Dataset Information

ChIP-Seq Data Mining: Remarkable Differences in NRSF/REST Target Genes between Human ESC and ESC-Derived Neurons.

ABSTRACT: The neuron-restrictive silencer factor (NRSF) is a zinc finger transcription factor that represses neuronal gene transcription in non-neuronal cells by binding to the consensus repressor element-1 (RE1) located in regulatory regions of target genes. NRSF silences the expression of a wide range of target genes involved in neuron-specific functions. Previous studies showed that aberrant regulation of NRSF plays a key role in the pathological process of human neurodegenerative diseases. However, a comprehensive set of NRSF target genes relevant to human neuronal functions has not yet been characterized. We performed genome-wide data mining from chromatin immunoprecipitation followed by deep sequencing (ChIP-Seq) datasets of NRSF binding sites in human embryonic stem cells (ESC) and the corresponding ESC-derived neurons, retrieved from the database of the ENCODE/HAIB project. Using bioinformatics tools such as Avadis NGS and MACS, we identified 2,172 NRSF target genes in ESC and 308 genes in ESC-derived neurons based on stringent criteria. Only 40 NRSF target genes overlapped between both data sets. According to motif analysis, binding regions showed an enrichment of the consensus RE1 sites in ESC, whereas they were mainly located in poorly defined non-RE1 sites in ESC-derived neurons. Molecular pathways of NRSF target genes were linked with various neuronal functions in ESC, such as neuroactive ligand-receptor interaction, CREB signaling, and axonal guidance signaling, while they were not directed to neuron-specific functions in ESC-derived neurons. Remarkable differences in ChIP-Seq-based NRSF target genes and pathways between ESC and ESC-derived neurons suggested that NRSF-mediated silencing of target genes is highly effective in human ESC but not in ESC-derived neurons.

SUBMITTER: Satoh J

PROVIDER: S-EPMC3855043 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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ChIP-Seq Data Mining: Remarkable Differences in NRSF/REST Target Genes between Human ESC and ESC-Derived Neurons.

Satoh Jun-Ichi J Kawana Natsuki N Yamamoto Yoji Y

Bioinformatics and biology insights 20131201

The neuron-restrictive silencer factor (NRSF) is a zinc finger transcription factor that represses neuronal gene transcription in non-neuronal cells by binding to the consensus repressor element-1 (RE1) located in regulatory regions of target genes. NRSF silences the expression of a wide range of target genes involved in neuron-specific functions. Previous studies showed that aberrant regulation of NRSF plays a key role in the pathological process of human neurodegenerative diseases. However, a ...[more]

PMID: 24324330

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Project description:The repressor element-1 silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) is an epigenetic master regulator that plays a crucial role during nervous system development and maturation. REST function was originally described during development, where it determines neuronal phenotype. However, recent studies showed that REST participates in several processes in the adult brain, including neuronal plasticity and epileptogenesis. In this regard, the relationships between REST and epilepsy are still controversial and need further investigation. As forebrain excitatory neurons are the common final pathway of seizure susceptibility, we investigated the role of REST in epilepsy by inducing REST conditional knockout (REST-cKO) specifically in excitatory neurons of the hippocampus. To target the excitatory neuronal population, we cloned the calcium/calmodulin-dependent protein kinase IIα minimal promoter upstream of Cre recombinase. After assessing the specificity of the promoter's expression, the transgenes were packaged in an engineered adeno-associated virus able to cross the blood-brain and blood-cerebrospinal fluid barriers and delivered in the lateral ventricles of 2-month-old RESTflox/flox mice to characterize, after 1 month, the cognitive phenotype and the seizure propensity. We show that REST-cKO mice display lower levels of anxiety in the light-dark test with respect to control mice but have unaltered motor, social, and cognitive profiles. The evaluation of the susceptibility to epileptic seizures showed that REST-cKO mice are more resistant to pentylenetetrazole-induced kindling but not to seizures induced by a single administration of the convulsant and show higher survival rates. Overall, these data suggest that the absence of REST in forebrain excitatory neurons decreases seizure susceptibility, pointing to a pro-epileptogenic role of the transcriptional repressor under conditions of pathological excitation/inhibition imbalance.

Project description:UnlabelledDuring embryonic development, regulation of gene expression is key to creating the many subtypes of cells that an organism needs throughout its lifetime. Recent work has shown that maternal genetics and environmental factors have lifelong consequences on diverse processes ranging from immune function to stress responses. The RE1-silencing transcription factor (Rest) is a transcriptional repressor that interacts with chromatin-modifying complexes to repress transcription of neural-specific genes during early development. Here we show that in zebrafish, maternally supplied rest regulates expression of target genes during larval development and has lifelong impacts on behavior. Larvae deprived of maternal rest are hyperactive and show atypical spatial preferences. Adult male fish deprived of maternal rest present with atypical spatial preferences in a novel environment assay. Transcriptome sequencing revealed 158 genes that are repressed by maternal rest in blastula stage embryos. Furthermore, we found that maternal rest is required for target gene repression until at least 6 dpf. Importantly, disruption of the RE1 sites in either snap25a or snap25b resulted in behaviors that recapitulate the hyperactivity phenotype caused by absence of maternal rest Both maternal rest mutants and snap25a RE1 site mutants have altered primary motor neuron architecture that may account for the enhanced locomotor activity. These results demonstrate that maternal rest represses snap25a/b to modulate larval behavior and that early Rest activity has lifelong behavioral impacts.Significance statementMaternal factors deposited in the oocyte have well-established roles during embryonic development. We show that, in zebrafish, maternal rest (RE1-silencing transcription factor) regulates expression of target genes during larval development and has lifelong impacts on behavior. The Rest transcriptional repressor interacts with chromatin-modifying complexes to limit transcription of neural genes. We identify several synaptic genes that are repressed by maternal Rest and demonstrate that snap25a/b are key targets of maternal rest that modulate larval locomotor activity. These results reveal that zygotic rest is unable to compensate for deficits in maternally supplied rest and uncovers novel temporal requirements for Rest activity, which has implications for the broad roles of Rest-mediated repression during neural development and in disease states.

Dataset Information

ChIP-Seq Data Mining: Remarkable Differences in NRSF/REST Target Genes between Human ESC and ESC-Derived Neurons.

Publications

ChIP-Seq Data Mining: Remarkable Differences in NRSF/REST Target Genes between Human ESC and ESC-Derived Neurons.

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