Dual role of Brg chromatin remodeling factor in Sonic hedgehog signaling during neural development

Zhan, Xiaoming; Shi, Xuanming; Zhang, Zilai; Chen, Yu; Wu, Jiang

doi:10.1073/pnas.1018510108

Cited by 86 publications

(127 citation statements)

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“…Peptides purchased from EpiCypher were as follows: H3.3(22-44) (12-0020); H3.3K36Me1 (12-0022); H3.3K36Me2 (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23), and H3.3K36Me3 (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24).…”

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confidence: 99%

“…Co-IP-Cross-linked cells were subjected to co-IP as delineated elsewhere (20). In brief, after cross-linking the cells were lysed with 50 mM HEPES (pH 7.5), 150 mM NaCl, 1.5 mM MgCl 2 , 1 mM EDTA, 1 mM EGTA, 1% Triton X-100, 0.5% sodium deoxycholate, 5% glycerol, 1 mM DTT, 2 mM PMSF, 1 mM trichostatin A, 5 mM sodium butyrate, and complete protease inhibitor mixture and incubated on ice for 1 h followed by centrifugation at 13,000 rpm for 10 min at 4°C.…”

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confidence: 99%

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Selective Recognition of H3.1K36 Dimethylation/H4K16 Acetylation Facilitates the Regulation of All-trans-retinoic Acid (ATRA)-responsive Genes by Putative Chromatin Reader ZMYND8

Adhikary

Sanyal

Basu

et al. 2016

Journal of Biological Chemistry

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ZMYND8 (zinc finger MYND (Myeloid, Nervy and DEAF-1)-type containing 8), a newly identified component of the transcriptional coregulator network, was found to interact with the Nucleosome Remodeling and Deacetylase (NuRD) complex. Previous reports have shown that ZMYND8 is instrumental in recruiting the NuRD complex to damaged chromatin for repressing transcription and promoting double strand break repair by homologous recombination. However, the mode of transcription regulation by ZMYND8 has remained elusive. Here, we report that through its specific key residues present in its conserved chromatin-binding modules, ZMYND8 interacts with the selective epigenetic marks H3.1K36Me2/H4K16Ac. Furthermore, ZMYND8 shows a clear preference for canonical histone H3.1 over variant H3.3. Interestingly, ZMYND8 was found to be recruited to several developmental genes, including the all-trans-retinoic acid (ATRA)-responsive ones, through its modified histone-binding ability. Being itself inducible by ATRA, this zinc finger transcription factor is involved in modulating other ATRA-inducible genes. We found that ZMYND8 interacts with transcription initiation-competent RNA polymerase II phosphorylated at Ser-5 in a DNA templatedependent manner and can alter the global gene transcription. Overall, our study identifies that ZMYND8 has CHD4-independent functions in regulating gene expression through its modified histone-binding ability.ZMYND8 (zinc finger MYND (Myeloid, Nervy and DEAF-1)-type containing 8) is a putative chromatin reader/effector harboring a PWWP domain, a bromodomain, and a PHD type zinc finger. It associates with the CHD4 protein of NuRD chromatin remodeling complex implicated in gene transcription, cell cycle progression, and genome integrity (1, 2). Reader proteins specifically recognize histone post-translational modifications (PTMs) 5 and translate such recognition(s) into meaningful biological outcomes by virtue of either their intrinsic activities or those of their interacting partners (3). These readers may interpret histone PTMs via "monovalent" or "multivalent" recognition (4). In monovalent recognition, a chromatin reader recognizes one histone PTM. In contrast, in multivalent recognition, readers recognize multiple histone modifications intra/inter-nucleosomally. An accessible surface is provided by these readers (such as a cavity or surface groove), which accommodates the modified histone residues, and determines the modification (e.g. acetylation versus methylation) or state specificity (such as mono-versus trimethylation of lysine) (3).ZMYND8 is a well known component of the transcription coregulator complex and is associated with several demethylase machinery components, including KDM5A, KDM5C, or LSD1 (5, 6). Through its ability to interact with Xenopus RCoR2, ZMYND8 plays a significant role in embryonic neural differentiation (7). Apart from this, ZMYND8 is also involved in T-cell lymphoma and breast and cervical cancer (8 -10). Another interesting feature is that ZMYND8 is significantly involved...

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confidence: 99%

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confidence: 99%

Selective Recognition of H3.1K36 Dimethylation/H4K16 Acetylation Facilitates the Regulation of All-trans-retinoic Acid (ATRA)-responsive Genes by Putative Chromatin Reader ZMYND8

Adhikary

Sanyal

Basu

et al. 2016

Journal of Biological Chemistry

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“…The experiments were repeated at least three times. Standard errors were calculated according to a previously described method (37). The sequences of all the primers are listed in Table S3 in the supplemental material.…”

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confidence: 99%

“…Chromatin immunoprecipitation (ChIP) experiments were performed as described previously (37,42). Tissue disrupted by Dounce homogenization or dissociated cells were cross-linked with PFA and sonicated to fragments (200 to 500 bp).…”

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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

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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 ...

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“…Gli proteins harbor a five zinc finger (ZF) region in which ZF4 and ZF5 domains bind target DNA in a sequence-specific way, whereas ZF1, ZF2 and ZF3 bind the phosphate backbone and possibly contributed to control binding stability and recruitment of co-regulatory factors (Kinzler & Vogelstein, 1990;Pavletich & Pabo, 1993). A C-terminal region is provided of transactivating function through modulation of chromatin remodeling induced by recruitment of TFIID TATA box-binding proteinassociated factor TAFII31 (Yoon et al, 1998;Bosco-Clément et al, 2013) or HAT and HDAC Malatesta et al, 2013), SWI-SNF5 (Jagani et al, 2010) and SWI/SNF-like Brg/Brmassociated factor (Zhan et al, 2011). In this way, Gli transcription factors behave as the final effectors for the control of specific oncogenic target genes (Aberger & Ruiz I Altaba, 2014).…”

Section: Introductionmentioning

confidence: 99%

Gli1/DNA interaction is a druggable target for Hedgehog-dependent tumors

Infante¹,

Mori²,

Alfonsi³

et al. 2016

European Journal of Cancer

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Hedgehog signaling is essential for tissue development and stemness, and its deregulation has been observed in many tumors. Aberrant activation of Hedgehog signaling is the result of genetic mutations of pathway components or other Smo-dependent or independent mechanisms, all triggering the downstream effector Gli1. For this reason, understanding the poorly elucidated mechanism of Gli1-mediated transcription allows to identify novel molecules blocking the pathway at a downstream level, representing a critical goal in tumor biology. Here, we clarify the structural requirements of the pathway effector Gli1 for binding to DNA and identify Glabrescione B as the first small molecule binding to Gli1 zinc finger and impairing Gli1 activity by interfering with its interaction with DNA. Remarkably, as a consequence of its robust inhibitory effect on Gli1 activity, Glabrescione B inhibited the growth of Hedgehog-dependent tumor cells in vitro and in vivo as well as the self-renewal ability and clonogenicity of tumor-derived stem cells. The identification of the structural requirements of Gli1/DNA interaction highlights their relevance for pharmacologic interference of Gli signaling.

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Dual role of Brg chromatin remodeling factor in Sonic hedgehog signaling during neural development

Cited by 86 publications

References 40 publications

Selective Recognition of H3.1K36 Dimethylation/H4K16 Acetylation Facilitates the Regulation of All-trans-retinoic Acid (ATRA)-responsive Genes by Putative Chromatin Reader ZMYND8

Selective Recognition of H3.1K36 Dimethylation/H4K16 Acetylation Facilitates the Regulation of All-trans-retinoic Acid (ATRA)-responsive Genes by Putative Chromatin Reader ZMYND8

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

Gli1/DNA interaction is a druggable target for Hedgehog-dependent tumors

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