Glioblastomas (GBMs) are incurable brain tumors with a high degree of cellular heterogeneity and genetic mutations. Transcription factors that normally regulate neural progenitors and glial development are aberrantly coexpressed in GBM, conferring cancer stem‐like properties to drive tumor progression and therapeutic resistance. However, the functional role of individual transcription factors in GBMs in vivo remains elusive. Here, we demonstrate that the basic‐helix–loop–helix transcription factor ASCL1 regulates transcriptional targets that are central to GBM development, including neural stem cell and glial transcription factors, oncogenic signaling molecules, chromatin modifying genes, and cell cycle and mitotic genes. We also show that the loss of ASCL1 significantly reduces the proliferation of GBMs induced in the brain of a genetically relevant glioma mouse model, resulting in extended survival times. RNA‐seq analysis of mouse GBM tumors reveal that the loss of ASCL1 is associated with downregulation of cell cycle genes, illustrating an important role for ASCL1 in controlling the proliferation of GBM.

中文翻译：

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ASCL1 调节神经胶质瘤小鼠模型脑肿瘤中的神经发育转录因子和细胞周期基因。

胶质母细胞瘤 (GBM) 是无法治愈的脑肿瘤，具有高度的细胞异质性和基因突变。通常调节神经祖细胞和神经胶质发育的转录因子在 GBM 中异常共表达，赋予癌症干细胞样特性以驱动肿瘤进展和治疗抵抗。然而，个体转录因子在体内 GBM 中的功能作用仍然难以捉摸。在这里，我们证明了基本-螺旋-环-螺旋转录因子 ASCL1 调节对 GBM 发育至关重要的转录目标，包括神经干细胞和神经胶质转录因子、致癌信号分子、染色质修饰基因以及细胞周期和有丝分裂基因。我们还表明，ASCL1 的缺失显着降低了在遗传相关神经胶质瘤小鼠模型的大脑中诱导的 GBM 的增殖，从而延长了生存时间。小鼠 GBM 肿瘤的 RNA-seq 分析表明，ASCL1 的缺失与细胞周期基因的下调有关，说明 ASCL1 在控制 GBM 增殖中的重要作用。