Dynamics of NRSF/REST motif evolution favor the canonical NRSE/RE1 form
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA310756 | ENA |
REPOSITORIES: ENA
Similar Datasets
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.
2024-01-01 | GSE77543 | GEO
Project description:Both upregulation and downregulation by cis-regulatory elements help establish precise gene expression. Our understanding of how elements repress transcriptional activity is far more limited than activating elements. To address this gap, we characterized RE1, a group of transcriptional silencers bound by REST, on a genome-wide scale using an optimized massively parallel reporter assay (MPRAduo). MPRAduo empirically defined a minimal binding strength of REST required by silencer (REST m-value), above which multiple cofactors colocalize and act to directly silence transcription. We identified 1,500 human variants that alter RE1 silencing and found their effect sizes are predictable when they overlap with REST binding sites above the m-value. In addition, we demonstrate that non-canonical REST binding motifs exhibit silencer function only if they precisely align two half sites with specific spacer length. Our results show mechanistic insights into RE1 silencer which allows us to predict its activity and effect of variants on RE1, providing a paradigm for performing genome-wide functional characterization transcription factors binding sites.
2022-02-17 | GSE196171 | GEO
Project description:Both upregulation and downregulation by cis-regulatory elements help establish precise gene expression. Our understanding of how elements repress transcriptional activity is far more limited than activating elements. To address this gap, we characterized RE1, a group of transcriptional silencers bound by REST, on a genome-wide scale using an optimized massively parallel reporter assay (MPRAduo). MPRAduo empirically defined a minimal binding strength of REST required by silencer (REST m-value), above which multiple cofactors colocalize and act to directly silence transcription. We identified 1,500 human variants that alter RE1 silencing and found their effect sizes are predictable when they overlap with REST binding sites above the m-value. In addition, we demonstrate that non-canonical REST binding motifs exhibit silencer function only if they precisely align two half sites with specific spacer length. Our results show mechanistic insights into RE1 silencer which allows us to predict its activity and effect of variants on RE1, providing a paradigm for performing genome-wide functional characterization transcription factors binding sites.
2022-09-30 | GSE212253 | GEO
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: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:Rest (RE1 silencing transcription factor, also called NRSF) is involved in the maintenance of the undifferentiated state of neuronal stem/progenitor cells in vitro by preventing precocious expression of neuronal genes. However, the function of Rest during neurogenesis in vivo remains to be elucidated because of the early embryonic lethal phenotype of the conventional Rest knockout mice. In the present study, we have generated Rest conditional knockout mice, and the effect of genetic ablation of Rest during the embryonic neurogenesis can be examined in vivo. We herein show that Rest plays a role in suppressing the expression of neuronal genes in cultured neuronal cells in vitro, as well as in non-neuronal cells outside of the central nervous system, but that it is dispensable for the embryonic neurogenesis in vivo. Our findings highlight the significance of extrinsic signals for the proper intrinsic regulation of neuronal gene expression levels in the specification of cell fate during embryonic neurogenesis in vivo. Total RNAs from E13.5 limbs and brains were analyzed for global gene expressions by Agilent microarray.
2013-01-01 | E-GEOD-34625 | biostudies-arrayexpress
Project description:Rest (RE1 silencing transcription factor, also called NRSF) is involved in the maintenance of the undifferentiated state of neuronal stem/progenitor cells in vitro by preventing precocious expression of neuronal genes. However, the function of Rest during neurogenesis in vivo remains to be elucidated because of the early embryonic lethal phenotype of the conventional Rest knockout mice. In the present study, we have generated Rest conditional knockout mice, and the effect of genetic ablation of Rest during the embryonic neurogenesis can be examined in vivo. We herein show that Rest plays a role in suppressing the expression of neuronal genes in cultured neuronal cells in vitro, as well as in non-neuronal cells outside of the central nervous system, but that it is dispensable for the embryonic neurogenesis in vivo. Our findings highlight the significance of extrinsic signals for the proper intrinsic regulation of neuronal gene expression levels in the specification of cell fate during embryonic neurogenesis in vivo.
2013-01-01 | GSE34625 | GEO
Project description:REST has been initially described as a repressor of neuronal genes in non-neuronal cells by binding to its recognition sequence RE1. Over-activation of this factor has been shown in several diseases such as Huntington disease or central nervous system cancers. High-throughput screening of a library of 6,984 compounds with luciferase-assay measuring REST activity in neural derivatives of human embryonic stem cells led to the identification of one benzoimidazole-5-carboxamide derivative (X5050) that inhibited REST silencing in a RE1-dependent manner. Differential transcriptomic analysis revealed the upregulation of neuronal genes targeted by REST.
2013-10-01 | GSE40695 | 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:REST has been initially described as a repressor of neuronal genes in non-neuronal cells by binding to its recognition sequence RE1. Over-activation of this factor has been shown in several diseases such as Huntington disease or central nervous system cancers. High-throughput screening of a library of 6,984 compounds with luciferase-assay measuring REST activity in neural derivatives of human embryonic stem cells led to the identification of one benzoimidazole-5-carboxamide derivative (X5050) that inhibited REST silencing in a RE1-dependent manner. Differential transcriptomic analysis revealed the upregulation of neuronal genes targeted by REST. RNA was extracted from 6 samples, corresponding to 3 independent cultures of NSC SA-01, each one treated either with DMSO (0.1 % final) or with X5050 (100 õM final). RNA was isolated using RNeasy Mini kit with DNase I digestion and genome-wide gene expression profiling was performed by hybridization on Affymetrix microarrays
2013-10-01 | E-GEOD-40695 | biostudies-arrayexpress