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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE34625 | GEO | 2013/01/01

SECONDARY ACCESSION(S): PRJNA151271

REPOSITORIES: GEO

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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

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

Expression data from NSCs treated with REST inhibitor X5050

2013-10-01 | GSE40695 | GEO

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. 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

2013-10-01 | E-GEOD-40695 | 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

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

ZNF335 regulates stem cell proliferation and neuronal differentiation via Trithorax complex and REST/NRSF [gene expression]

Project description:The progression from stem cell to differentiated neuron is associated with extensive chromatin remodeling that controls gene expression, but the mechanisms that connect chromatin to gene expression are not well defined. Here we show that mutation of ZNF335 causes severe human microcephaly ("small brain"), small somatic size, and neonatal death. Germline Znf335 null mutations are embryonically lethal in mice, whereas RNA-interference studies and postmortem human studies show that Znf335 is essential for neural progenitor self-renewal, neurogenesis, and neuronal differentiation. Znf335 is a component of a vertebrate-specific, trithorax H3K4 methylation complex, while global ChIP-seq and mRNA expression studies show that Znf335 is a previously unsuspected, direct regulator of REST/NRSF, a master regulator of neural gene expression and neural cell fate, as well as other essential neural-specific genes. Our results reveal ZNF335 as an essential link between H3K4 complexes and REST/NRSF, and provide the first direct evidence that this pathway regulates human neurogenesis and neuronal differentiation. ShRNA knockdown cells were FACS sorted and analyzed for changes in gene expression

2012-12-31 | E-GEOD-36384 | biostudies-arrayexpress

ZNF335 regulates stem cell proliferation and neuronal differentiation via Trithorax complex and REST/NRSF [ChIP-Seq]

Project description:The progression from stem cell to differentiated neuron is associated with extensive chromatin remodeling that controls gene expression, but the mechanisms that connect chromatin to gene expression are not well defined. Here we show that mutation of ZNF335 causes severe human microcephaly ("small brain"), small somatic size, and neonatal death. Germline Znf335 null mutations are embryonically lethal in mice, whereas RNA-interference studies and postmortem human studies show that Znf335 is essential for neural progenitor self-renewal, neurogenesis, and neuronal differentiation. Znf335 is a component of a vertebrate-specific, trithorax H3K4 methylation complex, while global ChIP-seq and mRNA expression studies show that Znf335 is a previously unsuspected, direct regulator of REST/NRSF, a master regulator of neural gene expression and neural cell fate, as well as other essential neural-specific genes. Our results reveal ZNF335 as an essential link between H3K4 complexes and REST/NRSF, and provide the first direct evidence that this pathway regulates human neurogenesis and neuronal differentiation. Examination of Znf335-bound genes with two separate antisera

2012-12-31 | E-GEOD-36385 | biostudies-arrayexpress

dyrk1a

Project description:Transcription profiling of transgenic down syndrome mouse model to show the role of DYRK1A gene. 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 Dyrk1Adosage 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 | GSE14072 | GEO

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