[PMC free article] [PubMed] [Google Scholar]Hodges C, Kirkland JG, and Crabtree GR (2016). probably modulating BRG1-mediated transcription results. Using mice with knockin mutations, we display that non-phosphorylatable BRG1 fails to efficiently induce activity-dependent genes, whereas phosphomimic BRG1 raises enhancer activity and inducibility. These mutant mice display anxiety-like phenotypes L-Tyrosine and modified responses to stress. Therefore, we reveal a mechanism linking neuronal signaling to enhancer activities through BRG1 phosphorylation. Graphical abstract In brief Kim et al. find a crucial function of the BRG1 chromatin remodeler in regulating basal activities and inducibilities of neuronal activity-induced enhancers. Neuronal activity-induced BRG1 phosphorylation regulates its connection with additional transcription co-factors and target gene activation. This study provides insights to BRG1 function in neural development and plasticity. Intro Activity-regulated gene (ARG) manifestation takes on a central part in short-term neural reactions, as well as with long-term memory formation, homeostasis, and adaptation (Western and Greenberg, 2011; Yap and Greenberg, 2018). Modified ARG manifestation may lead to behavior problems in stress reactions, learning and memory, habit, and psychiatric disorders (Gallo et al., 2018; L-Tyrosine Manning et al., 2017). ARGs include immediate early genes (IEGs) that are induced within minutes and late response genes (LRGs) that are induced over hours. ARG manifestation is directed through activity-induced enhancers by specific neuronal stimuli (Kim et al., 2010; Nord and West, 2020; Tyssowski et al., 2018). Activated distal enhancers designated by H3K27Ac interact with promoters to form enhancer-promoter (E-P) loops (Kim and Shiekhattar, 2015). Cohesin-mediated E-P looping facilitates RNA polymerase II (RNA Pol II) recruitment and enhancer RNA (eRNA) manifestation, which drives mRNA transcription (Kagey et al., 2010; Kim and Shiekhattar, 2015). Thousands of neuronal activity-induced enhancers designated by improved H3K27Ac have been recognized in cultured main cortical neurons in response to KCl-mediated depolarization (Malik et al., 2014). Many chromatin regulators, such as histone acetyl transferase (HAT) CBP and histone deacetylases (HDACs), methyl DNA realizing protein MECP2, and chromatin redesigning regulators BRG1/BRM-Associated Element (BAF) and Nucleosome Redesigning Deacetylase (NuRD) complexes, have been shown to play important functions in Rabbit Polyclonal to Androgen Receptor ARG rules (Chen et al., 2003, 2019; Qiu and Ghosh, 2008; Yang et al., 2016; Zhang et al., 2015). Importantly, it remains mainly unclear how these factors functionally interact with each other to regulate enhancer activity and modulate transcription results. Mammalian SWItch/Sucrose Non-Fermentable (SWI/SNF)-like ATP-dependent chromatin redesigning BAF complexes, which contain core ATPase subunits BRG1/SMARCA4 or BRM/SMARCA2 and 10C12 tightly connected subunits, use energy derived from ATP hydrolysis to modulate chromatin constructions and regulate transcription (Son and Crabtree, 2014). Mutations in BAF subunits are the genetic causes of Coffin-Siris syndrome (Santen et al., 2012; Tsurusaki et al., 2012; Vehicle Houdt et al., 2012), which results in severe neural developmental problems. In addition, practical mutations in genes encoding BAF subunits are observed in individuals with autism spectrum disorders, amyotrophic lateral sclerosis, and schizophrenia (De Rubeis et al., 2014; Halgren et al., 2012; Helsmoortel et al., 2014; Neale et al., 2012). Moreover, is a key node in the autism spectrum disorder gene network (De Rubeis et al., 2014). Animal studies demonstrated important functions of BAF subunits in neural development and plasticity (Sokpor et al., 2017; Child and Crabtree, 2014; Wu, 2012). BRG1 and BAF complexes preferentially bind to enhancers during development and cancer progression (Alexander et al., 2015; Alver et al., 2017; Yu et al., 2013). Mechanistic analyses are complicated because BAF complexes can function as activators or as repressors. Previously, we as well as others have shown that neuronal BAF complexes play important L-Tyrosine but context-dependent functions in ARG rules. It has been demonstrated that BAF subunits could repress ARG basal manifestation or either limit or promote ARG induction in different contexts (Qiu and Ghosh, 2008; Wenderski et al., 2020; Wu et al., 2007; Zhang et al., 2015). However, it remains unclear how BAF complexes execute specific functions in basal and triggered neuronal conditions. Neuronal activities, which result in Ca2+ influx, initiate multiple signaling pathways into the nucleus to regulate transcription. Intermediates, such as cyclic AMP/protein kinase A (cAMP/PKA), RAS/mitogen-activated protein kinase (MAPK),.
[PMC free article] [PubMed] [Google Scholar]Hodges C, Kirkland JG, and Crabtree GR (2016)