们研究模拟导致神经胶质瘤的表观遗传损伤。相关研究成果2023年7月25日在线发表于《细胞》杂志上。

据介绍，破坏调控元件的表观遗传损伤是潜在的癌症驱动因素。然而，科学家们缺乏实验模型来验证它们的致瘤作用。

研究人员对异柠檬酸脱氢酶突变型胶质瘤中出现的畸变进行了建模，这种胶质瘤表现出DNA超甲基化。研究人员关注PDGFRA癌基因附近的CTCF绝缘子，该绝缘子在这些肿瘤中被甲基化反复破坏。研究人员证明，破坏小鼠少突胶质细胞祖细胞（OPC）中的同基因绝缘子可以使OPC特异性增强子接触并诱导Pdgfra，从而促进增殖。

研究人员发现，第二种病变，Cdkn2a肿瘤抑制因子的甲基化依赖性沉默，与OPC中的绝缘子损失协同作用。Pdgfra绝缘子和Cdkn2a的协同失活在体内驱动胶质瘤。尽管基因座同源，但绝缘子仅在人类中富含CpG，这一特征可能会增加人类神经胶质瘤的风险，但会使小鼠建模复杂化。

总之，这一研究证明，复发性表观遗传损伤具有在体外驱动OPC增殖和在体内驱动胶质瘤形成的能力。

附：英文原文

Title: Modeling epigenetic lesions that cause gliomas

Author: Gilbert J. Rahme, Nauman M. Javed, Kaitlyn L. Puorro, Shouhui Xin, Volker Hovestadt, Sarah E. Johnstone, Bradley E. Bernstein

Issue&Volume: 2023-07-25

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 exhibitDNA hypermethylation. We focus on a CTCF insulator near the PDGFRA oncogene that is recurrently disrupted by methylation in these tumors. We demonstratethat 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-dependentsilencing of the Cdkn2a tumor suppressor, cooperates with insulator loss in OPCs. Coordinate inactivationof the Pdgfra insulator and Cdkn2a drives gliomagenesis in vivo. Despite locus synteny, the insulator is CpG-rich only in humans, a feature thatmay confer human glioma risk but complicates mouse modeling. Our study demonstratesthe capacity of recurrent epigenetic lesions to drive OPC proliferation in vitro and gliomagenesis in vivo.

DOI: 10.1016/j.cell.2023.06.022

Source: https://www.cell.com/cell/fulltext/S0092-8674(23)00729-8