Chromatin Disruption After Prenatal Hypoxia Predicts Lasting Neuron Deficits

Prenatal exposure to transient hypoxia can result in various developmental disabilities presumably by disrupting normal neurodevelopmental processes, even in milder injuries without detectable cell death or structural damage ^1,2 . Emerging evidence suggests that disruption of the epigenome may be one of the most critical consequences of prenatal brain exposure to hypoxia ^3–8 . However, the cell-type-selective effects of hypoxia on the developing brain’s transcriptome and epigenome remain unknown. Here, we demonstrate that immediately after hypoxia, transcriptional and chromatin disruptions occur in all cell types, consistent with the energy deficit dynamics caused by prenatal hypoxia. Unexpectedly, we identify a selective dissociation of transcriptional and chromatin regulation in glutamatergic neurons after hypoxia. Genes neighboring sites of differential chromatin accessibility, but not differential gene expression, correlate with structural and functional deficits in glutamatergic neurons one month after the injury. Our approach reveals novel, shared, and cell-type-specific changes that reflect potential short- and long-term consequences of the hypoxic response. Together, these data provide insight into the mechanisms that lead to lasting changes in the epigenome following an injury to the developing brain, resulting in long-term functional deficits.