Wdr5 mediates self-renewal and reprogramming via the embryonic stem cell core transcriptional network
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE22934 | GEO | 2011/04/08
SECONDARY ACCESSION(S): PRJNA127937
REPOSITORIES: GEO
Similar Datasets
Project description:The embryonic stem (ES) cell transcriptional and epigenetic networks are critical for the maintenance of ES cell self-renewal. However, it remains unclear whether components of these networks functionally interact and if so, what factors mediate such interactions. Here we show that WD-repeat protein-5 (Wdr5), a core member of the mammalian Trithorax (trxG) complex, positively correlates with the undifferentiated state and is a novel regulator of ES cell self-renewal. We demonstrate that Wdr5, an ‘effector’ of H3K4 methylation, interacts with the pluripotency transcription factor Oct4. In concordance, genome-wide ChIP-Seq and transcriptome analyses demonstrate overlapping gene regulatory functions between Oct4 and Wdr5. We show that the Oct4-Sox2-Nanog circuitry cooperates with trxG for transcriptional activation of key self-renewal regulators. Furthermore, Wdr5 expression is required for the efficient formation of induced pluripotent stem (iPS) cells. Collectively, these findings implicate an integrated model of transcriptional and epigenetic control, mediated by select trxG members, for the maintenance of ES cell self-renewal and somatic cell reprogramming. 7 Samples
2011-04-08 | E-GEOD-22934 | biostudies-arrayexpress
Project description:The embryonic stem (ES) cell transcriptional and epigenetic networks are critical for the maintenance of ES cell self-renewal. It remains unclear whether interactions. Here we show that a core member of the Set/MLL complex, WDrepeat protein-5 (Wdr5), is a novel regulator of self-renewal and partners with Oct4 to maintain an intact transcriptional network and for efficient formation of induced pluripotent stem (iPS) cells. Moreover, we provide evidence that Oct4 interacts with chromatin components and is indispensible for epigenetic regulation. These findings suggest an integrated transcriptional and epigenetic model, mediated through Wdr5, for the maintenance of ES cell self-renewal and somatic cell reprogramming. Differential gene expressions upon down-regulation of Wdr5 was analysed by comparing Wdr5R4 –dox (triplicate) and LucR +dox (duplicate) RNA samples Gene expression changes upon down-regulation of Oct4 was analysed by comparing Oct4 shRNA (duplicate) and GFP shRNA (duplicate) after 4day transfection Wdr5: 5 samples are analyzed: Luciferase (Luc, 2 replicates) and Wdr5 with no dox (minusDox, 3 replicates) Oct4-GFP: 4 samples are analyzed: Oct4 shRNA (Oct4, 2 replicates) and GFP shRNA (GFP, 2 replicates)
2011-04-08 | E-GEOD-19588 | biostudies-arrayexpress
Project description:The embryonic stem (ES) cell transcriptional and epigenetic networks are critical for the maintenance of ES cell self-renewal. It remains unclear whether interactions. Here we show that a core member of the Set/MLL complex, WDrepeat protein-5 (Wdr5), is a novel regulator of self-renewal and partners with Oct4 to maintain an intact transcriptional network and for efficient formation of induced pluripotent stem (iPS) cells. Moreover, we provide evidence that Oct4 interacts with chromatin components and is indispensible for epigenetic regulation. These findings suggest an integrated transcriptional and epigenetic model, mediated through Wdr5, for the maintenance of ES cell self-renewal and somatic cell reprogramming. Differential gene expressions upon down-regulation of Wdr5 was analysed by comparing Wdr5R4 –dox (triplicate) and LucR +dox (duplicate) RNA samples Gene expression changes upon down-regulation of Oct4 was analysed by comparing Oct4 shRNA (duplicate) and GFP shRNA (duplicate) after 4day transfection
2011-04-08 | GSE19588 | GEO
Project description:We have used mouse embryonic stem cells (ESCs) as a model to study the signaling mechanisms that regulate self-renewal and commitment to differentiation. We hypothesized that genes critical to stem cell fate would be dynamically regulated at the initiation of commitment. Time course microarray analysis following initiation of commitment led us to propose a model of ESC maintenance in which highly regulated transcription factors and chromatin remodeling genes (down-regulated in our time course) maintain repression of genes responsible for cell differentiation, morphogenesis and development (up-regulated in our time course). Microarrays of Oct4, Nanog and Sox2 shRNA knockdown cell lines confirmed predicted regulation of target genes. shRNA knockdowns of candidate genes were tested in a novel high throughput screen of self-renewal, confirming their role in ESC pluripotency. We have identified genes that are critical for self-renewal and those that initiate commitment and developed draft transcriptional networks that control self-renewal and early development. Keywords: genetic modification Gene expression in Oct4 knockdown, Sox2 knockdown and their empty vector contol ES cells was analyzed.
2010-06-11 | E-GEOD-7520 | biostudies-arrayexpress
Project description:Oct4 is considered a master transcription factor for pluripotent cell self-renewal and embryo development. It primarily collaborates with other transcriptional factors or coregulators to maintain pluripotency. However, it is still unclear how Oct4 interacts with its partners. Here, we show that the Oct4 linker interface mediates competing and balanced Oct4 protein interactions which are crucial for maintaining pluripotency. Linker mutant ESCs maintain the key pluripotency genes expression, but show decreased expression of self-renewal genes and increased expression of differentiation genes which result in impaired ESCs self-renewal and early embryonic lethality. Linker mutation dose not affect Oct4 genomic binding and transactivation potential, but breaks the balanced Oct4 interactome. In mutant ESCs, the interaction between Oct4 and Klf5 was decreased, but interactions between Oct4 and Cbx1, Ctr9, Cdc73 were increased which disrupt the epigenetic state of ESCs. Overexpression of Klf5 or knockdown Cbx1, Cdc73 rescue the cellular phenotype of linker mutant ESCs by rebalancing Oct4 interactome indicating that different partners interact with Oct4 competitively. Thus, by showing how Oct4 interacts with different partners, we provide novel molecular insights to explain how Oct4 contributes to the maintenance of pluripotency.
2021-12-10 | PXD017456 | Pride
Project description:Understanding the transcriptional regulatory circuitry responsible for pluripotency and self-renewal in embryonic stem (ES) cells is fundamental to understanding human development and realizing the therapeutic potential of these cells. The transcription factor Oct4 and the chromatin-modifying Polycomb complex, key regulators of ES cell pluripotency and self-renewal, contribute to positive and negative control of a known set of protein-coding genes. MicroRNAs (miRNAs), non-coding transcripts that participate in post-transcriptional gene regulation are also important for normal pluripotency and self-renewal in ES cells, but there has been no systematic investigation of how miRNA expression is controlled by transcriptional regulators of ES cell identity. Here we identify promoters for miRNAs in the human and mouse genomes and describe the subset of these genes that are under the control of Oct4 and Polycomb in ES cells. We find that the majority of miRNAs that are uniquely or preferentially expressed in ES cells are bound by and dependent on Oct4. Oct4 also occupies a set of miRNA genes that are co-occupied by the Polycomb Group protein, Suz12. These miRNAs, repressed in ES cells, are later expressed in differentiated cells in a highly tissue-specific fashion, suggesting that they may contribute to cell-fate determinations. These data reveal how the core transcriptional regulatory circuitry of ES cells controls the miRNA expression program that contributes to pluripotency and self-renewal.
2010-12-01 | E-TABM-365 | biostudies-arrayexpress
Project description:Trophoblast stem cells (TS cells), derived from the trophectoderm (TE) of blastocysts, require transcription factors (TFs) and external signals (Fgf4, Activin/Nodal/Tgfb) for self-renewal. While many reports have focused on TF networks that regulate embryonic stem cell (ES cell) self-renewal and pluripotency, little is know about TF networks that regulate self-renewal in TS cells. To further understand transcriptional networks in TS cells we used chromatin immunopreciptiation and DNA microarray analysis (ChIP-chip) to investigate targets of TFs Ap-2g (Tcfap2c), Eomes, Ets2, and Gata3, and a chromatin remodeling factor, Brg1 (Smarca4). We then evaluated the transcriptional states of target genes using transcriptome analysis and genome-wide analysis of histone H3 acetylation (AcH3). Our results describe previously unknown transcriptional networks in TS cells, including TF occupancy of genes involved in ES cell self-renewal and pluripotency, co-occupancy of multiple TFs at target genes, and transcriptional regulatory circuitry within the 5 factors. Through genome-wide mapping and global expression analysis of 5 TF target genes, our data provide a comprehensive analysis of transcriptional networks that regulate TS cell self-renewal.
2010-02-09 | GSE18507 | GEO
Project description:Of the thousands of long non-coding RNAs expressed in embryonic stem (ES) cells, few have known roles and fewer have been functionally implicated in the regulation of self-renewal and pluripotency or reprogramming somatic cells to the pluripotent state. In ES cells, Cyrano is a stably expressed long intergenic non-coding RNA with no previously assigned role. We demonstrate that Cyrano contributes to ES cell maintenance, as its depletion results in loss of hallmarks of self-renewal. Delineation of Cyrano's network through transcriptomics revealed widespread effects on signaling pathways and gene expression networks that contribute to ES cell maintenance. Cyrano shares unique sequence complementarity with the differentiation-associated microRNA, mir-7, and mir-7 overexpression reduces expression of a key self-renewal factor to a similar extent as Cyrano knockdown. This suggests that Cyrano functions to restrain the action of mir-7. Altogether, we provide a view into the multifaceted function of Cyrano in ES cell maintenance.
2017-04-28 | GSE98297 | GEO
Project description:Chickarmane2006 - Stem cell switch irreversible
Kinetic modeling approach of the transcriptional dynamics of the embryonic stem cell switch.
This model is described in the article:
Transcriptional dynamics of the embryonic stem cell switch.
Chickarmane V, Troein C, Nuber UA, Sauro HM, Peterson C
PLoS Computational Biology. 2006; 2(9):e123
Abstract:
Recent ChIP experiments of human and mouse embryonic stem cells have elucidated the architecture of the transcriptional regulatory circuitry responsible for cell determination, which involves the transcription factors OCT4, SOX2, and NANOG. In addition to regulating each other through feedback loops, these genes also regulate downstream target genes involved in the maintenance and differentiation of embryonic stem cells. A search for the OCT4-SOX2-NANOG network motif in other species reveals that it is unique to mammals. With a kinetic modeling approach, we ascribe function to the observed OCT4-SOX2-NANOG network by making plausible assumptions about the interactions between the transcription factors at the gene promoter binding sites and RNA polymerase (RNAP), at each of the three genes as well as at the target genes. We identify a bistable switch in the network, which arises due to several positive feedback loops, and is switched on/off by input environmental signals. The switch stabilizes the expression levels of the three genes, and through their regulatory roles on the downstream target genes, leads to a binary decision: when OCT4, SOX2, and NANOG are expressed and the switch is on, the self-renewal genes are on and the differentiation genes are off. The opposite holds when the switch is off. The model is extremely robust to parameter changes. In addition to providing a self-consistent picture of the transcriptional circuit, the model generates several predictions. Increasing the binding strength of NANOG to OCT4 and SOX2, or increasing its basal transcriptional rate, leads to an irreversible bistable switch: the switch remains on even when the activating signal is removed. Hence, the stem cell can be manipulated to be self-renewing without the requirement of input signals. We also suggest tests that could discriminate between a variety of feedforward regulation architectures of the target genes by OCT4, SOX2, and NANOG.
This model is hosted on BioModels Database
and identified by: MODEL7957942740
.
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models
.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication
for more information.
2008-11-26 | BIOMD0000000204 | BioModels
Project description:Chickarmane2006 - Stem cell switch reversible
Kinetic modeling approach of the transcriptional dynamics of the embryonic stem cell switch.
This model is described in the article:
Transcriptional dynamics of the embryonic stem cell switch.
Chickarmane V, Troein C, Nuber UA, Sauro HM, Peterson C
PLoS Computational Biology. 2006; 2(9):e123
Abstract:
Recent ChIP experiments of human and mouse embryonic stem cells have elucidated the architecture of the transcriptional regulatory circuitry responsible for cell determination, which involves the transcription factors OCT4, SOX2, and NANOG. In addition to regulating each other through feedback loops, these genes also regulate downstream target genes involved in the maintenance and differentiation of embryonic stem cells. A search for the OCT4-SOX2-NANOG network motif in other species reveals that it is unique to mammals. With a kinetic modeling approach, we ascribe function to the observed OCT4-SOX2-NANOG network by making plausible assumptions about the interactions between the transcription factors at the gene promoter binding sites and RNA polymerase (RNAP), at each of the three genes as well as at the target genes. We identify a bistable switch in the network, which arises due to several positive feedback loops, and is switched on/off by input environmental signals. The switch stabilizes the expression levels of the three genes, and through their regulatory roles on the downstream target genes, leads to a binary decision: when OCT4, SOX2, and NANOG are expressed and the switch is on, the self-renewal genes are on and the differentiation genes are off. The opposite holds when the switch is off. The model is extremely robust to parameter changes. In addition to providing a self-consistent picture of the transcriptional circuit, the model generates several predictions. Increasing the binding strength of NANOG to OCT4 and SOX2, or increasing its basal transcriptional rate, leads to an irreversible bistable switch: the switch remains on even when the activating signal is removed. Hence, the stem cell can be manipulated to be self-renewing without the requirement of input signals. We also suggest tests that could discriminate between a variety of feedforward regulation architectures of the target genes by OCT4, SOX2, and NANOG.
This model is hosted on BioModels Database
and identified by: MODEL7957907314
.
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models
.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication
for more information.
2008-11-25 | BIOMD0000000203 | BioModels