scholarly journals An interplay between extracellular signalling and the dynamics of the exit from pluripotency drives cell fate decisions in mouse ES cells

Biology Open ◽  
2014 ◽  
Vol 3 (7) ◽  
pp. 614-626 ◽  
Author(s):  
D. A. Turner ◽  
J. Trott ◽  
P. Hayward ◽  
P. Rue ◽  
A. Martinez Arias
Keyword(s):  
Cell Fate ◽  
Es Cells ◽  
Cell Fate Decisions ◽  
Mouse Es Cells ◽  
Extracellular Signalling

scholarly journals An interplay between extracellular signalling and the dynamics of the exit from pluripotency drives cell fate decisions in mouse ES cells

2013 ◽  
Author(s):  
David A Turner ◽  
Jamie Trott ◽  
Penelope Hayward ◽  
Pau Rué ◽  
Alfonso Martinez Arias
Keyword(s):  
Cell Fate ◽  
Neural Development ◽  
Es Cells ◽  
Initial Period ◽  
Embryonic Stem ◽  
Primitive Streak ◽  
Wnt Signalling ◽  
Dependent Manner ◽  
Cell Fate Decisions ◽  
Mouse Es Cells

Embryonic Stem cells derived from the epiblast tissue of the mammalian blastocyst retain the capability to differentiate into any adult cell type and are able to self-renew indefinitely under appropriate culture conditions. Despite the large amount of knowledge that we have accumulated to date about the regulation and control of self-renewal, efficient directed differentiation into specific tissues remains elusive. In this work, we have analysed in a systematic manner the interaction between the dynamics of loss of pluripotency and Activin/Nodal, BMP4 and Wnt signalling in fate assignment during the early stages of differentiation of mouse ES cells in culture. During the initial period of differentiation, cells exit from pluripotency and enter an Epi-like state. Following this transient stage, and under the influence of Activin/Nodal and BMP signalling, cells face a fate choice between differentiating into neuroectoderm and contributing to Primitive Streak fates. We find that Wnt signalling does not suppress neural development as previously thought and that it aids both fates in a context dependent manner. Our results suggest that as cells exit pluripotency they are endowed with a primary neuroectodermal fate and that the potency to become endomesodermal rises with time. We suggest that this situation translates into a ?race for fates? in which the neuroectodermal fate has an advantage.

scholarly journals TERRA regulate the transcriptional landscape of pluripotent cells through TRF1-dependent recruitment of PRC2

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Rosa María Marión ◽  
Juan J Montero ◽  
Isabel López de Silanes ◽  
Osvaldo Graña-Castro ◽  
Paula Martínez ◽  
...  
Keyword(s):  
Cell Fate ◽  
Es Cells ◽  
Epigenetic Changes ◽  
Pluripotent Cells ◽  
Telomere Repeat ◽  
Mouse Es Cells ◽  
Genome Wide ◽  
Binding Factor ◽  
Transcriptional Landscape ◽  
Pluripotency Genes

The mechanisms that regulate pluripotency are still largely unknown. Here, we show that Telomere Repeat Binding Factor 1 (TRF1), a component of the shelterin complex, regulates the genome-wide binding of polycomb and polycomb H3K27me3 repressive marks to pluripotency genes, thereby exerting vast epigenetic changes that contribute to the maintenance of mouse ES cells in a naïve state. We further show that TRF1 mediates these effects by regulating TERRA, the lncRNAs transcribed from telomeres. We find that TERRAs are enriched at polycomb and stem cell genes in pluripotent cells and that TRF1 abrogation results in increased TERRA levels and in higher TERRA binding to those genes, coincidental with the induction of cell-fate programs and the loss of the naïve state. These results are consistent with a model in which TRF1-dependent changes in TERRA levels modulate polycomb recruitment to pluripotency and differentiation genes. These unprecedented findings explain why TRF1 is essential for the induction and maintenance of pluripotency.

scholarly journals Endogenous fluctuations of OCT4 and SOX2 bias pluripotent cell fate decisions

2018 ◽  
Author(s):  
Daniel Strebinger ◽  
Cédric Deluz ◽  
Elias T. Friman ◽  
Subashika Govindan ◽  
Andrea B. Alber ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cell Fate ◽  
Es Cells ◽  
Embryonic Stem ◽  
Chromatin Accessibility ◽  
Directed Differentiation ◽  
Es Cell ◽  
Endogenous Fluctuations ◽  
Cell Fate Decisions ◽  
Oct4 Protein

AbstractSOX2 and OCT4 are pioneer transcription factors playing a key role in embryonic stem (ES) cell self-renewal and differentiation. However, how temporal fluctuations in their expression levels bias lineage commitment is unknown. Here we generated knock-in reporter fusion ES cell lines allowing to monitor endogenous SOX2 and OCT4 protein fluctuations in living cells and to determine their impact on mesendodermal and neuroectodermal commitment. We found that small differences in SOX2 and OCT4 levels impact cell fate commitment in G1 but not in S phase. Elevated SOX2 levels modestly increased neuroectodermal commitment and decreased mesendodermal commitment upon directed differentiation. In contrast, elevated OCT4 levels strongly biased ES cell towards both neuroectodermal and mesendodermal fates. Using ATAC-seq on ES cells gated for different endogenous SOX2 and OCT4 levels, we found that high OCT4 levels increased chromatin accessibility at differentiation-associated enhancers. This suggests that small endogenous fluctuations of pioneer transcription factors can bias cell fate decisions by concentration-dependent priming of differentiation-associated enhancers.

scholarly journals Cleavage of histone H2A during embryonic stem cell differentiation destabilizes nucleosomes to counteract gene activation

2021 ◽  
Author(s):  
Mariel Coradin ◽  
Joseph Cesare ◽  
Yemin Lan ◽  
Zhexin Zhu ◽  
Peder J. Lund ◽  
...  
Keyword(s):  
Cell Fate ◽  
Es Cells ◽  
Expression Patterns ◽  
Gene Activation ◽  
Embryonic Stem ◽  
Maximum Level ◽  
Stem Cell Differentiation ◽  
Embryonic Stem Cell Differentiation ◽  
Cell Fate Decisions ◽  
Lysosomal Protease

Histone proteolysis is a poorly understood phenomenon in which the N-terminal tails of histones are irreversibly cleaved by intracellular proteases. During development, histone post-translational modifications are known to orchestrate gene expression patterns that ultimately drive cell fate decisions. Therefore, deciphering the mechanisms of histone proteolysis is necessary to enhance the understanding of cellular differentiation. Here we show that H2A is cleaved by the lysosomal protease Cathepsin L during ESCs differentiation. Using quantitative mass spectrometry (MS), we identified L23 to be the primary cleavage site that gives rise to the clipped form of H2A (cH2A), which reaches a maximum level of ~1% of total H2A after four days of differentiation. Using ChIP-seq, we found that preventing proteolysis leads to an increase in acetylated H2A at promoter regions in differentiated ES cells. We also report the identification of novel readers of acetylated H2A in pluripotent ES cells, including members of the PBAF remodeling complex, which can recognize different acetylated forms of H2A. Finally, we show that H2A proteolysis abolishes this recognition. Altogether, our data suggests that proteolysis serves as an efficient mechanism to silence pluripotency genes and destabilize the nucleosome core particle.

scholarly journals The activation of a Suv39h1-repressive antisense lncRNA by OCT4 couples the control of H3K9 methylation to pluripotency

2021 ◽  
Author(s):  
Laure D. Bernard ◽  
Agnès Dubois ◽  
Victor Heurtier ◽  
Almira Chervova ◽  
Alexandra Tachtsidi ◽  
...  
Keyword(s):  
Cell Fate ◽  
Es Cells ◽  
Embryonic Stem ◽  
H3k9 Methylation ◽  
Targeted Deletion ◽  
Mouse Es Cells ◽  
Non Coding Rna ◽  
Fate Restriction ◽  
In Cis ◽  
Long Non Coding Rna

Histone H3 Lysine 9 (H3K9) methylation, a characteristic mark of heterochromatin, is progressively implemented during development to contribute to cell fate restriction as differentiation proceeds. For instance, in pluripotent mouse Embryonic Stem (ES) cells the global levels of H3K9 methylation are rather low and increase only upon differentiation. Conversely, H3K9 methylation represents an epigenetic barrier for reprogramming somatic cells back to pluripotency. How global H3K9 methylation levels are coupled with the acquisition and loss of pluripotency remains largely unknown. Here, we identify SUV39H1, a major H3K9 di- and tri-methylase, as an indirect target of the pluripotency network of Transcription Factors (TFs). We find that pluripotency TFs, principally OCT4, activate the expression of an uncharacterized antisense long non-coding RNA to Suv39h1, which we name Suv39h1as. In turn, Suv39h1as downregulates Suv39h1 transcription in cis via a mechanism involving the modulation of the chromatin status of the locus. The targeted deletion of the Suv39h1as promoter region triggers increased SUV39H1 expression and H3K9me2 and H3K9me3 levels, leading to accelerated and more efficient commitment into differentiation. We report, therefore, a simple genetic circuitry coupling the global levels of H3K9 methylation to pluripotency in mouse ES cells.

Transcriptional heterogeneity in mouse embryonic stem cells

2009 ◽  
Vol 21 (1) ◽  
pp. 67 ◽  
Author(s):  
Tetsuya S. Tanaka
Keyword(s):  
Cell Fate ◽  
Es Cells ◽  
Embryonic Stem ◽  
Cell Types ◽  
The Body ◽  
Cell Subpopulation ◽  
Es Cell ◽  
Differentiation Potential ◽  
Mouse Es Cells

The embryonic stem (ES) cell is a stem cell derived from early embryos that can indefinitely repeat self-renewing cell division cycles as an undifferentiated cell in vitro and give rise to all specialised cell types in the body. However, manipulating ES cell differentiation in vitro is a challenge due to, at least in part, heterogeneous gene induction. Recent experimental evidence has demonstrated that undifferentiated mouse ES cells maintained in culture exhibit heterogeneous expression of Dppa3, Nanog, Rex1, Pecam1 and Zscan4 as well as genes (Brachyury/T, Rhox6/9 and Twist2) normally expressed in specialised cell types. The Nanog-negative, Rex1-negative or T-positive ES cell subpopulation has a unique differentiation potential. Thus, studying the mechanism that generates ES cell subpopulations will improve manipulation of ES cell fate and help our understanding of the nature of embryonic development.

scholarly journals Abscission couples cell division to embryonic stem cell fate

2019 ◽  
Author(s):  
Agathe Chaigne ◽  
Celine Labouesse ◽  
Meghan Agnew ◽  
Edouard Hannezo ◽  
Kevin J Chalut ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Division ◽  
Cell Fate ◽  
Es Cells ◽  
Embryonic Stem ◽  
Strongly Correlated ◽  
Cellular Mechanisms ◽  
Mouse Es Cells ◽  
Cytoplasmic Bridges

Cell fate transitions are key to development and homeostasis. It is thus essential to understand the cellular mechanisms controlling fate transitions. Cell division has been implicated in fate decisions in many stem cells, including neuronal and epithelial progenitors. In other stem cells, such as embryonic stem (ES) cells, the role of division remains unclear. Here we show that exit from naïve pluripotency in mouse ES cells generally occurs after a division. We further show that exit timing is strongly correlated between sister cells, which remain connected by cytoplasmic bridges long after division, and that bridge abscission progressively accelerates as cells exit naïve pluripotency. Finally, interfering with abscission impairs exit from naïve pluripotency. Altogether, our data indicate that a switch in the division machinery leading to faster abscission is crucial for pluripotency exit. Our study identifies abscission as a key step coupling cell division to fate transitions.

scholarly journals FGF/MAPK signaling sets the switching threshold of a bistable circuit controlling cell fate decisions in ES cells

2015 ◽  
Author(s):  
Christian Schröter ◽  
Pau Rué ◽  
Jonathan P Mackenzie ◽  
Alfonso Martinez Arias
Keyword(s):  
Cell Fate ◽  
Network Architecture ◽  
Cell Model ◽  
Es Cells ◽  
Embryonic Stem ◽  
Transcriptional Regulators ◽  
Mapk Signaling ◽  
Threshold Concentration ◽  
Cell Fates ◽  
Cell Fate Decisions

Intracellular transcriptional regulators and extracellular signaling pathways together regulate the allocation of cell fates during development, but how their molecular activities are integrated to establish the correct proportions of cells with particular fates is not known. Here we study this question in the context of the decision between the epiblast (Epi) and the primitive endoderm (PrE) fate that occurs in the mammalian preimplantation embryo. Using an embryonic stem (ES) cell model, we discover two successive functions of FGF/MAPK signaling in this decision. First, the pathway needs to be inhibited to make the PrE-like gene expression program accessible for activation by GATA transcription factors in ES cells. In a second step, MAPK signaling levels determine the threshold concentration of GATA factors required for PrE-like differentiation, and thereby control the proportion of cells differentiating along this lineage. Our findings can be explained by a simple mutual repression circuit modulated by FGF/MAPK signaling. This may be a general network architecture to integrate the activity of signal transduction pathways and transcriptional regulators, and serve to balance proportions of cell fates in several contexts.

scholarly journals Defining Essential Enhancer for Pluripotent stem cells using Features Oriented CRISPR-Cas9 Screen

2019 ◽  
Author(s):  
Hao Fei Wang ◽  
Tushar Warrier ◽  
Chadi EL Farran ◽  
Zheng Zihao ◽  
Qiao Rui Xing ◽  
...  
Keyword(s):  
Cell Fate ◽  
Target Genes ◽  
Es Cells ◽  
Functional Characterization ◽  
Regulatory Elements ◽  
Downstream Target ◽  
Mouse Es Cells ◽  
Cellular Processes ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway

ABSTRACTCis Regulatory Elements (CREs) regulate the expression of the genes in their genomic neighborhoods and influence cellular processes such as cell-fate maintenance and differentiation. To date, there remain major gaps in the functional characterization of CREs and the identification of its target genes in the cellular native environment. In this study, we performed a Features Oriented CRISPR Utilized Systematic (FOCUS) screen of OCT4-bound CREs using CRISPR/Cas9 to identify functional enhancers important for pluripotency maintenance in mouse ES cells. From the initial 235 candidates tested, 16 CREs were identified to be essential stem cell enhancers. Using RNA-seq and genomic 4C-seq, we further uncovered a complex network of candidate CREs and their downstream target genes, which supports the growth and self-renewal of mESCs. Notably, an essential enhancer, CRE111, and its target, Lrrc31, form the important switch to modulate the LIF-JAK1-STAT3 signaling pathway.

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