Neuronal Activity-Induced BRG1 Phosphorylation Regulates Enhancer Activation

Neuronal activity-induced enhancers drive the gene induction in response to stimulation. activity-regulated gene expression plays a central role in both short-term neural responses and long-term neural adaptation. Altered expression causes changes in neuronal function and connection that may lead to behavior defects and brain disorders. Mammalian SWI/SNF-like ATP-dependent chromatin remodeling BAF complexes, which contain core ATPase subunits BRG1, modulate chromatin structures and regulate transcription. BRG1 is a key node in the autism spectrum disorder gene network. Mutations in BAF subunits lead to neural developmental disorders. Previously, we and others have shown that neuronal BAF complexes are important for activity-regulated gene expression and synaptic development and plasticity. Here, we demonstrate that BRG1 regulates neuronal activity-induced enhancers. Upon stimulation, BRG1 is recruited to enhancers in an H3K27Ac-dependent manner. BRG1 regulates enhancer basal activities and inducibility by affecting cohesin binding, enhancer-promoter looping, local H3K27Ac levels, RNA polymerase II recruitment, and enhancer RNA expression. Furthermore, using a proteomic approach, we identified a serine phosphorylation site in BRG1 that is induced by neuronal activities and is sensitive to CaMKII inhibition. BRG1 phosphorylation affects its interaction with several transcription co-factors including NuRD co-repressor complexes and cohesin, possibly modulating BRG1 mediated transcription outcomes. Using mice with knock-in mutations, we showed that non-phosphorylatable BRG1 fails to efficiently induce activity-dependent genes, whereas phosphomimic BRG1 increases the enhancer activities and inducibility. These BRG1 phospho-mutant mice displayed anxiety-like phenotypes and altered responses to stress. Therefore, our data reveal a mechanism connecting neuronal signaling to enhancer activities through BRG1 phosphorylation. Our study also provides significant insights into the function of chromatin remodeling complexes in neural plasticity and brain disorders.