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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE27114 | GEO | 2012/09/04

SECONDARY ACCESSION(S): PRJNA141959

REPOSITORIES: GEO

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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

A comparative epigenomics approach reveals REST as a mediator of Polycomb reprogramming during neuronal differentiation

Project description:Transcription factors (TFs) in concert with chromatin pathways stably reset transcriptional programs during differentiation. Yet we know little how local sites of chromatin reprogramming are specified and how the estimated 3000 TF encoded in mammalian genomes contribute to chromatin dynamics. To identify candidate TFs we developed an integrated computational approach (Epi-MARA) that models chromatin dynamics in terms of predicted transcription factor binding sites and show that it correctly predicts key TFs involved in epigenome reorganization. When applied to a time course of genome-wide H3 lysine 27 trimethylation (H3K27me3), a chromatin mark set by the Polycomb system, during neuronal differentiation of murine stem cells Epi-MARA predicted that the repressive transcription factor REST contributes to a gain of H3K27me3 at a subset of promoters during the transition from the stem to the progenitor state. To test this prediction we identified, genome-wide, the actual binding sites of REST and H3K27me3 during the differentiation in cells that are either wildtype or in which REST had been deleted. REST indeed localizes to a subset of sites that gain H3K27me3 in progenitors. Importantly, absence of REST in trans leads to a loss of H3K27me3 predominantly in the neuronal progenitor state and specifically at those regions where REST was bound. This function further requires REST binding sites in cis as their mutation leads to substantial loss of H3K27me3. Taken together we provide a novel approach to identify epigenome and TF crosstalk during cellular reprogramming and prove experimentally the prediction that REST acts as an important recruiter of Polycomb repression during early steps of neurogenesis. Dataset comprises of 15 ChIP-seq samples using chromatin from embryonic stem (ES) and neuronal progentor (NP) of wildtype and RESTko cells, which was immunoprecipitated, using antibodies against REST, H3K27me3, or Suz12

2012-09-04 | E-GEOD-27148 | biostudies-arrayexpress

A comparative epigenomics approach reveals REST as a mediator of Polycomb reprogramming during neuronal differentiation

2012-09-04 | GSE27148 | GEO

REST–Mediated Recruitment of Polycomb Repressor Complexes in Mammalian Cells

Project description:Genome-wide analysis of REST and Polycomb binding in Rest-/- and Eed-/- mouse embryonic stem (mES) cells showed that Rest was required for PRC1 recruitment to a subset of Polycomb regulated neuronal genes. Furthermore, we found that PRC1 can be recruited to Rest binding sites independently of CpG islands and the H3K27Me3 mark., and that PRC2 was frequently increased around Rest binding sites located in CpG-rich regions in the Rest2/2 mES cells. Published here: PLoS Genet 8(3): e1002494. doi:10.1371/journal.pgen.1002494 Examination of REST and Polycomb binding in Rest-/-, Eed-/-, and wt mES cells using ChIP-sequencing. Submitter cannot locate the raw data for GSM1169003, GSM1169004, GSM1169011, GSM1169012, GSM1169015, and GSM1169016.

2013-06-20 | E-GEOD-48122 | biostudies-arrayexpress

REST–Mediated Recruitment of Polycomb Repressor Complexes in Mammalian Cells

2013-06-20 | GSE48122 | GEO

Polycomb Repressor Complex 2 and REST-associated histone deacetylases are independent pathways toward a mature neuronal phenotype.

Project description:These experiments were designed to test the hypothesis that REST and Polycomb Repressor Complex 2 function cooperatively in undifferentiated ESCs. Our results showed that a majority of REST-bound genomic regions were not associated with H3K27me3 enrichment and loss of H3K27me3 enrichment was not a general observation in REST -/- ESCs. These results support the conclusion that REST and PRC2 function independently in ESCs and similarly contribute to maintaing a transcriptionally poised state through antagonism of H3K4me3. Examination of REST-bound regions in undifferentiated mouse embryonic stem cells (ESC), and a comparison of H3K27me3 distribution between WT and REST-/- ESCs.

2014-09-30 | E-GEOD-48320 | biostudies-arrayexpress

Polycomb Repressor Complex2 and REST-associated histone deacetylases are independent pathways toward a mature neuronal phenotype

Project description:These experiments were designed to test the hypothesis that REST and Polycomb Repressor Complex 2 function cooperatively in undifferentiated ESCs. Our results show that H3K27me3-enriched genes show no de-repression in REST-/- ESCs, while REST target genes show significant de-repression.

2014-09-30 | GSE59442 | GEO

REST knock-out ESCs: a role for REST in embryonic stem cells' cardiac lineage specification

Project description:During development, lineage specification is controlled by several signaling pathways involving various transcription factors (TFs). Here, we studied the RE1-silencing transcription factor (REST) and identified an important role of this TF in cardiac differentiation. Using mouse embryonic stem cells (ESC) to model development, we analyzed the effect of REST knock-out on the ability to these cells to differentiate into the cardiac lineage. Detailed analysis of specific lineage markers expression showed selective down-regulation of endoderm markers in REST-null cells, thus contributing to a loss of cardiogenic signals. We propose here a new role for REST in cell fate specification besides its well-known repressive role of neuronal differentiation.

2016-02-01 | GSE76580 | GEO

Polycomb Repressor Complex 2 and REST-associated histone deacetylases are independent pathways toward a mature neuronal phenotype.

2014-09-30 | GSE48320 | GEO

Polycomb Repressor Complex2 and REST-associated histone deacetylases are independent pathways toward a mature neuronal phenotype

Project description:These experiments were designed to test the hypothesis that REST and Polycomb Repressor Complex 2 function cooperatively in undifferentiated ESCs. Our results show that H3K27me3-enriched genes show no de-repression in REST-/- ESCs, while REST target genes show significant de-repression. RNA-seq was performed and analyzed using two biological replicates for each genotype, WT (N6) and REST-/- (N8) mouse embryonic stem cells.

2014-09-30 | E-GEOD-59442 | biostudies-arrayexpress

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