Mechanism of REST/NRSF Regulation of Clustered Protocadherin Alpha Genes
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PROVIDER: PRJNA631681 | ENA |
REPOSITORIES: ENA
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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.
2021-04-14 | GSE150254 | GEO
Project description: Not available
| S-EPMC8096226 | biostudies-literature
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.
2010-06-06 | GSE14326 | GEO
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.
2023-05-01 | E-MTAB-10480 | biostudies-arrayexpress
Project description:Investigating the role of SMCHD1 in regulating clustered protocadherin (Pcdh) and Hox genes
| PRJNA521408 | ENA
Project description:The goal of this study was to identify genomic binding sites of the NRSF/REST transcription factor under conditions of basal and increased SF-1 dosage in the H295R human adrenocortical tumor cell line. 4 samples: input DNA (2 replicates) - NRSF/REST ChIP basal SF-1 dosage - NRSF/REST ChIP increased SF-1 dosage
2013-08-01 | E-GEOD-49014 | biostudies-arrayexpress
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.
2013-08-01 | GSE43033 | GEO
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:Namgyu Lee has participated in the experimental part of this project and she is a co-first author of the under-going manuscript. RE-1 silencing transcription factor (REST) is a transcriptional repressor with a role in regulating gene expression through binding to repressor element 1. We identified REST/NRSF-interacting proteins by proteomics-based analyses using the complementary mass spectrometry approach. Our interactome revealed 204 REST-interacting proteins. Among those proteins, nuclear proteins were mostly enriched reflecting nuclear localization of REST. The interaction networks of interactome indicated biological processes associated with mRNA processing, chromatin organization and transcription. Interactions of ALYREF, HnRNP M, HnRNP Q, NPM1, NCL, PARP1, HDAC5, TRIM28 and HMGA1 with REST were confirmed by co-immunoprecipitation. Using public microarray dataset, a highly significant overlaps were observed in differentially expressed transcripts following knockdown of REST and interacting proteins such as HDAC5, HMGA1 and TRIM28, suggesting that the REST might cross-talk with those transcription regulators to regulate transcription of shared target genes. Our interactomic study of REST implies novel cross-talks with transcription regulators by its associations with interacting proteins.
2018-10-25 | PXD003210 | Pride