Serotonin transporter-dependent histone serotonylation in placenta contributes to the neurodevelopmental transcriptome [ChIP-seq]

Brain development requires appropriate regulation of serotonin (5-HT) signaling from distinct tissue sources across embryogenesis. At the maternal-fetal interface, the placenta is thought to be an important contributor of offspring brain 5-HT and is critical to overall fetal health. Yet, how placental 5-HT is acquired, and the mechanisms through which 5-HT influences placental functions, are not well understood. Recently, our group identified a novel epigenetic role for 5-HT, in which 5-HT can be added to histone proteins to regulate transcription, a process called H3 serotonylation. Here, we show that H3 serotonylation undergoes dynamic regulation during placental development, corresponding to gene expression changes that are known to influence key metabolic processes. Using transgenic mice, we demonstrate that placental H3 serotonylation largely depends on 5-HT uptake by the serotonin transporter (Sert/Slc6a4). Sert deletion robustly reduces enrichment of H3 serotonylation across the placental genome, and disrupts neurodevelopmental gene networks in offspring brain tissues. Thus, these findings suggest a novel role for H3 serotonylation in coordinating placental transcription at the intersection of maternal physiology and offspring brain development. Overall design: This study examined male and female placental tissues across embryogenesis at E9.5, E12.5 and E17.5 (H3K4me3Q5ser ChIP-seq and bulk RNA-seq), compared E12.5 WT vs Sert KO, Tph1 KO, and Oct3 KO placenta tissues (H3K4me3 and H3K4me3Q5ser ChIP-seq), and examined associated offspring brains at E12.5 (bulk RNA-seq)