Non-canonical Targets of HIF1a Impair Oligodendrocyte Progenitor Cell Function

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. [Display omitted] •HIF1a activates both canonical hypoxia response and unique OPC-specific genes•OLIG2 physically interacts with HIF1a and is enriched at OPC-specific HIF1a targets•OPC-specific HIF1a targets suppress Sox10 to impair oligodendrocyte formation•MEK inhibition increases Sox10 expression to rescue OPC function from hypoxia Hypoxia impairs the generation of oligodendrocytes and myelin in various neurological disorders. Allan et al. map the genome-wide binding profile of HIF1a in oligodendrocyte progenitor cells (OPCs). HIF1a activated non-canonical, cell-type-specific target genes in OPCs that converge to suppress Sox10 expression and block oligodendrocyte formation.