Mapping of transcription factor binding sites in mouse embryonic stem cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE11431 | GEO | 2008/06/12
SECONDARY ACCESSION(S): PRJNA106455
REPOSITORIES: GEO
Similar Datasets
Project description:Transcription factors and their specific interactions with targets are crucial in specifying gene expression programs. To gain insights into the transcriptional regulatory networks in embryonic stem cells, we use chromatin immunoprecipitation coupled to ultra-high-throughput DNA sequencing (ChIP-seq) to map the locations of thirteen sequence specific transcription factors (Nanog, Oct4, STAT3, Smad1, Sox2, Zfx, c-Myc, n-Myc, Klf4, Esrrb, Tcfcp2l1, E2f1 and CTCF) and two transcription regulators (p300 and Suz12). These factors are known to play different roles in ES cell biology as components of the LIF and BMP signaling pathways, self-renewal regulators and key reprogramming factors. Our study provides insights into the integration of the signaling pathways to the ES cell-specific transcription circuitries. Intriguingly, we find specific genomic regions extensively targeted by different transcription factors. Collectively, the comprehensive mapping of transcription factor binding sites identifies important features of the transcriptional regulatory networks that define ES cell identity. Keywords: Transcription factor binding sites in undifferentiated mouse embryonic stem cells ChIP-enriched DNA from pooled ChIP samples were analyzed by Solexa sequencing.
2008-06-12 | E-GEOD-11431 | biostudies-arrayexpress
Project description:Esrrb is a transcription factor implicated in embryonic stem (ES) cell self-renewal, yet its knockout causes intrauterine lethality due to defects in trophoblast development. Here we show that in trophoblast stem (TS) cells, Esrrb is a downstream target of fibroblast growth factor (Fgf) signalling and is critical to drive TS cell self-renewal. In contrast to its occupancy of pluripotency-associated loci in ES cells, Esrrb sustains the stemness of TS cells by direct binding and regulation of TS cell-specific transcription factors including Elf5 and Eomes. To elucidate the mechanisms whereby Esrrb controls the expression of its targets, we characterized its TS cell-specific interactome by mass spectrometry. Unlike in ES cells, Esrrb interacts in TS cells with the histone demethylase Lsd1 and with the RNA Polymerase II-associated Integrator complex. Our findings provide new insights into both, the general and context-dependent wiring of transcription factor networks in stem cells by master transcription factors.
2015-07-24 | PXD002183 | Pride
Project description:The tumor suppressor p53 regulates the differentiation of embryonic stem (ES) cells upon DNA damage. However, our understanding of this critical tumor suppressive role of p53 in ES cells is limited, mainly because of the lack of molecular mechanism. Here, we report a widespread cross-regulation of p53-mediated DNA damage signaling and the pluripotent gene network in ES cells using chromatin-immunoprecipitation assay-based sequencing (ChIP-seq) and gene expression microarray. Upon DNA damage, p53 directly regulates the transcription of 3644 genes (p<0.005) in mouse ES cells. Genome-wide analysis revealed a dramatic difference between the regulation of p53-activated and -repressed genes. p53 mainly regulates the promoter regions of activated genes, whereas the main regulatory regions for repressed genes reside in distal regions. Among p53-repressed genes, many are pluripotent transcription factors of ES cells, such as Oct4, Nanog, Sox2, Esrrb, c-Myc, n-Myc and Sall4. Strikingly, these transcriptional factors also directly regulate the transcription of the Trp53 gene, highlighting a previously under-estimated transcriptional regulation of p53 in ES cells. Therefore, p53 signaling and ES pluripotent transcriptional networks form an intertwined circuitry. Together, our results provide mechanistic insights into the crosstalk of p53-mediated DNA damage and ES cell "stemness" transcriptional gene networks and shed light on the tumor suppressive function of p53 in ES cells.
2012-03-05 | GSE26360 | GEO
Project description:The tumor suppressor p53 regulates the differentiation of embryonic stem (ES) cells upon DNA damage. However, our understanding of this critical tumor suppressive role of p53 in ES cells is limited, mainly because of the lack of molecular mechanism. Here, we report a widespread cross-regulation of p53-mediated DNA damage signaling and the pluripotent gene network in ES cells using chromatin-immunoprecipitation assay-based sequencing (ChIP-seq) and gene expression microarray. Upon DNA damage, p53 directly regulates the transcription of 3644 genes (p<0.005) in mouse ES cells. Genome-wide analysis revealed a dramatic difference between the regulation of p53-activated and -repressed genes. p53 mainly regulates the promoter regions of activated genes, whereas the main regulatory regions for repressed genes reside in distal regions. Among p53-repressed genes, many are pluripotent transcription factors of ES cells, such as Oct4, Nanog, Sox2, Esrrb, c-Myc, n-Myc and Sall4. Strikingly, these transcriptional factors also directly regulate the transcription of the Trp53 gene, highlighting a previously under-estimated transcriptional regulation of p53 in ES cells. Therefore, p53 signaling and ES pluripotent transcriptional networks form an intertwined circuitry. Together, our results provide mechanistic insights into the crosstalk of p53-mediated DNA damage and ES cell "stemness" transcriptional gene networks and shed light on the tumor suppressive function of p53 in ES cells. The goal of this experiment is to identify the gene expression changes after adriamycin treatment in a p53-dependent manner. Total six samples: triplicates for untreated mES cells and triplicates for mES cells treated with adriamycin.
2012-03-05 | E-GEOD-26360 | biostudies-arrayexpress
Project description:Induced pluripotent stem (iPS) cells can be obtained from fibroblasts by expression of Oct4, Sox2, Klf4, and c-Myc. To determine how these factors induce this change in cell identity, we carried out genomewide promoter analysis of their binding in iPS and partially reprogrammed cells. Most targets in iPS cells are shared with ES cells and the factors cooperate to activate the ES-like expression program. In partially reprogrammed cells, genes bound by c-Myc have achieved a more ES-like binding and expression pattern. In contrast, genes that are co-bound by Oct4, Sox2, and Klf4 in ES cells and that encode pluripotency regulators show severe lack of both binding and transcriptional activation. Among the factors, c-Myc has a pivotal effect on the initiation of the ES transcription program, including the repression of fibroblast-specific genes. Our analysis begins to unravel how the four factors function together and suggests a temporal and separable order of their effects during reprogramming.
2009-01-28 | GSE14012 | GEO
Project description:Self-renewal and pluripotency of the embryonic stem cell (ESC) state is established and maintained by multiple regulatory networks that comprise transcription factors and epigenetic regulators. Although many studies have been performed, the function of epigenetic regulators in these networks is incompletely defined. We conducted a CRISPR-Cas9 mediated loss-of-function genetic screen to target 323 epigenetic and ESC-specific transcription factor genes. This screen identified two new epigenetic regulators—TAF5L and TAF6L—with high confidence for the mouse ESC state. TAF5L and TAF6L are also essential for the efficient somatic reprogramming. In-depth analyses demonstrate that TAF5L and TAF6L belong to and establish a regulatory circuitry with MYC and CORE networks. Moreover, detailed molecular studies reveal TAF5L and TAF6L predominantly regulate their target genes through the c-MYC and MYC regulatory network to control self-renewal of mouse ESCs. Our findings illuminate the multi-layered regulatory networks of TAF5L and TAF6L for gene regulation to maintain the ESC state.
2019-01-01 | GSE113329 | GEO
Project description:Self-renewal and pluripotency of the embryonic stem cell (ESC) state is established and maintained by multiple regulatory networks that comprise transcription factors and epigenetic regulators. Although many studies have been performed, the function of epigenetic regulators in these networks is incompletely defined. We conducted a CRISPR-Cas9 mediated loss-of-function genetic screen to target 323 epigenetic and ESC-specific transcription factor genes. This screen identified two new epigenetic regulators—TAF5L and TAF6L—with high confidence for the mouse ESC state. TAF5L and TAF6L are also essential for the efficient somatic reprogramming. In-depth analyses demonstrate that TAF5L and TAF6L belong to and establish a regulatory circuitry with MYC and CORE networks. Moreover, detailed molecular studies reveal TAF5L and TAF6L predominantly regulate their target genes through the c-MYC and MYC regulatory network to control self-renewal of mouse ESCs. Our findings illuminate the multi-layered regulatory networks of TAF5L and TAF6L for gene regulation to maintain the ESC state.
2019-01-01 | GSE113334 | GEO
Project description:Chavez2009 - a core regulatory network of OCT4 in human embryonic stem cells
A core OCT4-regulated network has been identified as a test case, to analyase stem cell characteristics and cellular differentiation.
This model is described in the article:
In silico identification of a core regulatory network of OCT4 in human embryonic stem cells using an integrated approach.
Chavez L, Bais AS, Vingron M, Lehrach H, Adjaye J, Herwig R
BMC Genomics, 2009, 10:314
Abstract:
BACKGROUND: The transcription factor OCT4 is highly expressed in pluripotent embryonic stem cells which are derived from the inner cell mass of mammalian blastocysts. Pluripotency and self renewal are controlled by a transcription regulatory network governed by the transcription factors OCT4, SOX2 and NANOG. Recent studies on reprogramming somatic cells to induced pluripotent stem cells highlight OCT4 as a key regulator of pluripotency.
RESULTS: We have carried out an integrated analysis of high-throughput data (ChIP-on-chip and RNAi experiments along with promoter sequence analysis of putative target genes) and identified a core OCT4 regulatory network in human embryonic stem cells consisting of 33 target genes. Enrichment analysis with these target genes revealed that this integrative analysis increases the functional information content by factors of 1.3 - 4.7 compared to the individual studies. In order to identify potential regulatory co-factors of OCT4, we performed a de novo motif analysis. In addition to known validated OCT4 motifs we obtained binding sites similar to motifs recognized by further regulators of pluripotency and development; e.g. the heterodimer of the transcription factors C-MYC and MAX, a prerequisite for C-MYC transcriptional activity that leads to cell growth and proliferation.
CONCLUSION: Our analysis shows how heterogeneous functional information can be integrated in order to reconstruct gene regulatory networks. As a test case we identified a core OCT4-regulated network that is important for the analysis of stem cell characteristics and cellular differentiation. Functional information is largely enriched using different experimental results. The de novo motif discovery identified well-known regulators closely connected to the OCT4 network as well as potential new regulators of pluripotency and differentiation. These results provide the basis for further targeted functional studies.
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2005-01-01 | MODEL1305010000 | BioModels
Project description:Our study focuses on a family of ubiquitously expressed human C2H2 zinc finger proteins comprised of ZFX, ZFY, and ZNF711. Although their protein structure suggests that ZFX, ZFY, and ZNF711 are transcriptional regulators, the mechanisms by which they influence transcription have not yet been elucidated. We used CRISPR-mediated deletion to create bi-allelic knockouts of ZFX and/or ZNF711 in female HEK293T cells (which naturally lack ZFY). We found that loss of either ZFX or ZNF711 reduced cell growth and that the double knockout cells have major defects in proliferation. RNA-seq analysis revealed that thousands of genes showed altered expression in the double knockout clones, suggesting that these TFs are critical regulators of the transcriptome. To gain insight into how these TFs regulate transcription, we created mutant ZFX proteins and analyzed them for DNA binding and transactivation capability. We found that zinc fingers 11-13 are necessary and sufficient for DNA binding and, in combination with the N terminal region, constitute a functional transactivator. Our functional analyses of the ZFX family provides important new insights into transcriptional regulation in human cells by members of the large, but under-studied family of C2H2 zinc finger proteins.
2020-04-30 | GSE145160 | GEO
Project description:Our study focuses on a family of ubiquitously expressed human C2H2 zinc finger proteins comprised of ZFX, ZFY, and ZNF711. Although their protein structure suggests that ZFX, ZFY, and ZNF711 are transcriptional regulators, the mechanisms by which they influence transcription have not yet been elucidated. We used CRISPR-mediated deletion to create bi-allelic knockouts of ZFX and/or ZNF711 in female HEK293T cells (which naturally lack ZFY). We found that loss of either ZFX or ZNF711 reduced cell growth and that the double knockout cells have major defects in proliferation. RNA-seq analysis revealed that thousands of genes showed altered expression in the double knockout clones, suggesting that these TFs are critical regulators of the transcriptome. To gain insight into how these TFs regulate transcription, we created mutant ZFX proteins and analyzed them for DNA binding and transactivation capability. We found that zinc fingers 11-13 are necessary and sufficient for DNA binding and, in combination with the N terminal region, constitute a functional transactivator. Our functional analyses of the ZFX family provides important new insights into transcriptional regulation in human cells by members of the large, but under-studied family of C2H2 zinc finger proteins.
2023-01-28 | GSE148960 | GEO