Oct4-driven epigenetic reprogramming induces embryonic-like microRNA expression signatures in human fibroblasts
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE126284 | GEO | 2019/02/09
REPOSITORIES: GEO
Similar Datasets
Project description:The enhancer landscape is dramatically restructured as naïve preimplantation epiblasts transition to the post-implantation state of primed pluripotency. A key factor in this process is Otx2, which is upregulated during the early stages of this transition and ultimately recruits Oct4 to a different set of enhancers. In this study we discover that the acetylation status of Oct4 regulates the induction of the primed pluripotency gene network. Maintenance of the naïve state requires Oct4 deacetylation by the NAD-dependent deacetylase, SirT1. The activity of SirT1 is reduced during the naïve to primed transition, thereby increasing the acetylation of Oct4 and promoting its binding to an Otx2 enhancer to induce Otx2 expression. Induction of Otx2 causes the reorganization of acetylated Oct4 and results in the induction of the primed pluripotency gene network. Regulation of Oct4 by SirT1 may link stem cell development to environmental conditions and provide strategies to manipulate epiblast cell state.
2016-09-20 | GSE81494 | GEO
Project description:HUES24 cell line was nucleofected with POU5f1 cDNA to overexpress OCT4; This leads to the formation of mesendodermal cells Short- and Long-scales intra- and inter-chromosomal interactions are linked to gene transcription, but the molecular event underlying these structures and how it affects cell fate decision during embryonic development are poorly understood. One of the first embryonic cell fate decisions (i.e mesendoderm determination) is driven by the POU factor OCT4, acting in concert with the high mobility group genes SOX-2 and SOX-17. Here, we identify novel chromatin remodelling mechanism and enhancer function driven by both OCT4 and SALL4 that mediate cell fate switching. We found that OCT4 alters the higher-order chromatin structure at both Sox-2 and Sox-17 loci. OCT4 titrates out cohesin and switches the Sox-17 enhancer from a locked (within an inter-chromosomal Sox-2 enhancer/CTCF/cohesin loop) to an active (within an intra-chromosomal Sox-17 promoter/enhancer/cohesin loop) state. SALL4 concomitantly mobilizes the polycomb complexes at the Soxs loci. Thus, OCT4/SALL4-driven cohesin-and polycombs-mediated changes in higher order chromatin structure mediate instruction of early cell fate in embryonic cells. ChIP anti-OCT4 on chip. results_v2.xls file description: Enriched binding sites. Mutant means oct4 overexpressing cells , wt GFP nucleofected cells.
2015-04-02 | E-GEOD-58125 | biostudies-arrayexpress
Project description:HUES24 cell line was nucleofected with POU5f1 cDNA to overexpress OCT4; This leads to the formation of mesendodermal cells Short- and Long-scales intra- and inter-chromosomal interactions are linked to gene transcription, but the molecular event underlying these structures and how it affects cell fate decision during embryonic development are poorly understood. One of the first embryonic cell fate decisions (i.e mesendoderm determination) is driven by the POU factor OCT4, acting in concert with the high mobility group genes SOX-2 and SOX-17. Here, we identify novel chromatin remodelling mechanism and enhancer function driven by both OCT4 and SALL4 that mediate cell fate switching. We found that OCT4 alters the higher-order chromatin structure at both Sox-2 and Sox-17 loci. OCT4 titrates out cohesin and switches the Sox-17 enhancer from a locked (within an inter-chromosomal Sox-2 enhancer/CTCF/cohesin loop) to an active (within an intra-chromosomal Sox-17 promoter/enhancer/cohesin loop) state. SALL4 concomitantly mobilizes the polycomb complexes at the Soxs loci. Thus, OCT4/SALL4-driven cohesin-and polycombs-mediated changes in higher order chromatin structure mediate instruction of early cell fate in embryonic cells.
2015-04-02 | GSE58125 | GEO
Project description:Embryonic stem cell (ESC) pluripotency is governed by a gene regulatory network centred on the transcription factors Oct4 and Nanog. ESCs fluctuate between states of high and low Nanog expression that direct efficient or inefficient self-renewal. To date, robust self-renewing ESC states have only been attained by chemical inhibition of signalling pathways or enforced transgene expression. Here we show that ESCs expressing a reduced range of Oct4 concentrations, typified by Oct4 heterozygous ESCs exhibit stable robust pluripotency. Despite this reduced Oct4 concentration range, this state is characterised by increased genome-wide binding of Oct4, particularly at pluripotency-associated enhancers, homogeneous expression of pluripotency transcription factors, enhanced self-renewal efficiency and delayed differentiation kinetics. In this state, ESCs exhibit increased wnt expression, enhanced LIF-sensitivity, non-responsiveness to FGF signalling and can clonally maintain pluripotency without BMP but remain dependent upon LIF. Robust pluripotency is destabilised either by alteration of the Oct4 level or by removal of LIF. Our findings suggest that robust pluripotency originates from cells with a reduced Oct4 protein concentration and that the wild-type Oct4 range enables effective differentiation.
2013-05-07 | E-MTAB-1617 | biostudies-arrayexpress
Project description:Forced expression of four transcription factors Oct4,Sox2, Klf4 and Myc (OSKM) induces somatic cell reprogramming towards pluripotency. Major efforts have been made to characterize the molecular events involved in this process. Yet, it remains elusive how gene expression change, epigenetic landscape remodelling and cell fate conversion are triggered by expression of these Yamanaka factors.To address this gap,we utilized a secondary inducible reprogramming system and performed genome-wide profilings of Oct4 binding, histone modification(H3K4me3/H3K27me3/H3K4me1/H3K27ac), and gene expression analysis during this process. Through integrative analysis, we revealed stage-specific Oct4 binding and enhancer signatures in consistence with gene expression changes,in which the initial regression of somatic program is followed by the gradual acquisition of pluripotent program. Oct4 preferatially binds to H3K4me1 marked enhancer regions and Oct4 binding is positively correlated with active mark H3K27ac. Moreover,we observed significant enhancer activation of epigenetic related genes, especially acetylation associated genes, prior to pluripotency network activation, suggesting a pivotal role of epigenetic remodelling in the process of pluripotency acquisition and maintenance. We used ChIP-seq to explore the global changes of Oct4 binding profiling during OSKM-mediated somatic cell reprogramming. The exogenous Oct4 was tagged with 3XFlag, thus we used anti-flag antibody to monitor exogenous Oct4 changes; anti-Oct4 antibody which recognizes both endogenous and exogenous Oct4 was used to monitor total Oct4 changes during iPSC induction. In addition, we also examined genome-wide H3K4me1/H3K27ac/H3K4me3/H3K27me3/RNAPII profiling during 3Flag-OSKM 2' reprogramming.
2015-12-31 | E-GEOD-67520 | 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:Forced expression of four transcription factors Oct4,Sox2, Klf4 and Myc (OSKM) induces somatic cell reprogramming towards pluripotency. Major efforts have been made to characterize the molecular events involved in this process. Yet, it remains elusive how gene expression change, epigenetic landscape remodelling and cell fate conversion are triggered by expression of these Yamanaka factors. To address this gap,we utilized a secondary inducible reprogramming system and performed genome-wide profilings of Oct4 binding, histone modification (H3K4me3/H3K27me3/H3K4me1/H3K27ac), and gene expression analysis during this process. Through integrative analysis, we revealed stage-specific Oct4 binding and enhancer signatures in consistence with gene expression changes, in which the initial regression of somatic program is followed by the gradual acquisition of pluripotent program. Oct4 preferatially binds to H3K4me1 marked enhancer regions and Oct4 binding is positively correlated with active mark H3K27ac. Moreover, we observed significant enhancer activation of epigenetic related genes, especially acetylation associated genes, prior to pluripotency network activation, suggesting a pivotal role of epigenetic remodelling in the process of pluripotency acquisition and maintenance.
2015-12-31 | GSE67520 | GEO
Project description:Lineage segregation in the mouse embryo is a finely controlled process dependent upon coordination of signalling pathways and transcriptional responses. We employed conditional deletion of Oct4 to investigate consequences of interference with embryonic patterning and lineage specification. Nanog becomes upregulated in the first epiblast cells to lose Oct4, leading to an expanded Nanog-positive domain. The primitive streak forms in the presumptive proximal posterior region, but epithelial to mesenchymal transition is impeded by dramatic increase of E-cadherin, leading to complete disorganisation and failure to generate germ layers. Formerly, expression domains of lineage markers were disrupted. Specifically, definitive endoderm expanded, the boundaries between presumptive anterior and posterior domains blurred and an ectopic posterior-like region appeared anteriorly, suggesting a role for Oct4 in maintaining the embryonic axis. Despite intermixing of lineage marker domains in mutants, cells co-expressing distinct lineage genes were not observed, suggesting that Oct4 deletion does not alter the connectivity of the transcription networks which underlie cell fate decisions in vivo. Molecular profiling corroborated genome-wide posteriorisation of mutants and disrupted expression of genes involved in gastrulation. Lastly, we confirmed a requirement for Oct4 in self-renewal of post-implantation epiblast ex vivo
2018-06-11 | GSE103403 | GEO
Project description:ChIP Seq of Oct4, Nanog, H3K27me3 in Oct4+/+ and Oct4 +/- mES cells
| PRJEB1833 | ENA
Project description:Mariana Esther Martinez-Sanchez, Luis Mendoza, Carlos Villarreal & Elena R. Alvarez-Buylla. A Minimal Regulatory Network of Extrinsic and Intrinsic Factors Recovers Observed Patterns of CD4+ T Cell Differentiation and Plasticity. PLOS Computational Biology 11, 6 (2015).
CD4+ T cells orchestrate the adaptive immune response in vertebrates. While both experimental and modeling work has been conducted to understand the molecular genetic mechanisms involved in CD4+ T cell responses and fate attainment, the dynamic role of intrinsic (produced by CD4+ T lymphocytes) versus extrinsic (produced by other cells) components remains unclear, and the mechanistic and dynamic understanding of the plastic responses of these cells remains incomplete. In this work, we studied a regulatory network for the core transcription factors involved in CD4+ T cell-fate attainment. We first show that this core is not sufficient to recover common CD4+ T phenotypes. We thus postulate a minimal Boolean regulatory network model derived from a larger and more comprehensive network that is based on experimental data. The minimal network integrates transcriptional regulation, signaling pathways and the micro-environment. This network model recovers reported configurations of most of the characterized cell types (Th0, Th1, Th2, Th17, Tfh, Th9, iTreg, and Foxp3-independent T regulatory cells). This transcriptional-signaling regulatory network is robust and recovers mutant configurations that have been reported experimentally. Additionally, this model recovers many of the plasticity patterns documented for different T CD4+ cell types, as summarized in a cell-fate map. We tested the effects of various micro-environments and transient perturbations on such transitions among CD4+ T cell types. Interestingly, most cell-fate transitions were induced by transient activations, with the opposite behavior associated with transient inhibitions. Finally, we used a novel methodology was used to establish that T-bet, TGF-β and suppressors of cytokine signaling proteins are keys to recovering observed CD4+ T cell plastic responses. In conclusion, the observed CD4+ T cell-types and transition patterns emerge from the feedback between the intrinsic or intracellular regulatory core and the micro-environment. We discuss the broader use of this approach for other plastic systems and possible therapeutic interventions.
2024-09-02 | BIOMD0000000592 | BioModels