Neuronal activity-induced BRG1 phosphorylation regulates enhancer activation

Neuronal activity-induced enhancers drive gene activation. 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. We identify a serine phosphorylation site in BRG1 that is induced by neuronal stimulations and is sensitive to CaMKII inhibition. BRG1 phosphorylation affects its interaction with several transcription co-factors, including the NuRD repressor complex and cohesin, possibly modulating BRG1-mediated transcription outcomes. Using mice with knockin mutations, we show that non-phosphorylatable BRG1 fails to efficiently induce activity-dependent genes, whereas phosphomimic BRG1 increases enhancer activity and inducibility. These mutant mice display anxiety-like phenotypes and altered responses to stress. Therefore, we reveal a mechanism connecting neuronal signaling to enhancer activities through BRG1 phosphorylation. [Display omitted] •BRG1 binds neuronal activity-induced enhancers and regulates enhancer activities•Neuronal activities induce BRG1 phosphorylation at S1382, which depends on CAMKII•BRG1 phosphorylation regulates its interactions with transcription co-factors•BRG1 phosphorylation modulates inducibilities of c-Fos enhancers and ARGs in vivo Kim et al. find a critical function of the BRG1 chromatin remodeler in regulating basal activities and inducibilities of neuronal activity-induced enhancers. Neuronal activity-induced BRG1 phosphorylation regulates its interaction with other transcription co-factors and target gene activation. This study provides insights to BRG1 function in neural development and plasticity.