Neuronal Activity-Induced BRG1 Phosphorylation Regulates Enhancer Activation

Abstract

Neuronal activity-induced enhancers drive the gene induction in response to stimulation. Here, we demonstrate that BRG1, the core subunit of SWI/SNF-like BAF ATP-dependent chromatin remodeling complexes, 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, RNA polymerase II recruitment, and enhancer RNA expression. Furthermore, 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, 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 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.