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Expression analyses of E12.5 embryonic brains from Nestin Cre+, Rest GTi/GTi, p53 fl/fl vs Rest GTi/GTi, p53 fl/fl littermates

ABSTRACT: We use mice containing a gene trap in the first intron of the Rest gene, which effectively eliminates transcription from all coding exons, to prematurely remove REST from neural progenitors. We find catastrophic DNA damage that occurs during S-phase of the cell cycle, with consequences including abnormal chromosome separation, apoptosis, and smaller brains. Further support for persistent effects is the latent appearance of proneural glioblastomas in adult mice also lacking the tumor suppressor, p53. A Rest deficient mouse line generated previously, using a conventional gene targeting approach, does not exhibit these phenotypes, likely due to a remaining C terminal peptide that still binds chromatin and recruits REST chromatin modifiers.Our results indicate that REST-mediated chromatin remodeling is required for proper S-phase dynamics, prior to its well-established role in relieving repression of neuronal genes at terminal differentiation.

ORGANISM(S): Mus musculus

PROVIDER: GSE68368 | GEO | 2015/08/01

SECONDARY ACCESSION(S): PRJNA282527

REPOSITORIES: GEO

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Expression analyses of E12.5 embryonic brains from Nestin Cre+, Rest GTi/GTi, p53 fl/fl vs Rest GTi/GTi, p53 fl/fl littermates

Project description:We use mice containing a gene trap in the first intron of the Rest gene, which effectively eliminates transcription from all coding exons, to prematurely remove REST from neural progenitors. We find catastrophic DNA damage that occurs during S-phase of the cell cycle, with consequences including abnormal chromosome separation, apoptosis, and smaller brains. Further support for persistent effects is the latent appearance of proneural glioblastomas in adult mice also lacking the tumor suppressor, p53. A Rest deficient mouse line generated previously, using a conventional gene targeting approach, does not exhibit these phenotypes, likely due to a remaining C terminal peptide that still binds chromatin and recruits REST chromatin modifiers.Our results indicate that REST-mediated chromatin remodeling is required for proper S-phase dynamics, prior to its well-established role in relieving repression of neuronal genes at terminal differentiation. extract RNA from E12.5 brain in triplicates, compare gene expression profile between Gene Trap REST knockout mice and control littermates

2015-08-01 | E-GEOD-68368 | biostudies-arrayexpress

Expression analyses of E12.5 embryonic brains from Nestin Cre+, Rest GTi/GTi vs Rest GTi/GTi litermates

2015-08-01 | GSE68459 | GEO

Expression analyses of E12.5 embryonic brains from Nestin Cre+, Rest GTi/GTi vs Rest GTi/GTi litermates

2015-08-01 | E-GEOD-68459 | biostudies-arrayexpress

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

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

2012-09-04 | GSE27114 | 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

REST-interactome - Interactomic analysis of REST/NRSF and implications of its functional links with the transcription suppressor TRIM28 during neuronal differentiation

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

Effect of REST on cancer invasiveness in MCF-7 and MDA-MB-231 cells using RNA-sequencing (RNA-seq) analysis .

Project description:We report a negative correlation of invasiveness with REST expression. In addition, one alternatively spliced product (ASP) of REST, REST-003, shows a positive correlation with invasiveness. REST has a well-established role in regulating transcription of genes important for neuronal development. Its role in cancer, though significant, is less well understood. We would like to investigate the effect of REST on invasive phenotype. In order to do so, we downregulate REST by siRNA treatment in weakly invasive MCF-7 breast cancer cells in which REST is expressed highly: 1) si-GAPDH (control), two si-RESTs (2)si-REST_1 and 3) si-REST_2). Conversely, we overexpress REST by transfection of wt-REST cDNA in highly invasive MDA-MB-231 cells in which REST is expressed at the low level: 4) EGFP (control), 5) mt-REST (another control) and 6) wt-REST. REST (repressor element-1 (RE-1) silencing transcription factor) contains a DNA-binding domain that is localized within eight zinc fingers and two repressor domains located at the N-terminal and C-terminal, respectively. REST suppresses expression of neural-specific genes. mt-REST lacks two repressor domains, so it can be used as a control for wt-REST. In contrast, REST-003 is one of alternatively spliced products (ASPs) of REST.

2014-12-01 | GSE63608 | GEO

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

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

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