Browse
Submit Data
Databases
API
Help

Dataset Information

4 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A novel and critical role for Oct4 as a regulator of the maternal-embryonic transition.

ABSTRACT:

Background

Compared to the emerging embryonic stem cell (ESC) gene network, little is known about the dynamic gene network that directs reprogramming in the early embryo. We hypothesized that Oct4, an ESC pluripotency regulator that is also highly expressed at the 1- to 2-cell stages in embryos, may be a critical regulator of the earliest gene network in the embryo.

Methodology/principal findings

Using antisense morpholino oligonucleotide (MO)-mediated gene knockdown, we show that Oct4 is required for development prior to the blastocyst stage. Specifically, Oct4 has a novel and critical role in regulating genes that encode transcriptional and post-transcriptional regulators as early as the 2-cell stage. Our data suggest that the key function of Oct4 may be to switch the developmental program from one that is predominantly regulated by post-transcriptional control to one that depends on the transcriptional network. Further, we propose to rank candidate genes quantitatively based on the inter-embryo variation in their differential expression in response to Oct4 knockdown. Of over 30 genes analyzed according to this proposed paradigm, Rest and Mta2, both of which have established pluripotency functions in ESCs, were found to be the most tightly regulated by Oct4 at the 2-cell stage.

Conclusions/significance

We show that the Oct4-regulated gene set at the 1- to 2-cell stages of early embryo development is large and distinct from its established network in ESCs. Further, our experimental approach can be applied to dissect the gene regulatory network of Oct4 and other pluripotency regulators to deconstruct the dynamic developmental program in the early embryo.

SUBMITTER: Foygel K

PROVIDER: S-EPMC2614881 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

COPS2 Antagonizes OCT4 to Accelerate the G2/M Transition of Mouse Embryonic Stem Cells.

Project description:Proper regulation of the cell cycle is essential to safeguard the genomic integrity of embryonic stem cells (ESCs) while maintaining the fast proliferation rate. The pluripotency factor OCT4 has been shown to inhibit CDK1 activation, thus preventing mitotic entry and facilitating the maintenance of genomic integrity. Yet, how ESCs enter mitosis in the presence of OCT4 remains unclear. We previously reported that COPS2 promotes the progression through the G2/M phase of mouse ESCs. In this study, through co-immunoprecipitation and mass spectrometric analysis, we found that COPS2 interacts with OCT4 and CDK1. We further demonstrated that COPS2 stimulates the activity of CDK1/CYCLIN B only when OCT4 is present. Consistently, COPS2 promotes the G2/M transition only in the presence of OCT4 in HeLa cells. Mechanistically, COPS2 attenuates the interaction between OCT4 and CDK1 by sequestering OCT4 and forming a COPS2/CDK1 complex, thus blocking the inhibitory effect of OCT4 on CDK1 activation.

| S-EPMC6092711 | biostudies-literature

Otx2 and Oct4 drive early enhancer activation during embryonic stem cell transition from naive pluripotency.

Project description:Embryonic stem cells (ESCs) are unique in that they have the capacity to differentiate into all of the cell types in the body. We know a lot about the complex transcriptional control circuits that maintain the naive pluripotent state under self-renewing conditions but comparatively less about how cells exit from this state in response to differentiation stimuli. Here, we examined the role of Otx2 in this process in mouse ESCs and demonstrate that it plays a leading role in remodeling the gene regulatory networks as cells exit from ground state pluripotency. Otx2 drives enhancer activation through affecting chromatin marks and the activity of associated genes. Mechanistically, Oct4 is required for Otx2 expression, and reciprocally, Otx2 is required for efficient Oct4 recruitment to many enhancer regions. Therefore, the Oct4-Otx2 regulatory axis actively establishes a new regulatory chromatin landscape during the early events that accompany exit from ground state pluripotency.

| S-EPMC4074343 | biostudies-literature

A novel SALL4/OCT4 transcriptional feedback network for pluripotency of embryonic stem cells.

Project description:BackgroundSALL4 is a member of the SALL gene family that encodes a group of putative developmental transcription factors. Murine Sall4 plays a critical role in maintaining embryonic stem cell (ES cell) pluripotency and self-renewal. We have shown that Sall4 activates Oct4 and is a master regulator in murine ES cells. Other SALL gene members, especially Sall1 and Sall3 are expressed in both murine and human ES cells, and deletions of these two genes in mice lead to perinatal death due to developmental defects. To date, little is known about the molecular mechanisms controlling the regulation of expressions of SALL4 or other SALL gene family members.Methodology/principal findingsThis report describes a novel SALL4/OCT4 regulator feedback loop in ES cells in balancing the proper expression dosage of SALL4 and OCT4 for the maintenance of ESC stem cell properties. While we have observed that a positive feedback relationship is present between SALL4 and OCT4, the strong self-repression of SALL4 seems to be the "break" for this loop. In addition, we have shown that SALL4 can repress the promoters of other SALL family members, such as SALL1 and SALL3, which competes with the activation of these two genes by OCT4.Conclusions/significanceOur findings, when taken together, indicate that SALL4 is a master regulator that controls its own expression and the expression of OCT4. SALL4 and OCT4 work antagonistically to balance the expressions of other SALL gene family members. This novel SALL4/OCT4 transcription regulation feedback loop should provide more insight into the mechanism of governing the "stemness" of ES cells.

| S-EPMC2874005 | biostudies-literature

Dixdc1 is a critical regulator of DISC1 and embryonic cortical development.

Project description:The psychiatric illness risk gene Disrupted in Schizophrenia-1 (DISC1) plays an important role in brain development; however, it is unclear how DISC1 is regulated during cortical development. Here, we report that DISC1 is regulated during embryonic neural progenitor proliferation and neuronal migration through an interaction with DIX domain containing-1 (Dixdc1), the third mammalian gene discovered to contain a Disheveled-Axin (DIX) domain. We determined that Dixdc1 functionally interacts with DISC1 to regulate neural progenitor proliferation by co-modulating Wnt-GSK3beta/beta-catenin signaling. However, DISC1 and Dixdc1 do not regulate migration via this pathway. During neuronal migration, we discovered that phosphorylation of Dixdc1 by cyclin-dependent kinase 5 (Cdk5) facilitates its interaction with the DISC1-binding partner Ndel1. Furthermore, Dixdc1 phosphorylation and its interaction with DISC1/Ndel1 in vivo is required for neuronal migration. Together, these data reveal that Dixdc1 integrates DISC1 into Wnt-GSK3beta/beta-catenin-dependent and -independent signaling pathways during cortical development and further delineate how DISC1 contributes to neuropsychiatric disorders.

| S-EPMC2938013 | biostudies-literature

A tight control of Rif1 by Oct4 and Smad3 is critical for mouse embryonic stem cell stability.

Project description:Prolonged culture of embryonic stem cells (ESCs) leads them to adopt embryonal carcinoma cell features, creating enormous dangers for their further application. The mechanism involved in ESC stability has not, however, been extensively studied. We previously reported that SMAD family member 3 (Smad3) has an important role in maintaining mouse ESC stability, as depletion of Smad3 results in cancer cell-like properties in ESCs and Smad3-/- ESCs are prone to grow large, malignant teratomas. To understand how Smad3 contributes to ESC stability, we performed microarray analysis to compare the transcriptome of wild-type and Smad3-/- ESCs. We found that Rif1 (RAP1-associated protein 1), a factor important for genomic stability, is significantly upregulated in Smad3-/- ESCs. The expression level of Rif1 needs to be tightly controlled in ESCs, as a low level of Rif1 is associated with ESC differentiation, but a high level of Rif1 is linked to ESC transformation. In ESCs, Oct4 activates Rif1, whereas Smad3 represses its expression. Oct4 recruits Smad3 to bind to Rif1 promoter, but Smad3 joining facilitates the loading of a polycomb complex that generates a repressive epigenetic modification on Rif1 promoter, and thus maintains the expression of Rif1 at a proper level in ESCs. Interestingly, Rif1 short hairpin RNA (shRNA)-transduced Smad3-/- ESCs showed less malignant properties than the control shRNA-transduced Smad3-/- ESCs, suggesting a critical role of Rif1 in maintaining the stability of ESCs during proliferation.

| S-EPMC4669749 | biostudies-literature

Siva plays a critical role in mouse embryonic development.

Project description:The Siva protein, named after the Hindu God of Destruction, plays important roles in apoptosis in various contexts, including downstream of death receptor activation or p53 tumor suppressor engagement. The function of Siva in organismal development and homeostasis, however, has remained uncharacterized. Here, we generate Siva knockout mice to characterize the physiological function of Siva in vivo. Interestingly, we find that Siva deficiency causes early embryonic lethality accompanied by multiple phenotypes, including developmental delay, abnormal neural tube closure, and defective placenta and yolk sac formation. Examination of Siva expression during embryogenesis shows that Siva is expressed in both embryonic and extra-embryonic tissues, including within the mesoderm, which may explain the vascular defects observed in the placenta and yolk sac. The embryonic phenotypes caused by Siva loss are not rescued by p53 deficiency, nor do they resemble those of p53 null embryos, suggesting that the embryonic function of Siva is not related to the p53 pathway. Moreover, loss of the Ripk3 necroptosis protein does not rescue the observed lethality or developmental defects, suggesting that Siva may play a non-apoptotic role in development. Collectively, these studies reveal a key role for Siva in proper embryonic development.

| S-EPMC7205994 | biostudies-literature

Embryonic stem cells markers SOX2, OCT4 and Nanog expression and their correlations with epithelial-mesenchymal transition in nasopharyngeal carcinoma.

Project description:Expression of embryonic stem cells (ESCs) markers (SOX2, OCT4, Nanog and Nestin) is crucial for progression of various human malignancies. The purpose of this study was to investigate the expression and prognostic impact of these molecules in nasopharyngeal carcinoma (NPC) patients by immunohistochemistry and immunofluorescence. In the present study, we found that the expression levels of SOX2, OCT4 and Nanog were highly expressed in NPC compared with the non-tumorous tissues. Furthermore, these proteins correlated significantly with several clinicalpathological factors and epithelial-mesenchymal transition (EMT)-associated indicators (E-cadherin/N-cadherin and Snail). In multivariate analyses, high expression of OCT4 (P?=?0.013) and Nanog (P?=?0.040), but not that of SOX2, was associated with worse survival and had strongly independent prognostic effects. Of note, OCT4 and Nanog were more frequently located at the invasive front of tumors, and correlated significantly with various aggressive behaviors including T classification, N classification, M classification and clinical stage. Furthermore, patients with co-expression of OCT4 and Nanog in the invasive front had significantly worse survival (P?=?0.005). Interestingly, at the invasive front, these molecules correlated significantly with Nestin expression in endothelial cells (P<0.001). These findings provide evidence that ESCs biomarkers OCT4 and Nanog serves as independent prognostic factors for NPC. Additionally, cancer cells in the invasive front of NPC acquiring ESCs-like features should be maintained by vascular niches.

| S-EPMC3570418 | biostudies-literature

Discoidin domain receptor 2 is a critical regulator of epithelial-mesenchymal transition.

Project description:Discoidin domain receptor 2 (DDR2) is a collagen receptor that is expressed during epithelial-mesenchymal transition (EMT), a cellular transformation that mediates many stages of embryonic development and disease. However, the functional significance of this receptor in EMT is unknown. Here we show that Transforming Growth Factor-beta1 (TGF-?1), a common stimulator of EMT, promotes increased expression of type I collagen and DDR2. Inhibiting expression of COL1A1 or DDR2 with siRNA is sufficient to perturb activity of the NF-?B and LEF-1 transcription factors and to inhibit EMT and cell migration induced by TGF-?1. Furthermore, knockdown of DDR2 expression with siRNA inhibits EMT directly induced by type I collagen. These data establish a critical role for type I collagen-dependent DDR2 signaling in the regulation of EMT.

| S-EPMC3114285 | biostudies-literature

Genetic Deletion of miR-430 Disrupts Maternal-Zygotic Transition and Embryonic Body Plan.

Project description:MiR-430 is considered an important regulator during embryonic development, but genetic loss-of-function study is still lacking. Here we demonstrated that genetic deletion of the miR-430 cluster resulted in developmental defects in cell movement, germ layer specification, axis patterning and organ progenitor formation in zebrafish. Transcriptome analysis indicated that the maternally provided transcripts were not properly degraded whereas the zygotic genome expressed genes were not fully activated in the miR-430 mutants. We further found that a reciprocal regulatory loop exists between miR-430 and maternally provided transcripts: the maternally provided transcripts (Nanog, Dicer1, Dgcr8, and AGOs) are required for miR-430 biogenesis and function, whereas miR-430 is required for the clearance of these maternally provided transcripts. These data provide the first genetic evidence that miR-430 is required for maternal-zygotic transition and subsequent establishment of embryonic body plan.

| S-EPMC7417628 | biostudies-literature

Imprinted gene Zinc finger protein 127 is a novel regulator of master pluripotency transcription factor, Oct4.

Project description:Induced pluripotent stem cells (iPSCs) show great promise for replacing current stem cell therapies in the field of regenerative medicine. However, the original method for cellular reprogramming, involving four exogenous transcription factors, is characterized by low efficiency. Here, we focused on using epigenetic modifications to enhance the reprogramming efficiency. We hypothesized that there would be a new reprogramming factor involved in DNA demethylation, acting on the promoters of pluripotency-related genes. We screened proteins that bind to the methylated promoter of Oct4 and identified Zinc finger protein 127 (Zfp127), the functions of which have not yet been identified. We found that Zfp127 binds to the Oct4 promoter. Overexpression of Zfp127 in fibroblasts induced demethylation of the Oct4 promoter, thus enhancing Oct4 promoter activity and gene expression. These results demonstrate that Zfp127 is a novel regulator of Oct4, and may become a potent target to improve cellular reprogramming. [BMB Reports 2018; 51(5): 242-248].

| S-EPMC5988579 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data