Involvement of SMARCA2/BRM in the SWI/SNF chromatin-remodeling complex in schizophrenia

Koga, Minoru; Ishiguro, Hiroki; Yazaki, Saori; Horiuchi, Yasue; Arai, Makoto; Niizato, Kazuhiro; Iritani, Shyuji; Itokawa, Masanari; Inada, Toshiya; Iwata, Nakao; Ozaki, Norio; Ujike, Hiroshi; Kunugi, Hiroshi; Sasaki, Tsukasa; Takahashi, Makoto; Watanabe, Yuichiro; Someya, Toshiyuki; Kakita, Akiyoshi; Takahashi, Hitoshi; Nawa, Hiroyuki; Muchardt, Christian; Yaniv, Moshe; Arinami, Tadao

doi:10.1093/hmg/ddp166

Cited by 106 publications

(76 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…ARID1B mutations, such as the de novo deletion identified here, could have effects in autism similar to the affects of mutations in the related SMARC2A gene in schizophrenia. 19,20 Findings of decreased PRODH expression in autism cases carrying a deletion in this gene have been reported 5 and PRODH is known to be dosage-sensitive in mouse neurodevelopment. 21 Imprinting has been shown to cause allelespecific expression of ZNF215 but not the neighboring ZNF214 gene, 22 and this region is associated with maternally transmitted balanced chromosomal abnormalities causing Beckwith-Wiedemann syndrome, which can be comorbid with autism.…”

Section: Discussionmentioning

confidence: 93%

Reduced transcript expression of genes affected by inherited and de novo CNVs in autism

et al. 2011

View full text Add to dashboard Cite

Individuals with autism are more likely to carry rare inherited and de novo copy number variants (CNVs). However, further research is needed to establish which CNVs are causal and the mechanisms by which these CNVs influence autism. We examined genomic DNA of children with autism (N¼41) and healthy controls (N¼367) for rare CNVs using a high-resolution array comparative genomic hybridization platform. We show that individuals with autism are more likely to harbor rare CNVs as small as B10 kb, a threshold not previously detectable, and that CNVs in cases disproportionately affect genes involved in transcription, nervous system development, and receptor activity. We also show that a subset of genes that have known or suspected allele-specific or imprinting effects and are within rare-case CNVs may undergo loss of transcript expression. In particular, expression of CNTNAP2 and ZNF214 are decreased in probands compared with their unaffected transmitting parents. Furthermore, expression of PRODH and ARID1B, two genes affected by de novo CNVs, are decreased in probands compared with controls. These results suggest that for some genes affected by CNVs in autism, reduced transcript expression may be a mechanism of pathogenesis during neurodevelopment.

show abstract

Section: Discussionmentioning

confidence: 93%

Reduced transcript expression of genes affected by inherited and de novo CNVs in autism

et al. 2011

View full text Add to dashboard Cite

show abstract

“…Interestingly, in adult neurons, the Brg1 homolog Brm is highly expressed, and this might compensate for Brg1 deletion. Mutations in Brm, but not in Brg1, have been linked to schizophrenia (64). Thus, during different developmental stages, specific BAF complexes may be required for different aspects of neuronal development and function.…”

Section: Discussionmentioning

confidence: 99%

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

Zhang

Cao

Chang

et al. 2016

Molecular and Cellular Biology

View full text Add to dashboard Cite

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 ...

show abstract

“…A genome-wide screen of single nucleotide polymorphisms recently identified Brm as a gene associated with schizophrenia (24). Although behavioral analyses of Brm −/− mice have not been performed, nNOS −/− mice display a host of abnormalities that span from aggressive behavior to impaired cognitive performance (36).…”

Section: Discussionmentioning

confidence: 99%

S-nitrosylation of HDAC2 regulates the expression of the chromatin-remodeling factor Brm during radial neuron migration

Nott

Nitarska

Veenvliet

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Dynamic epigenetic modifications play a key role in mediating the expression of genes required for neuronal development. We previously identified nitric oxide (NO) as a signaling molecule that mediates S-nitrosylation of histone deacetylase 2 (HDAC2) and epigenetic changes in neurons. Here, we show that HDAC2 nitrosylation regulates neuronal radial migration during cortical development. Bead-array analysis performed in the developing cortex revealed that brahma (Brm), a subunit of the ATP-dependent chromatin-remodeling complex BRG/brahma-associated factor, is one of the genes regulated by S-nitrosylation of HDAC2. In the cortex, expression of a mutant form of HDAC2 that cannot be nitrosylated dramatically inhibits Brm expression. Our study identifies NO and HDAC2 nitrosylation as part of a signaling pathway that regulates cortical development and the expression of Brm in neurons.neural development | transcription | nitric oxide synthase | polar morphology | schizophrenia N euronal development relies on a number of sequential events whereby a pool of undifferentiated embryonic progenitor cells gives rise to a variety of highly specialized postmitotic neurons and glia. In the cortex, neuronal and glial cells derive from multipotent neural progenitor cells (NPCs) generated in the ventricular zone (VZ) of the developing brain. NPCs either undergo self-renewal or exit the cell cycle, differentiate into postmitotic neurons, and migrate to the external layers of the cortex (1). Cortical layers are formed between embryonic day 11 (E11) and E18 in an inside-out manner with deep layers formed first, followed by the more superficial layers, and the formation depends on radial neuron migration. Extracellular cues that regulate this process include brain-derived neurotrophic factor (BDNF) (2). Although BDNF and TrkB signaling are not required for neuronal survival in the embryonic cortex, they have been implicated in the regulation of NPC proliferation (3) and radial and tangential neuronal migration (2).In addition to the coordinated expression of nuclear factors that regulate, first, neurogenesis and neuronal migration and, later, promote gliogenesis, epigenetic modifications of both DNA and histones represent fundamental mechanisms by which neurons adapt their transcriptional response to corticogenic cues (4). Histone acetylases and deacetylases (HDACs) are nuclear enzymes that maintain chromatin acetylation in balance, thereby contributing to both transcriptional activation and repression. All HDACs identified so far are present in the nervous system and are often developmentally regulated. For example, the highly homologous HDAC1 and HDAC2 are detected at different stages of neuronal development, with HDAC1 confined to neural stem cells and glia and HDAC2 predominantly expressed in postmitotic neuroblasts and differentiated neurons (5).Although it is now established that many posttranslational modifications of HDACs impact on their activity, there is little evidence directly linking extrinsic stimuli to changes of nucle...

show abstract

Involvement of SMARCA2/BRM in the SWI/SNF chromatin-remodeling complex in schizophrenia

Cited by 106 publications

References 52 publications

Reduced transcript expression of genes affected by inherited and de novo CNVs in autism

Reduced transcript expression of genes affected by inherited and de novo CNVs in autism

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

S-nitrosylation of HDAC2 regulates the expression of the chromatin-remodeling factor Brm during radial neuron migration

Contact Info

Product

Resources

About