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Combinatorial Smad2/3 Activities Downstream of Nodal Signaling Maintain Embryonic/Extra-Embryonic Cell Identities during Lineage Priming [RNA-Seq]

ABSTRACT: Epiblast cells in the early post-implantation stage mammalian embryo undergo a transition described as lineage priming before cell fate allocation, but signaling pathways acting upstream remain ill defined. Genetic studies demonstrate that Smad2/3 double-mutant mouse embryos die shortly after implantation. To learn more about the molecular disturbances underlying this abrupt failure, here we characterised Smad2/3-deificient embryonic stem cells (ESCs). We found that Smad2/3 double-knockout ESCs induced to form epiblast-like cells (EpiLCs) display changes in naïve and primed pluripotency marker gene expression, associated with the disruption of Oct4-bound distal regulatory element. In the absence of Smad2/3, we observed enhanced Bmp target gene expression and de-repression of extra-embryonic gene expression. Cell fate allocation into all three embryonic germ lakers is disrupted. Collectively, these experiments demonstrate that combinatorial Smad2/3 functional activities are required to maintain distinct embryonic and/or extra-embryonic cell identity during lineage priming in the epiblast before gastrulation.

ORGANISM(S): Mus musculus

PROVIDER: GSE110163 | GEO | 2018/08/14

REPOSITORIES: GEO

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Combinatorial Smad2/3 Activities Downstream of Nodal Signaling Maintain Embryonic/Extra-Embryonic Cell Identities during Lineage Priming [array]

Project description:Epiblast cells in the early post-implantation stage mammalian embryo undergo a transition described as lineage priming before cell fate allocation, but signaling pathways acting upstream remain ill defined. Genetic studies demonstrate that Smad2/3 double-mutant mouse embryos die shortly after implantation. To learn more about the molecular disturbances underlying this abrupt failure, here we characterised Smad2/3-deificient embryonic stem cells (ESCs). We found that Smad2/3 double-knockout ESCs induced to form epiblast-like cells (EpiLCs) display changes in naïve and primed pluripotency marker gene expression, associated with the disruption of Oct4-bound distal regulatory element. In the absence of Smad2/3, we observed enhanced Bmp target gene expression and de-repression of extra-embryonic gene expression. Cell fate allocation into all three embryonic germ lakers is disrupted. Collectively, these experiments demonstrate that combinatorial Smad2/3 functional activities are required to maintain distinct embryonic and/or extra-embryonic cell identity during lineage priming in the epiblast before gastrulation.

2018-08-14 | GSE110058 | GEO

Combinatorial Smad2/3 Activities Downstream of Nodal Signaling Maintain Embryonic/Extra-Embryonic Cell Identities during Lineage Priming [ATAC-Seq]

2018-08-14 | GSE110162 | GEO

Differentiation to extra-embryonic primitive endoderm from naïve human ESCs on mouse embryonic fibroblasts (MEFs) or laminin-511 (LN511) substrates

Project description:Embryonic stem cells (ESCs) can exist in at least two states that transcriptionally resemble different stages of embryonic development. Naïve ESCs resemble peri-implantation stages and primed ESCs the pre-gastrulation epiblast. In mouse, primed ESCs give rise to definitive endoderm in response to pathways downstream of Nodal and Wnt signalling. However, when these cytokines are applied to naïve ESCs, they differentiate to a cell type that approximates early primitive endoderm (PrE), the blastocyst stage progenitor layer that gives rise to the extra-embryonic endoderm. Here, we apply this context dependency to human ESCs, showing that these cytokines drive the differentiation of naïve pluripotent cells to generate extra-embryonic PrE, or hypoblast, and, as in mouse, expanded as an in vitro model for naïve extra-embryonic endoderm (nEnd) in defined conditions. Consistent with observations made in mouse, human PrE differentiation is dependent on FGF signalling in vitro, and we show, that by inhibiting FGF receptor signalling, we could simplify naïve pluripotent culture such that inhibitor requirements closer resembled those used in mouse. These nEnd cultures represent stable extra-embryonic endoderm, or human hypoblast, cell lines.

2019-11-30 | GSE138013 | GEO

Naïve human pluripotency stem cells respond to Wnt, Nodal and LIF signalling to produce expandable naïve extra-embryonic endoderm

2019-11-30 | GSE138012 | GEO

REX1 is the critical target of RNF12 in imprinted X chromosome inactivation in mice.

Project description:In mice, imprinted X-chromosome inactivation (iXCI) of the paternal X in the pre-implantation embryo and extra-embryonic tissues is followed by X-reactivation in the epiblast precursors of the inner cell mass (ICM) of the blastocyst, to facilitate initiation of random XCI (rXCI) in all embryonic tissues. RNF12 is an E3 ubiquitin-ligase that plays a key role in XCI. RNF12 targets pluripotency protein REX1 for degradation to initiate rXCI in embryonic stem cells (ESCs) and loss of the maternal copy of Rnf12 leads to embryonic lethality due to iXCI failure. Here, we show that loss of Rex1 rescues the rXCI phenotype observed in Rnf12-/- ESCs, and that REX1 is the prime target of RNF12 in ESCs. Genetic ablation of Rex1 in Rnf12-/- mice rescues the Rnf12-/- iXCI phenotype, and results in viable and fertile Rnf12-/-:Rex1-/- female mice displaying normal iXCI and rXCI. Our results show that REX1 is the critical target of RNF12 in XCI.

2018-11-15 | PXD010944 | Pride

Dynamic proteomic profiling of extra-embryonic endoderm differentiation in mouse embryonic stem cells

Project description:During mammalian pre-implantation development, the cells of the blastocyst’s inner cell mass differentiate into the epiblast and primitive endoderm lineages, which give rise to the fetus and extra-embryonic tissues, respectively. Extra-embryonic endoderm differentiation can be modeled in vitro by induced expression of GATA transcription factors in mouse embryonic stem cells. Here we use this GATA-inducible system to quantitatively monitor the dynamics of global proteomic changes during the early stages of this differentiation event and also investigate the fully differentiated phenotype, as represented by embryo-derived extra-embryonic endoderm (XEN) cells. Using mass spectrometry-based quantitative proteomic profiling with multivariate data analysis tools, we reproducibly quantified 2,336 proteins across three biological replicates and have identified clusters of proteins characterized by distinct, dynamic temporal abundance profiles. We first used this approach to highlight novel marker candidates of the pluripotent state and extra-embryonic endoderm differentiation. Through functional annotation enrichment analysis, we have shown that the downregulation of chromatin-modifying enzymes, the re-organization of membrane trafficking machinery and the breakdown of cell-cell adhesion are successive steps of the extra-embryonic differentiation process. Thus, applying a range of sophisticated clustering approaches to a time-resolved proteomic dataset has allowed the elucidation of complex biological processes which characterize stem cell differentiation and could establish a general paradigm for the investigation of these processes.

2015-06-13 | PXD001901 | Pride

Jmjd2c/Kdm4c facilitates the assembly of essential enhancer-protein complexes at the onset of embryonic stem cell differentiation

Project description:Jmjd2/Kdm4 H3K9-demethylases cooperate in promoting mouse embryonic stem cell (ESC) identity. However, little is known about their importance at the exit of ESC pluripotency. Here, we uncover that Jmjd2c facilitates this process by stabilizing the assembly of Mediator-Cohesin complexes at lineage-specific enhancers. Functionally, we show that Jmjd2c is required in ESCs to initiate appropriate gene expression programs upon somatic multi-lineage differentiation. In the absence of Jmjd2c, differentiation is stalled at an early post-implantation epiblast-like stage, while Jmjd2c-knockout ESCs remain capable of forming extra-embryonic endoderm derivatives. Dissection of the underlying molecular basis revealed that Jmjd2c is re-distributed to lineage-specific enhancers during ESC priming for differentiation. Interestingly, Jmjd2c-bound enhancers are co-occupied by the H3K9-methyltransferase G9a/Ehmt2, independently of its H3K9-modifying activity. Loss of Jmjd2c abrogates G9a recruitment and furthermore destabilizes loading of the Mediator and Cohesin components Med1 and Smc1a at newly activated and poised enhancers in ESC-derived epiblast-like cells. These findings unveil Jmjd2c-G9a as novel enhancer-associated factors, and implicate Jmjd2c as a molecular scaffold for the assembly of essential enhancer-protein complexes with impact on timely gene activation.

2017-01-18 | GSE93721 | GEO

Combinatorial Smad2/3 Activities Downstream of Nodal Signaling Maintain Embryonic/Extra-Embryonic Cell Identities during Lineage Priming

Project description:Combinatorial Smad2/3 Activities Downstream of Nodal Signaling Maintain Embryonic/Extra-Embryonic Cell Identities during Lineage Priming

| PRJNA432991 | ENA

Lineage-specific functions of TET1 in the post-implantation mouse embryo

Project description:The TET dioxygenases erase mediate DNA dedemethylation in pre-implantation embryos and in primordial germ cells, yet limited studies address their contribution to the global gain of DNA methylation following implantation. Here, we show that Tet1 is expressed and non-redundantly contributes to 5-hydroxymethylctyosine (5hmC) non-redundantly in the pre-gastrulation mouse epiblast. Ablation of Tet1 in primed epiblast cells results in widespread loss of 5hmC associated with gain of 5-methylcytosine at CpG islands and promoters. Moreover, Tet1 is expressed, albeit at lower levels, in the extra-embryonic ectoderm. Tet1-deficiency in the pre-streak mouse embryos causes dysregulation of early lineage regulators in the epiblast and increased expression of metabolic genes in the extra-embryonic ectoderm. Our studies reveal a distinct role of Tet1 in regulating the methylome landscape of the post-implantation mammalian epiblast and a hitherto unknown gene repressive effect in the extra-embryonic lineage, providing insights into the early developmental origins of epigenetic-based basis of imprinting and developmental disorders.

2017-05-15 | GSE71744 | GEO

Transcription Factor Co-Expression Mediates Lineage Priming for Embryonic and Extra-Embryonic Differentiation [CUT&RUN]

Project description:In early mammalian development, cleavage stage blastomeres and cells of the inner cell mass (ICM) of the blastocyst co-express embryonic and extra-embryonic transcriptional determinants. Using a double protein-based reporter we identify embryonic stem cells (ESC) that co-express the extra-embryonic factor GATA6 alongside the embryonic factor SOX2 in specific conditions. Based on single cell transcriptomics we find these population resemble unsegregated ICM, exhibiting enhanced differentiation potential for endoderm while maintaining epiblast competence and suggesting they represent an ideal model to determine how GATA6 and SOX2 influence each other's DNA binding. To relate this binding to future fate, we describe a complete enhancer set in both ESCs and naïve extraembryonic endoderm stem cells and ask whether SOX2 and GATA6 recognize these elements in ICM-like ESC sub-population. Both factors support cooperative recognition in these lineages, with GATA6 bound alongside SOX2 on a fraction of pluripotency enhancers and SOX2 alongside GATA6 more extensively on endoderm enhancers. Our findings suggest that cooperative binding between these antagonistic factors both supports self-renewal and prepares progenitor cells for later differentiation

2023-12-05 | GSE227886 | GEO

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