NRSF/REST ChIP-seq binding profile in the rat paraventricular nucleus (PVN) of the hypothalamus
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE87709 | GEO | 2017/02/13
SECONDARY ACCESSION(S): PRJNA345615
REPOSITORIES: GEO
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Project description:Repressor element-1 silencing transcription factor (REST) or neuron-restrictive silencer factor (NRSF) is a zinc-finger (ZF) containing transcriptional repressor that recognizes thousands of neuron-restrictive silencer elements (NRSEs) in mammalian genomes. How REST/NRSF regulates gene expression remains incompletely understood. Here, we investigate the binding pattern and regulation mechanism of REST/NRSF in the clustered protocadherin (PCDH) genes. We find that REST/NRSF directionally forms base-specific interactions with NRSEs via tandem ZFs in an anti-parallel manner but with striking conformational changes. In addition, REST/NRSF recruitment to the HS5-1 enhancer leads to the decrease of long-range enhancer-promoter interactions and downregulation of the clustered PCDH alpha genes. Thus, REST/NRSF represses PCDH alpha gene expression through directional binding to a repertoire of NRSEs within the distal enhancer and variable target genes.
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Project description:The vertebrate-specific transcription factor RE-1 silencing transcription factor or neuron-restrictive silencer factor (REST/NRSF) was first described as a negative regulator restricting expression of neuronal genes to neurons in a variety of genetic contexts. However, REST/NRSF has a more general role in the regulation of gene expression that involves chromatin remodelling via a SWI/SNF complex. We identified a 677 gene repertoire of potential REST/NRSF-dependent genes taking advantage of Rest/Nrsf gene silencing in a mouse cell line. Using Ka/Ks analysis, we found that REST/NRSF protein, REST/NRSF interactors and the products of REST/NRSF-dependent genes display significantly higher rates of protein evolution in primates than in rodents. The McDonald-Kreitman test indicated positive selection for human REST/NRSF and nuclear RNA-binding proteins encoded by REST/NRSFdependent genes. In these proteins, we demonstrated sites under positive selection within the primate’s clade. Importantly, the REST/NRSF-dependent gene repertoire is statistically enriched in genes disrupted in neuropsychiatric diseases such as schizophrenia. In addition, we found that Smarca2 (Brm), Smarcd3 (Baf60c), Smarce1 (Baf57), Hdac1, RcoR1, and Mecp2, which are part of the REST/NRSFSWI/SNF chromatin remodelling complex, are transcriptionally regulated by REST/NRSF. Changing their gene dosage in vitro induced abnormal dendritic and dendritic spine phenotypes that were previously observed in rodent models of neuropsychiatric diseases. Altogether, these results suggest that genes encoding proteins of the REST/NRSF-SWI/SNF pathway display primate-specific accelerated evolution. It may be hypothesized that the subset of genes involved in this pathway, which display a primate evolutionary signature in specific sites, may represent a novel gene candidate repertoire for neuropsychiatric diseases.
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Project description:Analysis of HeLa cell with overexpression of an EGFP-tagged dominant-negative truncation (73- 563 a.a.) of human REST/NRSF. RNA polymerase II and DNA damage repair factor γ-H2AX binding data provide insight into the molecular bases of how REST/NRSF perturbation impairs genome stability.
2018-02-12 | GSE35964 | GEO
Project description:Genetic evidence indicates disrupted epigenetic regulation as a major risk factor for psychiatric disorders, but the molecular mechanisms that drive this association are undetermined. EHMT1 is an epigenetic repressor that is causal for Kleefstra Syndrome (KS), a neurodevelopmental disorder (NDD) leading to ID, and is associated with schizophrenia. Here, we show that reduced EHMT1 activity decreases NRSF/REST protein leading to abnormal neuronal gene expression and progression of neurodevelopment in human iPSC. We further show that EHMT1 regulates NRSF/REST indirectly via repression of miRNA leading to aberrant neuronal gene regulation and neurodevelopment timing. Expression of a NRSF/REST mRNA that lacks the miRNA-binding sites restores neuronal gene regulation to EHMT1 deficient cells. Importantly, the EHMT1-regulated miRNA gene set with elevated expression is enriched for NRSF/REST regulators with an association for ID and schizophrenia. This reveals a molecular interaction between H3K9 dimethylation and NSRF/REST contributing to the aetiology of psychiatric disorders.
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Project description:SF-1 is a nuclear receptor transcription factor playing a key role in adrenogonadal development and in adrenocortical tumorigenesis when overexpressed. NRSF/REST is a transcriptional repressor that represses expression of neuronal genes in non-neural tissues. Some data suggest that SF-1 and NRSF/REST can functionally interact in adrenocortical cancer cells. We studied gene expression profiles using Affymetrix microarrays in the H295R/TR SF-1 adrenocortical cancer cell line. In this cell line, SF-1 expression can be increased in a doxycycline-dependent manner (Mol. Endocrinol. 21: 2968–2987, 2007). The effects of a control siRNA and sRNAs specific for SF-1 and for NRSF/REST (in basal or increased SF-1 expression conditions) on gene expression were measured. In H295R/TR SF-1 cells SF-1 and NRSF/REST (in conditions of basal and increased SF-1 dosage) expression were knocked down by Amaxa nucleofection. RNA was extracted and hybridized to Human Gene 1.0 ST Affymetrix microarrays.
2013-08-01 | E-GEOD-43033 | biostudies-arrayexpress
Project description:The transcription factor NRSF/REST represses many vertebrate neuronal genes in non-neuronal cells by binding to 3 distinct motif classes, which are the canonical 21bp NRSEs, longer non-canonical sites and solo half-sites. We used ChIP-seq in four mammalian species to determine the evolution of the NRSF binding repertoire. We show that while some NRSEs are deeply conserved, genes with several NRSEs show evidence of compensatory site turnover, suggesting that the association of the transcription factor to its target gene is more important than the specific binding site. We also found that many newborn sites in human are associated with primate specific indels and transposable elements. Our analysis of sites with conserved ChIP-binding in all 4 species demonstrates that both the non-canonical and solo half-sites convert preferentially to canonical motifs. These findings support a model of dynamic conversion between different motif types that account for the preferential accumulation of the canonical NRSE during evolution.
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Project description:Melanocortins and their receptors are critical components of energy homeostasis and the paraventricular nucleus of the hypothalamus (PVH) is an important site of melanocortin action. Although best known for its role in osmoregulation, arginine vasopressin (AVP) has been implicated in feeding and is robustly expressed in the PVH. Since the anorectic melanocortin agonist MTII activates PVH-AVP neurons, we hypothesized that PVH-AVP neurons contribute to PVH-mediated anorexia. To test this, we used an AVP-specific Cre-driver mouse in combination with viral vectors to acutely manipulate PVH-AVP neuron function. Using designer receptors exclusively activated by designer drugs (DREADDs) to control PVH-AVP neuron activity, we show that activation of PVH-AVP neurons acutely inhibits food intake, whereas their inhibition partially reverses melanocortin-induced anorexia. We further show that MTII fails to fully suppress feeding in mice with virally-induced PVH-AVP neuron ablation. Thus PVH-AVP neurons contribute to feeding behaviors, including the acute anorectic response to MTII.
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