Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA299766 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Regulation of embryonic diapause, dormancy that interrupts the tight connection between develop- mental stage and time, is still poorly understood. Here, we characterize the transcriptional and metabolite profiles of mouse diapause embryos and identify unique gene expression and metabolic signatures with activated lipolysis, glycolysis, and metabolic pathways regulated by AMPK. Lipolysis is increased due to mTORC2 repression, increasing fatty acids to support cell survival. We further show that starvation in pre-implantation ICM-derived mouse ESCs induces a reversible dormant state, transcriptionally mimicking the in vivo diapause stage. During starvation, Lkb1, an upstream kinase of AMPK, represses mTOR, which induces a revers- ible glycolytic and epigenetically H4K16Ac-negative, diapause-like state. Diapause furthermore activates expression of glutamine transporters SLC38A1/2. We show by genetic and small molecule inhibitors that glutamine transporters are essential for the H4K16Ac-negative, diapause state. These data sug- gest that mTORC1/2 inhibition, regulated by amino acid levels, is causal for diapause metabolism and epigenetic state.
2020-01-14 | GSE143494 | GEO
Project description:Dormancy is a key feature of stem cell function in adult tissues as well as embryonic cells in the context of diapause. The establishment of dormancy is an active process that involves extensive transcriptional, epigenetic, and metabolic rewiring. How these processes are coordinated to successfully transition cells to the resting dormant state is not known. Here we show that microRNA activity, which is normally dispensable for pre-implantation development, is essential for the adaptation of early mouse embryos to the dormant state of diapause. In particular, the pluripotent epiblast depends on miRNA activity, the absence of which results in loss of pluripotency and embryo collapse. Through tissue-specific small RNA profiling of single embryos and computational analyses of miRNA targets, we identified the miRNA-protein network of diapause. Individual miRNA function contributes to combinatorial regulation by the network of most notably RNA processing and chromatin modifier proteins. Without miRNAs, multiple nuclear and cytoplasmic bodies show aberrant expression and structure in normal ESCs and fail to reorganize in response to stress. We find extensive alternative splicing in wild-type, but not miRNA-deficient ESCs, of cell cycle and metabolic regulators. Our results reveal that miRNAs are critical for the transcriptional and structural rewiring of pluripotent cells in response to stress and to establish dormancy in the pluripotent state.
2024-03-26 | PXD044550 | Pride
Project description:A Myc-mediated dormant state of naive ESCs
| PRJEB8752 | ENA
Project description:Here, we molecularly defined embryonic diapause at single-cell resolution, revealing hidden transcriptional dynamics while seemingly the embryo resides in a state of suspended animation. Alongside, we found that the dormant pluripotent cells are “aware” of their microenvironment which sustains their viability via Yap-mediated mechanotransduction.
2024-06-18 | GSE241462 | GEO
Project description:Cells and organisms can enter transient dormant states to survive unfavorable conditions during development, physiological adult states and disease. One paradigmatic case of dormancy is diapause, whereby embryos transiently pause development and enter a state of suspended animation. In mammals, diapause occurs pre-implantation at the blastocyst state and involves global growth suppression and metabolic rewiring towards lipid usage as energy source. The molecular regulation of diapause remains poorly understood, including whether it occurs by default or requires active signaling. Here, we identify the canonical TGF-β signaling pathway as an essential driver of transcriptional and metabolic reprogramming in diapause. TGF-β signaling was thought to only be required post-implantation, but we show that the ligand Nodal and its downstream effector Smad2 are essential for the survival of paused embryonic stem cells (ESCs) and blastocysts. Mechanistically, we found that Smad2 represses a Pparg, a transcription factor that is a master regulator of lipid storage, a process incompatible with pausing. Ablation of Pparg in Smad2-deficient ESCs rescues their survival and prevents excess lipid buildup in pausing conditions. These findings establish Nodal/Smad2 signaling as pivotal for sustaining embryonic diapause and suggest that the crosstalk between TGF-β signaling and the Pparg pathway may be broadly relevant for metabolic rewiring in dormancy contexts.
2026-06-22 | GSE302996 | GEO
Project description:Cells and organisms can enter transient dormant states to survive unfavorable conditions during development, physiological adult states and disease. One paradigmatic case of dormancy is diapause, whereby embryos transiently pause development and enter a state of suspended animation. In mammals, diapause occurs pre-implantation at the blastocyst state and involves global growth suppression and metabolic rewiring towards lipid usage as energy source. The molecular regulation of diapause remains poorly understood, including whether it occurs by default or requires active signaling. Here, we identify the canonical TGF-β signaling pathway as an essential driver of transcriptional and metabolic reprogramming in diapause. TGF-β signaling was thought to only be required post-implantation, but we show that the ligand Nodal and its downstream effector Smad2 are essential for the survival of paused embryonic stem cells (ESCs) and blastocysts. Mechanistically, we found that Smad2 represses a Pparg, a transcription factor that is a master regulator of lipid storage, a process incompatible with pausing. Ablation of Pparg in Smad2-deficient ESCs rescues their survival and prevents excess lipid buildup in pausing conditions. These findings establish Nodal/Smad2 signaling as pivotal for sustaining embryonic diapause and suggest that the crosstalk between TGF-β signaling and the Pparg pathway may be broadly relevant for metabolic rewiring in dormancy contexts.
2026-06-22 | GSE302766 | GEO
Project description:Cells and organisms can enter transient dormant states to survive unfavorable conditions during development, physiological adult states and disease. One paradigmatic case of dormancy is diapause, whereby embryos transiently pause development and enter a state of suspended animation. In mammals, diapause occurs pre-implantation at the blastocyst state and involves global growth suppression and metabolic rewiring towards lipid usage as energy source. The molecular regulation of diapause remains poorly understood, including whether it occurs by default or requires active signaling. Here, we identify the canonical TGF-β signaling pathway as an essential driver of transcriptional and metabolic reprogramming in diapause. TGF-β signaling was thought to only be required post-implantation, but we show that the ligand Nodal and its downstream effector Smad2 are essential for the survival of paused embryonic stem cells (ESCs) and blastocysts. Mechanistically, we found that Smad2 represses a Pparg, a transcription factor that is a master regulator of lipid storage, a process incompatible with pausing. Ablation of Pparg in Smad2-deficient ESCs rescues their survival and prevents excess lipid buildup in pausing conditions. These findings establish Nodal/Smad2 signaling as pivotal for sustaining embryonic diapause and suggest that the crosstalk between TGF-β signaling and the Pparg pathway may be broadly relevant for metabolic rewiring in dormancy contexts.
2026-06-22 | GSE303716 | GEO
Project description:Embryonic stem cell (ESC) cultures display a heterogeneous gene expression profile, ranging from a pristine naïve pluripotent state to a primed epiblast state. While it is known that the addition of inhibitors of GSK3β and MEK (so-called 2i conditions) push ESC cultures towards a more homogeneous naïve pluripotent state, the molecular underpinnings of this naïve transition are not completely understood. Here we demonstrate that Dazl, a RNA-binding protein previously thought to be expressed specifically in developing primordial germ cells (PGCs), marks a subpopulation of ESCs in vitro that is actively transitioning toward naïve pluripotency. In the absence of Dazl expression, ESCs fail to induce proper expression of Tet enzymes required for 5-hydroxymethylation in 2i-culture conditions. As a result, 5-hydroxymethylation of methylated cystosine residues is impaired. Indeed, we demonstrate that Tet1 and Tet2 are mRNA targets of Dazl, indicating that Dazl might play a role in protection or stabilizing these mRNA molecules. Our results provide insight in the regulation of the acquisition of naïve pluripotency and demonstrate that Dazl is required for TET-mediated cytosine hydroxymethylation in cells that are actively reprogramming to a pluripotent ground state. RNA-IP experiments were used to identify the RNA species bound to DAZL.
2015-07-01 | E-GEOD-69356 | biostudies-arrayexpress
Project description:The ground state of pluripotency is defined as a minimal unrestricted state as present in the Inner Cell Mass (ICM). Mouse embryonic stem cells (ESCs) grown in a defined serum-free medium with two kinase inhibitors (‘2i’) reflect this state, whereas ESCs grown in the presence of serum (‘serum’) share more similarities with post implantation epiblast cells. Pluripotency results from an intricate interplay between cytoplasmic, nuclear and chromatin-associated proteins. Therefore, quantitative information on the (sub)cellular proteome is essential to gain insight in the molecular mechanisms driving different pluripotent states. Here, we describe a full SILAC workflow and quality controls for proteomic comparison of 2i and serum ESCs. We demonstrate that this workflow is applicable for subcellular proteomics of the cytoplasm, nuclear and chromatin. The obtained quantitative information revealed increased levels of naïve pluripotency factors on the chromatin of 2i ESCs. Further, we demonstrate that these pluripotent states are supported by distinct metabolic programs, which include upregulation of free radical buffering by the glutathione pathway in 2i ESCs. Through induction of intracellular radicals, we show that the altered metabolic environment renders 2i ESCs less sensitive to oxidative stress. Altogether, this work provides novel insights into the proteome landscape underlying ground state pluripotency.
2018-11-07 | PXD009217 | Pride
Project description:Embryonic stem cells (ESCs) can be maintained in the naïve state through inhibition of Mek1/2 and Gsk3 (2i). A relevant effect of 2i is the inhibition of Cdk8/19, which are negative regulators of the Mediator complex, responsible for the activity of enhancers. Inhibition of Cdk8/19 (Cdk8/19i) stimulates enhancers and, similar to 2i, stabilizes ESCs in the naïve state. Here, we use mass spectrometry to describe the molecular events (phosphoproteome, proteome, and metabolome) triggered by 2i and Cdk8/19i on ESCs. Our data reveal widespread commonalities between these two treatments, suggesting overlapping processes. We find that post-transcriptional de-repression by both 2i and Cdk8/19i might support the mitochondrial capacity of naive cells. However, proteome reprogramming in each treatment is achieved by different mechanisms. Cdk8/19i acts directly on the transcriptional machinery, activating key identity genes to promote the naïve program. In contrast, 2i stabilizes the naïve circuitry through, in part, de-phosphorylation of downstream transcriptional effectors.
2021-02-10 | MTBLS301 | MetaboLights