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Non-Canonical Targets of HIF1a Impair Oligodendrocyte Progenitor Cell Function [ATAC-seq]

ABSTRACT: Non-Canonical Targets of HIF1a Impair Oligodendrocyte Progenitor Cell Function [ATAC-seq]

PROVIDER: PRJNA649534 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12344538.fastq.gz	Fastqsanger.gz
	SRR12344539.fastq.gz	Fastqsanger.gz

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Non-Canonical Targets of HIF1a Impair Oligodendrocyte Progenitor Cell Function [RNA-Seq]

Project description: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.

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Non-Canonical Targets of HIF1a Impair Oligodendrocyte Progenitor Cell Function [RNA-Seq]