Ablation of placental REST deregulates fetal brain metabolism and impacts gene expression of the offspring brain at the postnatal and adult stages.

In this study, the transcriptional repressor REST (Repressor Element 1 Silencing Transcription factor) was ablated in the mouse placenta to investigate molecular and cellular impacts on the offspring brain at different life stages. Ablation of placental REST deregulated several brain metabolites, including glucose and lactate that fuel brain energy, vitamin C (ascorbic acid) that functions in the epigenetic programming of the brain during postnatal development, and glutamate and creatine that help the brain to respond to stress conditions during adult life. Bulk RNA-seq analysis showed that a lack of placental REST persistently altered multiple transport genes, including those related to oxygen transportation in the offspring brain. While metabolic genes were impacted in the postnatal brain, different stress response genes were activated in the adult brain. DNA methylation was also impacted in the adult brain due to the loss of placental REST, but in a sex-biased manner. Single-nuclei RNA-seq analysis showed that specific cell types of the brain, particularly those of the choroid plexus and ependyma, which play critical roles in producing cerebrospinal fluid and maintaining metabolic homeostasis, were significantly impacted due to the loss of placental REST. These cells showed significant differential expression of genes associated with the metabotropic (G coupled protein) and ionotropic (ligand-gated ion channel) glutamate receptors, suggesting an impact of ablation of placental REST on the glutamatergic signaling of the offspring brain. The study expands our understanding of placental influences on the offspring brain.