Mammalian cells respond to insufficient oxygen through transcriptional regulators called hypoxia-inducible factors (HIFs). Although transiently protective, prolonged HIF activity drives distinct pathological responses in different tissues. Using a model of chronic HIF1a accumulation in pluripotent-stem-cell-derived oligodendrocyte progenitors (OPCs), we demonstrate that HIF1a activates non-canonical targets to impair generation of oligodendrocytes from OPCs. HIF1a activated a unique set of genes in OPCs through interaction with the OPC-specific transcription factor OLIG2. Non-canonical targets, including Ascl2 and Dlx3, were sufficient to block differentiation through suppression of the oligodendrocyte regulator Sox10. Chemical screening revealed that inhibition of MEK/ERK signaling overcame the HIF1a-mediated block in oligodendrocyte generation by restoring Sox10 expression without affecting canonical HIF1a activity. MEK/ERK inhibition also drove oligodendrocyte formation in hypoxic regions of human oligocortical spheroids. This work defines mechanisms by which HIF1a impairs oligodendrocyte formation and establishes that cell-type-specific HIF1a targets perturb cell function in response to low oxygen.

哺乳动物细胞通过称为缺氧诱导因子 (HIF) 的转录调节因子对氧气不足作出反应。尽管具有短暂的保护作用，但延长的 HIF 活性会在不同组织中产生不同的病理反应。使用多能干细胞衍生的少突胶质细胞祖细胞 (OPC) 中慢性 HIF1a 积累的模型，我们证明 HIF1a 激活非经典靶标以损害从 OPC 生成的少突胶质细胞。HIF1a 通过与 OPC 特异性转录因子 OLIG2 的相互作用激活 OPC 中一组独特的基因。非规范目标，包括Ascl2和Dlx3，足以通过抑制少突胶质细胞调节剂Sox10来阻止分化. 化学筛选显示，抑制 MEK/ERK 信号通过恢复Sox10表达而不影响典型的 HIF1a 活性，克服了 HIF1a 介导的少突胶质细胞生成阻滞。MEK/ERK 抑制还促进了人少皮质球体缺氧区域中少突胶质细胞的形成。这项工作定义了 HIF1a 损害少突胶质细胞形成的机制，并确定了细胞类型特异性 HIF1a 目标扰乱细胞功能以响应低氧。