The activity-dependent FOS regulon in stem cell-derived human neurons

Abstract

Cells integrate signals from the environment by activating gene programs that mediate the cells’ response to extracellular stimuli. This process is largely initiated by activation of distinct sets of immediate early genes (IEGs), which encode transcription factors (TFs) such as FOS. In growth-arrested mouse fibroblasts stimulated with serum to re-enter the cell cycle, FOS interacts with BRG1/BRM-associated factor (BAF) complex and cell type-specific factors to execute stereotyped transcriptional response to serum or growth factors. However, it is unknown whether FOS and the BAF complex colocalize to regulate activity-dependent gene programs in neurons. It also remains unclear whether there are unique features of FOS-binding sites that when mutated may render increased susceptibility to neurodevelopmental diseases. Here, we depolarize human neurons differentiated from human pluripotent stem cells (hPSCs) to identify FOS-binding sites across the genome. We demonstrate that FOS primarily interacts with putative enhancer regions, and that a subset of FOS-binding sites lies near activity-regulated genes that are associated with autism spectrum disorder (ASD). We observe localization of the BAF complex and an overall increase in chromatin accessibility at the FOS-bound sites following membrane depolarization. Examining variants found in individuals diagnosed with ASD from the SFARI SPARK datasets, we identify rare de novo ASD variants occurring within the FOS-binding sites that may contribute to the etiology of ASD in these patients. We validate the functional effects of these variants by demonstrating that they disrupt enhancer function in reporter assays. Finally, we model ARID1B haploinsufficiency and show that it results in decreased enhancer activation in hPSC-derived neurons. Our results suggest a potential link between FOS and ASD, and reveal the role of FOS and the BAF complex in regulating activity-dependent gene programs in human neurons.