NANOG initiates epiblast fate through the coordination of pluripotency genes expression

Allègre, Nicolas; Chauveau, Simon; Dennis, Cynthia; Renaud, Yoan; Meistermann, Dimitri; Estrella, Lorena Valverde; Pouchin, Pierre; Cohen-Tannoudji, Michel; David, Laurent; Chazaud, Claire

doi:10.1038/s41467-022-30858-8

Cited by 28 publications

(20 citation statements)

References 108 publications

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“…Additionally, a recent paper reports NANOG dependent coordinated expression of pluripotency related gene expression during the 16-to 32-cell stage transition, suggesting EPI specification may actually originate (in part) in primary ICM founders [74]. Whilst not definitive, these collective data at least support an aspect of developmental history underlying ICM cell fate, that is nonetheless potentially subject to regulative and compensatory mechanisms.…”

Section: Discussionmentioning

confidence: 91%

“…Although previously, we reported clonal inhibition of TE cell fate, using microinjected siRNAs specific for Tead4 transcripts, generates excess ICM contribution favouring EPI and biased against PrE formation, respectively [43]; strongly suggesting an extra ∼12 hours of polarity-dependent Hippo-pathway suppression in outer 16-cell stage blastomeres may prime derived secondary ICM founders to preferentially differentiate towards PrE. Additionally, a recent paper reports NANOG dependent coordinated expression of pluripotency related gene expression during the 16-to 32-cell stage transition, suggesting EPI specification may actually originate (in part) in primary ICM founders [74]. Whilst not definitive, these collective data at least support an aspect of developmental history underlying ICM cell fate, that is nonetheless potentially subject to regulative and compensatory mechanisms.…”

Section: Discussionmentioning

confidence: 99%

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Spatial positioning of preimplantation mouse embryo blastomeres is regulated by mTORC1 and 7mG-cap dependent translation at the 8- to 16-cell transition

Gahurová

Tomankova

Cerna

et al. 2023

Preprint

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Preimplantation stages of mouse embryo development involve temporal and spatial specification and segregation of three late blastocyst cell lineages; trophectoderm (TE), primitive endoderm (PrE) and epiblast (EPI). Spatial separation of the outer TE lineage from the two inner cell mass (ICM) lineages (PrE and EPI) starts with the 8- to 16-cell transition and concludes following transit through the 16- to 32-cell stages. This results in an early blastocyst ICM derived from descendants of primary founding inner cells and a secondarily contributed population, of which subsequent relative EPI versus PrE potencies are subject to debate. Here, we report generation of primary but not the secondary ICM populations is highly dependent on temporally discreet activation of the mammalian target of Rapamycin (mTOR, specifically mTORC1) during M-phase entry at the 8-cell stage. This role is mediated via regulation of the 7-methylguanosine- (7mG) cap binding initiation complex (EIF4F), linked to translation of a subset of key mRNAs containing 5[prime] UTR terminal oligopyrimidine (TOP-) or TOP-like sequence motifs; as knockdown of identified TOP-like motif containing transcripts also impairs generation of 16-cell stage primary ICM founders. However, mTOR inhibition induced ICM cell number deficits at the early blastocyst stage can be compensated by the late blastocyst stage, in the absence of inhibition. This compensation is likely initiated at the 32-cell stage when supernumerary outer cells in mTOR-inhibited embryos exhibit molecular characteristics of inner cells. Collectively, the data identify a novel mechanism specifically governing initial spatial segregation of blastomeres in the mouse embryo, that is distinct from those directing subsequent inner cell formation and contributes to germane segregation of late blastocyst lineages.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Spatial positioning of preimplantation mouse embryo blastomeres is regulated by mTORC1 and 7mG-cap dependent translation at the 8- to 16-cell transition

Gahurová

Tomankova

Cerna

et al. 2023

Preprint

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“…Genes implicated in the literature to correspond with 13 of our cell type annotations are represented in the 3012 cESFW gene set (Cockburn and Rossant 2010; Taubenschmid-Stowers et al 2022; Giuliano G. Stirparo et al 2018; M. Singh et al 2023; Corujo-Simon, A. H. Radley, and Nichols 2023; Liu et al 2022; Zadora et al 2017; Yue et al 2020; Yabe et al 2016; Yang et al 2021). Such genes show specific gene expression in the UMAP embedding (Fig 3E, Fig 5A Fig S3).…”

Section: Resultsmentioning

confidence: 99%

“…Cells in these clusters become specified to alternative fates but may not be committed. For example, PDGFRA has been implicated as a hypoblast marker (Corujo-Simon, A. H. Radley, and Nichols 2023), whereas NANOG has been demonstrated as an epiblast marker (Allègre et al 2022), yet both markers are heterogeneous in Epi/Hyp branching population. Notably the cluster boundaries extend beyond the topological branch point, which may indicate that cells remain plastic and could be respecified.…”

Section: Discussionmentioning

confidence: 99%

Branching topology of the human embryo transcriptome revealed by entropy sort feature weighting

Radley,

Smith

2023

Preprint

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Single cell transcriptomics (scRNA-seq) transforms our capacity to define cell states and reveal developmental trajectories. Resolution is challenged, however, by high dimensionality and noisy data. Analysis is therefore typically performed after sub-setting to highly variable genes (HVGs). However, existing HVG selection techniques have been found to have poor agreement with one another, and tend to be biased towards highly expressed genes. Entropy sorting provides an alternative mathematical framework for feature subset selection. Here we implement continuous entropy sort feature weighting (cESFW). On synthetic datasets, cESFW outperforms HVG selection in distinguishing cell state specific genes. We apply cESFW to six merged scRNA-seq datasets spanning human early embryo development. Without smoothing or augmenting the raw counts matrices, cESFW generates a high-resolution embedding displaying coherent developmental progression from 8-cell to post-implantation stages, delineating 15 distinct cell states. The embedding highlights sequential lineage decisions during blastocyst development while unsupervised clustering identifies branch point populations. Cells previously claimed to lack a developmental trajectory reside in the first branching region where morula differentiates into Inner Cell Mass (ICM) or Trophectoderm (TE). We quantify the relatedness of pluripotent stem cell cultures to embryo cell types and identify naïve and primed marker genes conserved across culture conditions and the human embryo. Finally, by identifying genes with specifically enriched and dynamic expression during blastocyst formation, we provide markers for staging lineage progression from morula to blastocyst. Together these analyses indicates that cESFW provides the ability to reveal gene expression dynamics in scRNA-seq data that HVG selection may can to elucidate.

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“…The exit from naïve pluripotency in vivo is accompanied by a substantial increase in molecular and phenotypic cell heterogeneity. Cellular heterogeneity, in terms of gene expression and morphology, was observed since the formation of the ICM in mouse blastocysts [ 62 , 63 , 64 ]. Similar changes accompany the transition from naïve ESCs to PiCs as well as the generation of other intermediate states of pluripotency, including RSCs [ 3 ] and intermediate epiblast stem cells (IESCs) [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

Capturing Transitional Pluripotency through Proline Metabolism

Minchiotti

D’Aniello

Fico

et al. 2022

Cells

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In this paper, we summarize the current knowledge of the role of proline metabolism in the control of the identity of Embryonic Stem Cells (ESCs). An imbalance in proline metabolism shifts mouse ESCs toward a stable naïve-to-primed intermediate state of pluripotency. Proline-induced cells (PiCs), also named primitive ectoderm-like cells (EPLs), are phenotypically metastable, a trait linked to a rapid and reversible relocalization of E-cadherin from the plasma membrane to intracellular membrane compartments. The ESC-to-PiC transition relies on the activation of Erk and Tgfβ/Activin signaling pathways and is associated with extensive remodeling of the transcriptome, metabolome and epigenome. PiCs maintain several properties of naïve pluripotency (teratoma formation, blastocyst colonization and 3D gastruloid development) and acquire a few traits of primed cells (flat-shaped colony morphology, aerobic glycolysis metabolism and competence for primordial germ cell fate). Overall, the molecular and phenotypic features of PiCs resemble those of an early-primed state of pluripotency, providing a robust model to study the role of metabolic perturbations in pluripotency and cell fate decisions.

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NANOG initiates epiblast fate through the coordination of pluripotency genes expression

Cited by 28 publications

References 108 publications

Spatial positioning of preimplantation mouse embryo blastomeres is regulated by mTORC1 and 7mG-cap dependent translation at the 8- to 16-cell transition

Spatial positioning of preimplantation mouse embryo blastomeres is regulated by mTORC1 and 7mG-cap dependent translation at the 8- to 16-cell transition

Branching topology of the human embryo transcriptome revealed by entropy sort feature weighting

Capturing Transitional Pluripotency through Proline Metabolism

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