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Transcriptional profile of genes affected by the loss of Brd4 in the embryonic stem cells

ABSTRACT: BRD4 is an important epigenetic reader implicated in the pathogenesis of a number of different cancers and other diseases. Brd4-null mouse embryos die shortly after implantation and are compromised in their ability to maintain the inner cell mass (ICM), which gives rise to embryonic stem cells (ESCs). We investigated the functions of Brd4 in the ESCs in the present study. To determine the Brd4 target genes in embryonic stem cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE59142 | GEO | 2014/10/01

SECONDARY ACCESSION(S): PRJNA254490

REPOSITORIES: GEO

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Transcriptional profile of genes affected by the loss of Brd4 in the embryonic stem cells

Project description:BRD4 is an important epigenetic reader implicated in the pathogenesis of a number of different cancers and other diseases. Brd4-null mouse embryos die shortly after implantation and are compromised in their ability to maintain the inner cell mass (ICM), which gives rise to embryonic stem cells (ESCs). We investigated the functions of Brd4 in the ESCs in the present study. To determine the Brd4 target genes in embryonic stem cells. TL1 ESCs were transfected with control siRNA, or Brd4 siRNA. At 48 h post-transfection, total RNAs were isolated using the RNeasy minikit (Qiagen). Expression microarray analyses were performed on mRNA samples isolated from three independent experiments using a mouse Gene 2.0ST array (Affymetrix) at the University of Pennsylvania Microarray Core Facility. RMA from Affymetrix package was applied to the data for preprocessing and normalization. Limma was used for detection of differentially expressed genes. Benjamini & Hochberg correction was applied for the multiple comparisons.

2014-10-01 | E-GEOD-59142 | biostudies-arrayexpress

Transcription factors and Tet1/2 enable Brd4-independent maintenance of stem cell identity

Project description:Histone acetylation and the acetyl-lysine reader Brd4 have recently been implicated in embryonic stem cell (ESC) proliferation and self-renewal. We found that na•ve pluripotent ESCs exhibit increased incorporation of glucose-derived carbons onto acetylated histones and elevations in H3K9ac and Brd4 recruitment at pluripotency gene promoters. Surprisingly, both H3K9 acetyltransferases, GCN5 and PCAF, and Brd4 recruitment were dispensable for proliferation, self-renewal and pluripotency of na•ve ESCs. Na•ve ESCs maintain gene expression by stabilizing Mediator at core pluripotency genes in a Brd4-independent manner. Brd4-independent proliferation could also be achieved in metastable ESCs by overexpression of pluripotency transcription factors. Under all conditions, self-renewal required the DNA methylcytosine oxidases Tet1 and Tet2. These data reveal that there is minimal dependence on Brd4 for self-renewal of na•ve ESCs. Instead, the relative levels of DNA methylation and transcription factor abundance determine the requirement for bromodomain recognition of histone acetylation to the maintenance of stem cell identity.

2018-04-09 | GSE88769 | GEO

DNA-binding pluripotency factors and DNA demethylases can cooperate to maintain pluripotent stem cell identity even in the absence of Brd4 [RNA-seq]

Project description:Histone acetylation and the acetyl-lysine reader Brd4 have recently been implicated in embryonic stem cell (ESC) proliferation and self-renewal. We found that naïve pluripotent ESCs exhibit increased incorporation of glucose-derived carbons onto acetylated histones and elevations in H3K9ac and Brd4 recruitment at pluripotency gene promoters. Surprisingly, both H3K9 acetyltransferases, GCN5 and PCAF, and Brd4 recruitment were dispensable for proliferation, self-renewal and pluripotency of naïve ESCs. Naïve ESCs maintain gene expression by stabilizing Mediator at core pluripotency genes in a Brd4-independent manner. Brd4-independent proliferation could also be achieved in metastable ESCs by overexpression of pluripotency transcription factors. Under all conditions, self-renewal required the DNA methylcytosine oxidases Tet1 and Tet2. These data reveal that there is minimal dependence on Brd4 for self-renewal of naïve ESCs. Instead, the relative levels of DNA methylation and transcription factor abundance determine the requirement for bromodomain recognition of histone acetylation to the maintenance of stem cell identity.

2018-04-10 | GSE88760 | GEO

REX1 is the critical target of RNF12 in imprinted X chromosome inactivation in mice.

Project description:In mice, imprinted X-chromosome inactivation (iXCI) of the paternal X in the pre-implantation embryo and extra-embryonic tissues is followed by X-reactivation in the epiblast precursors of the inner cell mass (ICM) of the blastocyst, to facilitate initiation of random XCI (rXCI) in all embryonic tissues. RNF12 is an E3 ubiquitin-ligase that plays a key role in XCI. RNF12 targets pluripotency protein REX1 for degradation to initiate rXCI in embryonic stem cells (ESCs) and loss of the maternal copy of Rnf12 leads to embryonic lethality due to iXCI failure. Here, we show that loss of Rex1 rescues the rXCI phenotype observed in Rnf12-/- ESCs, and that REX1 is the prime target of RNF12 in ESCs. Genetic ablation of Rex1 in Rnf12-/- mice rescues the Rnf12-/- iXCI phenotype, and results in viable and fertile Rnf12-/-:Rex1-/- female mice displaying normal iXCI and rXCI. Our results show that REX1 is the critical target of RNF12 in XCI.

2018-11-15 | PXD010944 | Pride

Chimeric-competent, embryo-derived stem cell lines unveil the plasticity of pluripotency in rabbits

Project description:Conventional rabbit embryonic stem cell (ESC) lines are derived from the inner cell mass (ICM) of pre-implantation embryos using methods and culture conditions established for primate ESCs (partial dissociation with collagenase and culture with FGF2). In the present work, we explored the capacity of rabbit ICM to give rise to ESC lines using conditions similar to those utilized to generate ESCs in mice.

2017-02-12 | GSE79195 | GEO

Combinatorial Smad2/3 Activities Downstream of Nodal Signaling Maintain Embryonic/Extra-Embryonic Cell Identities during Lineage Priming [RNA-Seq]

Project description:Epiblast cells in the early post-implantation stage mammalian embryo undergo a transition described as lineage priming before cell fate allocation, but signaling pathways acting upstream remain ill defined. Genetic studies demonstrate that Smad2/3 double-mutant mouse embryos die shortly after implantation. To learn more about the molecular disturbances underlying this abrupt failure, here we characterised Smad2/3-deificient embryonic stem cells (ESCs). We found that Smad2/3 double-knockout ESCs induced to form epiblast-like cells (EpiLCs) display changes in naïve and primed pluripotency marker gene expression, associated with the disruption of Oct4-bound distal regulatory element. In the absence of Smad2/3, we observed enhanced Bmp target gene expression and de-repression of extra-embryonic gene expression. Cell fate allocation into all three embryonic germ lakers is disrupted. Collectively, these experiments demonstrate that combinatorial Smad2/3 functional activities are required to maintain distinct embryonic and/or extra-embryonic cell identity during lineage priming in the epiblast before gastrulation.

2018-08-14 | GSE110163 | GEO

Combinatorial Smad2/3 Activities Downstream of Nodal Signaling Maintain Embryonic/Extra-Embryonic Cell Identities during Lineage Priming [ATAC-Seq]

2018-08-14 | GSE110162 | GEO

Combinatorial Smad2/3 Activities Downstream of Nodal Signaling Maintain Embryonic/Extra-Embryonic Cell Identities during Lineage Priming [array]

2018-08-14 | GSE110058 | GEO

Control of embryonic stem cell identity by BRD4-dependent transcriptional elongation of super-enhancer associated pluripotency genes

2014-09-26 | GSE60171 | GEO

Control of embryonic stem cell identity by BRD4-dependent transcriptional elongation of super-enhancer associated pluripotency genes

Project description:BET-regulated transcriptome and BRD4, BRD2, BRD3 and Pol II ChIP-seq datasets in human ESCs before and after BET inhibition. Transcription factors and chromatin remodeling complexes are key determinants of embryonic stem cell (ESC) identity. In this study, we investigate the role of BRD4, a member of the bromodomain and extra-terminal domain (BET) family of epigenetic reader proteins, in control of ESC identity. We performed RNA-seq analyiss in the presense of small molecule inhibitors of BET proteins to show that BRD4 positively regulates the ESC transcriptome. We also integrated RNA-seq analysis with ChIP-sequencing datasets s for BRD4 (and for other BRD2 and BRD3) to demonstrate that BRD4 binds SEs and regulates the expression of SE-associated pluripotency genes. We have also conducted ChIP-seq analysis for Pol II binding to demonstrate that SE-associated genes depend on BRD4-dependent Pol II binding at TSS and gene body for their productive transcriptional elongation. Total RNA was extracted from samples using the RNeasy Qiagen kit according to the manufacturer’s instructions. Deep sequencing of RNA (1ug) from hESCs FGF- or MS436-treated at day 1 and day 5 was performed as described in (Higgin et al., 2010c). Samples were subjected to PolyA selection using magnetic oligo-dT beads. The resulting RNA samples were then used as input for library construction as described by the manufacturer (Illumina, CA, USA). RNA libraries were then sequenced on the GAIIx system using 50bp single reads. Chromatin for ChIP-sequencing was obtained from FGF-maintained hESCs, vehicle or MS417-treated (at 250nM concentration for 6h) (10 to 20x106 cells/IP). ChIP-Seq libraries were generated using standard Illumina kit and protocol as described in (Ntziachristos et al., 2012). We performed cluster amplification and single read 50 sequencing-method using the Illumina HiSeq 2000, following manufacturer’s protocols.

2014-09-26 | E-GEOD-60171 | biostudies-arrayexpress

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