Elevated FOXG1 and SOX2 in glioblastoma enforces neural stem cell identity through transcriptional control of cell cycle and epigenetic regulators.
Elevated FOXG1 and SOX2 in glioblastoma enforces neural stem cell identity through transcriptional control of cell cycle and epigenetic regulators.
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DOI：
10.1101/gad.293027.116
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发表时间：
2017-04-15
影响因子：
10.5
通讯作者：
Pollard SM
中科院分区：
文献类型：
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作者：
Bulstrode H;Johnstone E;Marques-Torrejon MA;Ferguson KM;Bressan RB;Blin C;Grant V;Gogolok S;Gangoso E;Gagrica S;Ender C;Fotaki V;Sproul D;Bertone P;Pollard SM
Bulstrode等人的研究表明FOXG1和SOX2的表达增加限制了星形胶质细胞的分化，并可以触发去分化到增生性神经干细胞状态。FOXG1和SOX2在胶质母细胞瘤干细胞中发挥着不同但互补的作用，通过对核心细胞周期调节因子和表观遗传靶点的转录控制，促进不受约束的自我更新。多形性胶质母细胞瘤（GBM）是一种由具有神经干细胞特征的细胞驱动的侵袭性脑肿瘤。GBM干细胞经常表达高水平的转录因子FOXG1和SOX2。本研究表明，这些因子的表达增加限制了星形胶质细胞的分化，并可以触发去分化到增殖性神经鞘细胞状态。转录靶点包括细胞周期和表观遗传调控因子（如Foxo3、Plk1、Mycn、Dnmt1、Dnmt3b和Tet3）。Foxo3是一种关键的受抑制的下游效应物，通过保守的FOXG1/ sox2结合的顺式调控元件来控制。Foxo3缺失，再加上暴露于DNA甲基化抑制剂5-氮杂胞苷，强制星形胶质细胞去分化。在星形胶质细胞分化过程中，DNA甲基化谱鉴定了多个多梳靶点的变化，包括Foxo3的启动子。在患者来源的GBM干细胞中，CRISPR/Cas9删除FOXG1不影响体外增殖；然而，在体内移植后，FOXG1-null细胞表现出星形胶质细胞分化增加和FOXO3上调。相反，SOX2消融会减弱增殖，突变细胞不能在体外扩增。因此，FOXG1和SOX2通过核心细胞周期和表观遗传调控因子的转录控制，在GBM干细胞中发挥互补但不同的作用，促进不受约束的自我更新。
Bulstrode et al. show that increased expression of FOXG1 and SOX2 restricts astrocyte differentiation and can trigger dedifferentiation to a proliferative neural stem cell state. FOXG1 and SOX2 operate in distinct but complementary roles to fuel unconstrained self-renewal in glioblastoma stem cells via transcriptional control of core cell cycle regulators and epigenetic targets. Glioblastoma multiforme (GBM) is an aggressive brain tumor driven by cells with hallmarks of neural stem (NS) cells. GBM stem cells frequently express high levels of the transcription factors FOXG1 and SOX2. Here we show that increased expression of these factors restricts astrocyte differentiation and can trigger dedifferentiation to a proliferative NS cell state. Transcriptional targets include cell cycle and epigenetic regulators (e.g., Foxo3, Plk1, Mycn, Dnmt1, Dnmt3b, and Tet3). Foxo3 is a critical repressed downstream effector that is controlled via a conserved FOXG1/SOX2-bound cis-regulatory element. Foxo3 loss, combined with exposure to the DNA methylation inhibitor 5-azacytidine, enforces astrocyte dedifferentiation. DNA methylation profiling in differentiating astrocytes identifies changes at multiple polycomb targets, including the promoter of Foxo3. In patient-derived GBM stem cells, CRISPR/Cas9 deletion of FOXG1 does not impact proliferation in vitro; however, upon transplantation in vivo, FOXG1-null cells display increased astrocyte differentiation and up-regulate FOXO3. In contrast, SOX2 ablation attenuates proliferation, and mutant cells cannot be expanded in vitro. Thus, FOXG1 and SOX2 operate in complementary but distinct roles to fuel unconstrained self-renewal in GBM stem cells via transcriptional control of core cell cycle and epigenetic regulators.