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Expression data from NSCs treated with REST inhibitor X5050

ABSTRACT: 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 ÃÂµM 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

ORGANISM(S): Homo sapiens

SUBMITTER: Florent Dumont

PROVIDER: E-GEOD-40695 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Expression data from NSCs treated with REST inhibitor X5050

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

Expression data from REST knock-out versus REST wild type cells during in vitro neurogenesis

Project description:While changes in chromatin are integral to transcriptional reprogramming during cellular differentiation, it is currently unclear how chromatin modifications are targeted to specific loci. We developed a computational model on the premise that transcription factors (TFs) direct dynamic chromatin changes during cell fate decisions. When applied to a neurogenesis paradigm, this approach predicted the TF REST as a determinant of gain of Polycomb-mediated H3K27me3 in neuronal progenitor cells. We prove this prediction experimentally by showing that the absence of REST causes loss of H3K27me3 at target promoters in trans at the same cellular state. Moreover, promoter fragments containing a REST binding site are sufficient to recruit H3K27me3 in cis, while deletion of their REST site results in loss of H3K27me3. These findings illustrate that computational modeling can systematically identify TFs that regulate chromatin dynamics genome-wide. Local determination of Polycomb activity by REST exemplifies such TF based regulation of chromatin. Expression profiling of REST knock-out (RESTko) versus REST wildtype (RESTwt) or REST heterozygous knock-out (RESThet) cells at three stages of in vitro neuronal differentiation. RESTko and RESTwt/RESThet embryonic stem (ES) cells were differentiated to terminal neurons (TN) via a defined neuronal progenitor (NP) state. Three biological replicates (suffixes a to c).

2012-09-04 | E-GEOD-27114 | biostudies-arrayexpress

Role of REST during neuronal differentiation

Project description:This SuperSeries is composed of the following subset Series: GSE27114: Expression data from REST knock-out versus REST wild type cells during in vitro neurogenesis GSE27148: A comparative epigenomics approach reveals REST as a mediator of Polycomb reprogramming during neuronal differentiation Refer to individual Series

2012-09-04 | E-GEOD-27341 | biostudies-arrayexpress

REST ChIP-seq in human and mouse hippocampus

Project description:The transcriptional repressor REST (RE1 Silencing Transcription Factor) is a master regulator of thousands of neuronal genes that together impart the terminally differentiated neuronal phenotype. Because of this unique feature, REST has been, and continues to be, a widely used model for understanding neurogenesis and neuronal cell function. These studies have focused primarily on murine embryonic development, but recent studies have pointed to distinct postnatal roles for REST in stroke, epilepsy, aging and cognitive decline. The function of REST in healthy human brain tissue, however, still remains poorly characterized. Here, we present deep sequencing chromatin immunoprecipitation evidence for divergent REST function in normal mouse and human postmortem adult hippocampus. In mouse, REST occupies only 221 peaks that are divided between prototypical REST target genes shared with non-neuronal cells, as well as peaks unique to the hippocampus. Surprisingly, the mouse hippocampal-unique sites are not conserved in human, which contains 1886 REST peaks unique to the hippocampus. Further, the REST peaks unique to the hippocampus represent a potentially new category of target genes encoding proteins important in the immune response. Our results suggest the possibility that REST protects against aberrant immunological responses during normal human aging and that mouse may not model this aging function.

2020-07-24 | GSE144226 | GEO

Expression data from E12.5 NSP cells, CTL v REST shRNA

Project description:REST is a master regulator of genes that are involved in the acqusition of neuronal fate. The role of REST is not well understood so we attempted to investigate the role of REST in the development of neural cells by analysing the genes that are upregulated when REST is knocked down via shRNA We used microarrays to assess the genes which were up and down regulated after REST is knocked down E12.5 NSP cells were infected with either control or REST shRNA expressing lentiviruses and collected after 6 days for RNA extraction

2012-06-06 | E-GEOD-38538 | biostudies-arrayexpress

C-terminal Domain Small Phosphatase 1 and MAP kinase reciprocally control REST stability and neuronal differentiation.

Project description:The RE1 Silencing Transcription Factor (REST) in stem cells represses hundreds of genes essential to neuronal function. During neurogenesis, REST is degraded in neural progenitors to promote subsequent elaboration of a mature neuronal phenotype. Prior studies indicate that part of the degradation mechanism involves phosphorylation of two sites in the C-terminus of REST that require activity of the E3 ubiquitin ligase, bTrCP. We identify a new proline-directed phosphorylation motif, at Serines 861/864 upstream of these sites, which is a substrate for the Peptidyl-prolyl cis-trans Isomerase, Pin1, as well as the ERK1/2 kinases. Mutation at S861/864 stabilizes REST, as does inhibition of Pin1 activity. Interestingly, we find that C-Terminal Domain Small Phosphatase1 (CTDSP1) is recruited by REST to neuronal genes, is present in REST immunocomplexes, dephosphorylates S861/864 and stabilizes REST. Expression of a REST peptide containing S861/864 in neural progenitors inhibits terminal neuronal differentiation. Together with previous work indicating that both REST and CTDSP1 are expressed to high levels in stem cells and down regulated during neurogenesis, our results suggest that CTDSP1 activity stabilizes REST in stem cells, and that ERK dependent phosphorylation combined with Pin1 activity promotes REST degradation in neural progenitors.

2014-09-15 | PXD001127 | Pride

Genome-wide characterization of REST binding regions in LNCaP prostate cancer cells

Project description:Transcriptional regulator REST plays a key role in repressing neuronal specific genes in prostate cancer and other non-neuronal tissues. Moreover, loss of REST is observed in neuroendocrine prostate tumors. Here, we use ChIP-seq analysis to study genome–wide REST occupied regions in the prostate cancer cell line, LNCaP. REST occupied regions were then correlated to gene expression changes occurring between prostate adenocarcinoma and neuroendocrine prostate tumors in vivo.

2019-09-03 | GSE119385 | GEO

Transcriptome profiling of microRNA-mediated neuronal reprogramming with REST repression at day 7

Project description:Ectopic expression of neuronal microRNAs (miRNAs), miR-9/9* and miR-124 (miR-9/9*-124) in adult human fibroblasts has been found to evoke extensive reconfigurations of the chromatin and direct the fate conversion to neurons. We found that miR-9/9* and miR-124 led to the repression of REST, a transcriptional repressor of neuronal genes, during microRNA-mediated neuronal conversion and knockdown of REST enhanced the activation of BAF53b, a mature neuronal marker. Furthermore, time series analysis of the transcriptome of cells undergoing the miR-9/9*-124-induced conversion indicated upregulated genetic pathways that were predicted to be targeted by REST although the transcript level of REST remained unchanged (Abernathy et al., 2017). Therefore, we reasoned that knocking down REST in addition to miR-9/9*-124 at an early time point (day 7), in which REST repression is minimally evident during neuronal conversion, would speed up the adoption of neuronal identity. We performed the RNA-seq analysis to compared differentially expressed genes (DEGs) between human adult fibroblasts expressing control shRNA (shCTL) and reprogramming cells expressing shCTL or shREST at day 7. Finally, we found that the repression of REST constitutes an important component of microRNA-mediated neuronal reprogramming of human fibroblasts.

2018-05-17 | GSE114541 | GEO

Genetic ablation of Rest leads to in vitro-specific derepression of neuronal genes during neurogenesis

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

Genetic ablation of Rest leads to in vitro-specific derepression of neuronal genes during neurogenesis

2013-01-01 | GSE34625 | GEO