Autism-Associated Chromatin Regulator Brg1/SmarcA4 Is Required for Synapse Development and Myocyte Enhancer Factor 2-Mediated Synapse Remodeling

Abstract

Synapse development requires normal neuronal activities and the precise expression of synapse-related genes. Dysregulation of synaptic genes results in neurological diseases such as autism spectrum disorders (ASD). Mutations in genes encoding chromatin-remodeling factor Brg1/SmarcA4 and its associated proteins are the genetic causes of several developmental diseases with neurological defects and autistic symptoms. Recent large-scale genomic studies predicted Brg1/SmarcA4 as one of the key nodes of the ASD gene network. We report that Brg1 deletion in early postnatal hippocampal neurons led to reduced dendritic spine density and maturation and impaired synapse activities. In developing mice, neuronal Brg1 deletion caused severe neurological defects. Gene expression analyses indicated that Brg1 regulates a significant number of genes known to be involved in synapse function and implicated in ASD. We found that Brg1 is required for dendritic spine/synapse elimination mediated by the ASDassociated transcription factor myocyte enhancer factor 2 (MEF2) and that Brg1 regulates the activity-induced expression of a specific subset of genes that overlap significantly with the targets of MEF2. Our analyses showed that Brg1 interacts with MEF2 and that MEF2 is required for Brg1 recruitment to target genes in response to neuron activation. Thus, Brg1 plays important roles in both synapse development/maturation and MEF2-mediated synapse remodeling. Our study reveals specific functions of the epigenetic regulator Brg1 in synapse development and provides insights into its role in neurological diseases such as ASD. Synapses formed between axons and dendrites connect neurons and generate neural circuits that control brain functions (1). The dysregulation of synapse formation, maturation, or plasticity causes many neurodevelopmental diseases such as autism (2). Autism spectrum disorders (ASDs) are complex diseases characterized by a range of behavior abnormalities and regulated by genetic and epigenetic factors (3-5). In ASDs with various genetic or environmental causes, synaptic dysfunction is a central defect.Many autism risk genes encode transcription factors and epigenetic regulators, which likely function to regulate the expression of synaptic genes (4, 6, 7). A gene network analysis predicted the core subunit of a SWI/SNF-like BRG1-associated factor (BAF) ATP-dependent chromatin remodeling complex, Brg1/SmarcA4, as one of the key nodes in autism pathogenesis (7). BAF complexes containing the ATPase Brg1 or Brm use energy derived from ATP hydrolysis to modulate chromatin structures and regulate transcription (8-10). Mutations in several BAF subunits are the genetic causes of Coffin-Siris syndrome and Nicolaides-Baraitser syndrome with autistic symptoms such as intellectual disability and delayed speech (11-15). In addition, de novo functional mutations of genes encoding several BAF subunits are identified repeatedly in autism patients (7,(16)(17)(18). Mutations in a gene encoding the BAF-associated protein activity-dependent ...

SMARCA4 regulates gene expression and higher-order chromatin structure in proliferating mammary epithelial cells

“…These factors may be functionally related because SMARCA4 is a coregulator for many of these factors. MEF2C has been shown to interact with SMARCA4 and is required for the activity-dependent recruitment of SMARCA4 to its target regions (Zhang et al 2015). Moreover, USF1/2 can bind a SMARCA4-associated factor, SMARCD3, and recruit other BAF subunits including SMARCA4 (Wang and Sul 1997).…”

Attenuation of epigenetic regulator SMARCA4 and ERK-ETS signaling suppresses aging-related dopaminergic degeneration

“…Brm with transcriptional factors downstream of MAPK/ERK signaling, such as Pnt or Aop, constituting a positive auto-regulation feedback loop. Alternative mechanisms await further investigation to elucidate the effects of Brm.Our finding that Brm inactivation protects DA degeneration seems to be at odds with the positive roles of Brm in the neural development[15,16,33]. However, previous studies have shown SWI/SNF complexes in different tissues at different stages have distinct functions byeliciting context-specific transcription programs.…”

“…Brm was found here to be progressively up-regulated in the aging brains of PD fly models. One possibility is through a genetic imprinting response to elevated calcium level triggered by aberrant neuronal activities or calcium metabolism [33]. Alternatively, Brm could be activated through NF-kB mediated inflammatory responses that are well recognized in the development of neurodegenerative diseases [34].…”

Understanding environmental contributions to autism: Causal concepts and the state of science

“…Variants enriched in ASD are found in genes that regulate synaptogenesis [De Rubeis et al, ; Patel, Ioannidis, Cullen, & Rehkopf, ], cell migration [Boitard et al, ; Reiner, Karzbrun, Kshirsagar, & Kaibuchi, ; Wang et al, ; Wong et al, ], dendritic growth [De Rubeis et al, ] as well as more basic functions such as chromatin remodeling, cell signaling and cell cycle regulation [Anney et al, ; De Rubeis et al, ]. Transcriptomics along with whole exome sequencing of histone modifying genes similarly suggest altered expression of genes involved in synapse formation, neuronal connectivity, and apoptosis [De Rubeis et al, ; Mahfouz, Ziats, Rennert, Lelieveldt, & Reinders, ; Zeidan‐Chulia et al, ; Zhang et al, ]. Gene expression is regulated by epigenetic changes, which in turn may have environmental origins.…”