Neuronal Activity-Induced BRG1 Phosphorylation Regulates Enhancer Activation

Abstract

SUMMARYNeuronal 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.

Reliance of neuronal gene expression on cohesin scales with chromatin loop length

“…The activation of inducible Fos enhancers involves H3K27ac (Ref. 27 ), recruitment of RNA polymerases 28 and Mediator complex 25 , as well as active transcription 50 . Our data show that cohesin is not required for the recruitment of histone acetyl transferase activity and of the transcriptional machinery to inducible Fos enhancers.…”

“…Activity-dependent neuronal genes and their associated enhancers are important for neuronal morphology, the formation of synapses and circuits, and ultimately learning and memory [20][21][22][23][24] . Activity-dependent gene expression is accompanied by acetylation of H3K27, recruitment of RNAP2, cohesin, and other chromatin binding proteins [22][23][24][25][26][27][28] . 3D contacts between enhancers and promoters increase in response to neuronal activation at a subset of activity-dependent genes 25,27,29 , and activity-dependent gene expression is impaired in the absence of cohesin or CTCF (Refs.…”

“…26,29 ). Current models attribute impaired activitydependent gene expression to a role for cohesin and CTCF in anchoring specific enhancerpromoter contacts at activity-dependent neuronal genes 3, 25,26,28,29 . In contrast to this model, we show that nearly all activity-dependent genes remain inducible in the absence of cohesin.…”

Activity-assembled nBAF complex mediates rapid immediate early gene transcription by regulating RNA Polymerase II productive elongation

“…The relationship between the BAF complex and RNA Pol2 has been studied over the years in many models and cell types. These studies include genome-wide studies where ChIP with high-throughput sequencing (ChIP-seq) and other global approaches suggest that BAF subunits largely enrich at gene promoters and enhancers, where they facilitate functions of these genomic regions 33,37,[78][79][80][81][82][83] . From these studies, the BAF complex may be inferred to have promoter-and enhancer-specific functions only.…”