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Dysregulation of NRSF/REST via EHMT1 is associated with psychiatric disorders

ABSTRACT: 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.

INSTRUMENT(S): Illumina HiSeq 4000

ORGANISM(S): Homo sapiens

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PROVIDER: E-MTAB-10480 | biostudies-arrayexpress |

SECONDARY ACCESSION(S): ERP130338

REPOSITORIES: biostudies-arrayexpress

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Dysregulation of NRSF/REST via EHMT1 is associated with psychiatric disorders

Project description:Dysregulation of NRSF/REST via EHMT1 is associated with psychiatric disorders

| PRJEB46133 | ENA

Transcriptional analysis of Rest/Nrsf silencing in N18 neuroblastoma cell line

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

Mechanism of REST/NRSF Regulation of Clustered Protocadherin Alpha Genes

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

Chromatin immunoprecipitation of REST/NRSF

Project description:ENCODE ChIP-chip study using 8 diverse human cell lines; 4 of neural origin (NB69, KELLY, SHSY-5Y, U373) and 4 of non-neural origin (HeLa, HepG2, HEK293 and K562) and anti-REST/NRSF antibody (Santa Cruz Biotech; sc-25398 aka H290) to asses REST-genome interactions across 1% of the human genome used in the pilot phase of the ENCODE project. Additionally the REST binding profile in K562 cells that had been transfected with REST specific siRNA oligos (72h and 96h) were determined revealing genomic in vivo binding affinity hierarchies for REST. Additionally the REST binding profile in K562 cells that had been transfected with REST specific siRNA oligos (72h and 96h) were determined

2009-03-31 | E-TABM-660 | biostudies-arrayexpress

Genome-wide mapping of REST-bound sites in human CD4+ T cells

Project description:We performed ChIP-seq to identify genome-wide REST (NRSF) binding in the human CD4+ T cells. The data were compared to REST occupancy in additional 15 human cell types analyzed by the ENCODE project (GSE32465) in order to study the dynamics and context-dependent functions of REST-chromatin interaction. Identification of REST binding by ChIP-seq in human CD4+ T cells.

2014-08-06 | E-GEOD-49570 | biostudies-arrayexpress

Epigenomics of neural cells: REST-induced down- and up-regulation of gene expression in a two clone PC12 cell model.

Project description:Cell epigenomics depends on the marks released by transcription factors operating via the assembly of complexes that induce focal changes of DNA and histone structure. Among these factors is REST, a repressor that, via its strong decrease, governs both neuronal and neural cell differentiation and specificity. REST operation on thousands of possible genes can occur directly or via indirect mechanisms including repression of other factors. In previous studies of gene down- and up-regulation, processes had been only partially investigated in neural cells. PC12 are well known neural cells sharing properties with neurons. In the widely used PC12 populations, low-REST cells coexist with few, spontaneous high-REST PC12 cells. High- and low-REST PC12 clones were employed to investigate the role and the mechanisms of the repressor action. Among 15,500 expressed genes we identified 1,770 target and non-target, RESTdependent genes. Functionally, these genes were found to operate in many pathways, from synaptic function to extracellular matrix. Mechanistically, downregulated genes were predominantly repressed directly by REST; up-regulated genes were mostly governed indirectly. Among other factors, Polycomb complexes cooperated with REST for down-regulation, Smad3 and Myod1 participated in up-regulation. In conclusion, we have highlighted that PC12 clones are a useful model to investigate REST, opening opportunities to development of epigenomic investigation. 4 samples have been analyzed: 2 replicates from wtPC12 clone and 2 replicates from the hrPC12 clones

2015-08-31 | E-GEOD-59946 | biostudies-arrayexpress

Transcriptional analysis of murine neurobastoma N18 cell line transfected with a pAd-Dyrk1a vector

Project description:The molecular mechanisms that lead to the cognitive defects characteristic of Down syndrome (DS), the most frequent cause of mental retardation, have remained elusive. Here we use a transgenic DS mouse model to show that DYRK1A gene dosage imbalance deregulates chromosomal clusters of genes located near neuron-restrictive silencer factor (REST/NRSF) binding sites. We found that DYRK1A binds the SWI/SNF-complex known to interact with REST/NRSF. Mutation of a REST/NRSF binding site in the promoter of the REST/NRSF target gene L1cam modifies the transcriptional effect of Dyrk1A-dosage imbalance on L1cam. DyrkA dosage imbalance perturbs Rest/Nrsf levels with decreased Rest/Nrsf expression in embryonic neurons and increased expression in adult neurons. We identified a coordinated deregulation of multiple genes that are responsible for the cellular phenotypic traits present in DS such as dendritic growth impairment and microcephaly during prenatal cortex development. Dyrk1a overexpression in primary mouse cortical neurons reduced the neuritic complexity. In the postnatal hippocampus, DYRK1A overexpression suppresses a form of synaptic plasticity that may be sufficient to cause DS cognitive defects. We propose that DYRK1A overexpression-related neuronal gene deregulation generates the brain phenotypic changes that characterize DS, with an accessory role for the gene dosage imbalance of other chromosome 21 genes.

2009-02-23 | GSE14030 | GEO

Transcriptional analysis of E12.5 telencephalon from 152F7 transgenic mouse

2009-02-23 | GSE14021 | GEO

Tumor suppressor REST/NRSF controls genome stability by preventing R-loop formation

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

Identification of NRSF/REST genomic binding sites in conditions of basal and increased SF-1 dosage in the H295R adrenocortical tumor cell line

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

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