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| Open AccessQuiescence enables unrestricted cell fate in naive embryonic stem cells
Stem cell quiescence is generally considered as an inactive state with poised potential. Here, Khoa et al. find that quiescent embryonic stem cells actively maintain a dynamic reservoir of cells with unrestricted cell fate that converges on S-adenosylmethionine and H3K27me3 status.
- Le Tran Phuc Khoa
- , Wentao Yang
- & Yali Dou
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| Open AccessMaintenance of pluripotency-like signature in the entire ectoderm leads to neural crest stem cell potential
How the neural crest gains its pluripotency-like stem cell potential is unclear. Here, the authors show that the entire post-gastrula ectoderm maintains expression of pluripotency genes, leading to the high stem cell capacity in the neural crest.
- Ceren Pajanoja
- , Jenny Hsin
- & Laura Kerosuo
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| Open AccessUnreprogrammed H3K9me3 prevents minor zygotic genome activation and lineage commitment in SCNT embryos
H3K9me3 is an epigenetic barrier to the reprogramming of somatic cells to a totipotent state during somatic cell nuclear transfer. Here, the authors uncover molecular mechanisms regulating H3K9me3 modifications in this process.
- Ruimin Xu
- , Qianshu Zhu
- & Xiaoyu Liu
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Article
| Open AccessPlakoglobin is a mechanoresponsive regulator of naive pluripotency
The mechanical microenvironment influences stem cell pluripotency. Here, the authors culture stem cells in microgels with controlled volumetric confinement and identify Plakoglobin as a mechanoresponsive regulator of pluripotency in mouse and human.
- Timo N. Kohler
- , Joachim De Jonghe
- & Florian Hollfelder
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| Open AccessThe nuclear lamina couples mechanical forces to cell fate in the preimplantation embryo via actin organization
Contractile forces are key to sorting the embryonic inner cell mass from the extraembryonic trophectoderm. Here they show that Lamin-A links changes in mechanical forces to cell fate specification, enabling Yap-Cdx2 signaling in outer, but not inner cells.
- Robin M. Skory
- , Adam A. Moverley
- & Nicolas Plachta
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Article
| Open AccessRSL24D1 sustains steady-state ribosome biogenesis and pluripotency translational programs in embryonic stem cells
Pluripotency is coordinated at multiple levels of gene expression. Here the authors show that ribosome biogenesis is tightly regulated in embryonic stem cells (ESC) to control the translation of transcription and chromatin factors and dictate ESC fate.
- Sébastien Durand
- , Marion Bruelle
- & Mathieu Gabut
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Article
| Open AccessMembrane potential drives the exit from pluripotency and cell fate commitment via calcium and mTOR
The plasma membrane’s electrical potential is maintained by ion channels, though the impact of this potential on cell fate has not been clearly elucidated. Here they show that changes in membrane potential can affect calcium levels and mTOR in pluripotent stem cells, altering their transition from pluripotency to differentiation.
- Emily Sempou
- , Valentyna Kostiuk
- & Mustafa K. Khokha
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Article
| Open AccessEvolutionary origin of vertebrate OCT4/POU5 functions in supporting pluripotency
By constructing an evolutionary trajectory of the cyclostome-gnathostome Pou5 gene family and comparing the structural and phenotypic protein variations, the authors uncover the origin of functional characteristics for the pluripotency factor Oct4.
- Woranop Sukparangsi
- , Elena Morganti
- & Joshua M. Brickman
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Article
| Open AccessDynamic enlargement and mobilization of lipid droplets in pluripotent cells coordinate morphogenesis during mouse peri-implantation development
Prior to its implantation into the uterus, the mammalian embryo stores substantial lipids. Here the authors unveil how lipid storage and morphogenesis of pluripotent stem cells are fundamentally connected during peri-implantation development.
- King Hang Tommy Mau
- , Donja Karimlou
- & Véronique Azuara
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Article
| Open AccessSatellite repeat transcripts modulate heterochromatin condensates and safeguard chromosome stability in mouse embryonic stem cells
Here the authors show satellite transcripts in mouse embryonic stem cells drive HP1α into droplets in vitro and also control HP1α organisation and association with chromatin in vivo. Depleting the satellite transcripts converts heterochromatin into a less dynamic and more static state and leads to chromosome instability.
- Clara Lopes Novo
- , Emily V. Wong
- & Peter J. Rugg-Gunn
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| Open AccessCell fate roadmap of human primed-to-naive transition reveals preimplantation cell lineage signatures
Cell fate dynamics during human naïve pluripotency establishment remain poorly understood. Here, Bi et al. depict a high-resolution cell roadmap of the primed-to-naïve pluripotency transition, providing hints for embryo modeling-related studies.
- Yan Bi
- , Zhifen Tu
- & Yixuan Wang
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Article
| Open AccessThe microRNA cluster C19MC confers differentiation potential into trophoblast lineages upon human pluripotent stem cells
Little is known about the epigenetic mechanisms of the first cell fate commitment in humans. Here, the authors show that activation of the miRNA cluster C19MC confers differentiation potential into trophoblast lineages on human embryonic stem cells.
- Norio Kobayashi
- , Hiroaki Okae
- & Takahiro Arima
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Article
| Open AccessPluripotency factors determine gene expression repertoire at zygotic genome activation
Zygotic genome activation in zebrafish relies on pluripotency transcription factors Pou5f3 and Sox19b. Here the authors investigate how these factors interact in vivo by analyzing the changes in chromatin state and time-resolved transcription in Pou5f3 and Sox19b single and double mutant embryos.
- Meijiang Gao
- , Marina Veil
- & Daria Onichtchouk
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Article
| Open AccessCTCF is a barrier for 2C-like reprogramming
Embryos at the 2-cell (2C) stage are totipotent, and overexpression of Dux transcription factor convert embryonic stem cells (ESCs) to a 2C-like state. Here the authors show that DUX-mediated 2C-like reprogramming is associated with DNA damage at CTCF sites and CTCF depletion promotes 2Clike conversion.
- Teresa Olbrich
- , Maria Vega-Sendino
- & Sergio Ruiz
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| Open AccessA single cell characterisation of human embryogenesis identifies pluripotency transitions and putative anterior hypoblast centre
Single cell analysis of early human embryos identifies key changes in pluripotency, the requirement of FGF signalling for embryo survival, and defines a putative anterior-like region of hypoblast cells, providing insights into how early human development is regulated.
- Matteo A. Molè
- , Tim H. H. Coorens
- & Magdalena Zernicka-Goetz
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Article
| Open AccessIntegrated analysis of Xist upregulation and X-chromosome inactivation with single-cell and single-allele resolution
X-chromosome inactivation (XCI) ensures dosage compensation between the sexes. Here the authors perform allele-specific single-cell RNA sequencing in differentiating mouse embryonic stem cells to provide a detailed profile of the onset of XCI.
- Guido Pacini
- , Ilona Dunkel
- & Edda G. Schulz
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Article
| Open AccessPHC1 maintains pluripotency by organizing genome-wide chromatin interactions of the Nanog locus
Phc1 is a subunit of the polycomb repressive complex 1 (PRC1), which represses gene expression during development. Here the authors show that Phc1 acts independently from PRC1 to activate Nanog transcription by stabilizing genome-wide chromatin interactions of the Nanog locus, and in turn stabilize pluripotency.
- Li Chen
- , Qiaoqiao Tong
- & Junfeng Ji
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Article
| Open AccessRecent evolution of a TET-controlled and DPPA3/STELLA-driven pathway of passive DNA demethylation in mammals
Active and passive demethylation pathways have been implicated in the genome-wide erasure of 5mC accompanying mammalian preimplantation development. Here the authors reveal a recently evolved, mammalian-specific pathway in which global hypomethylation is achieved by the coupling of active and passive demethylation.
- Christopher B. Mulholland
- , Atsuya Nishiyama
- & Heinrich Leonhardt
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| Open AccessTransition to naïve human pluripotency mirrors pan-cancer DNA hypermethylation
Epigenetic reprogramming is a hallmark of cancer. Here the authors find that resetting primed human embryonic stem cells to naïve state results in the acquisition of a DNA methylation landscape that mirrors the cancer DNA methylome and provides evidence that the transition to naïve pluripotency and oncogenic transformation share common epigenetic trajectories.
- Hemalvi Patani
- , Michael D. Rushton
- & Gabriella Ficz
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| Open AccessThe transcriptional regulator ZNF398 mediates pluripotency and epithelial character downstream of TGF-beta in human PSCs
The downstream pathway regulating how TGF-beta affects pluripotency of human PSCs is unclear. Here, the authors find that transcription factor ZNF398 binds active promoters/enhancers together with the histone acetyltransferase EP300 and SMAD3, enabling expression of pluripotency and epithelial genes.
- Irene Zorzan
- , Marco Pellegrini
- & Graziano Martello
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Article
| Open AccessA transcriptome-wide antitermination mechanism sustaining identity of embryonic stem cells
Besides its role in splicing, U1 snRNP can suppress pre-mRNA cleavage and polyadenylation. The authors show that the nuclear cap-binding complex component Srrt/Ars2 maintains embryonic stem cell identity by promoting U1 recruitment to first introns and preventing premature termination of multiple transcripts.
- Yaroslav A. Kainov
- & Eugene V. Makeyev
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Article
| Open AccessDifferential regulation of OCT4 targets facilitates reacquisition of pluripotency
Barriers underlying the inefficiency of reprogramming cells to pluripotency are poorly defined. Here the authors identify a transient interval soon after pluripotency exit that permits high-efficiency reprogramming and is facilitated by OCT4 bound elements displaying unique silencing behaviour during differentiation.
- Sudhir Thakurela
- , Camille Sindhu
- & Alexander Meissner
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| Open AccessMaternal pluripotency factors initiate extensive chromatin remodelling to predefine first response to inductive signals
Embryonic development produces different cell types in response to a small number of inductive signals. Here, the authors characterise how maternal factors modify chromatin to specify initial competence in Xenopus tropicalis, finding that the pioneering activity of the pluripotency factors Pou5f3 and Sox3 establishes competence for germ layer formation by remodelling chromatin before the onset of signalling.
- George E. Gentsch
- , Thomas Spruce
- & James C. Smith
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Article
| Open AccessSALL3 expression balance underlies lineage biases in human induced pluripotent stem cell differentiation
Human induced pluripotent stem cells (hiPSCs) generate all cell types in the body, but different lines can differ in their potential. Here, the authors determine that higher endogenous levels of SALL3 in hiPSCs lead to ectoderm differentiation bias and reduced mesoderm/endoderm due to DNMT3B mediated DNA methylation.
- Takuya Kuroda
- , Satoshi Yasuda
- & Yoji Sato
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Article
| Open AccessA non-canonical BRD9-containing BAF chromatin remodeling complex regulates naive pluripotency in mouse embryonic stem cells
The BAF complex is a multi-subunit chromatin remodeling complex that plays important roles in transcription regulation. Here the authors provide evidence that BRD9 and GLTSCR1/BICRA or its paralog GLTSCR1-like/BICRAL define a non-canonical BAF complex that regulates naive pluripotency in mouse embryonic stem cells.
- Jovylyn Gatchalian
- , Shivani Malik
- & Diana C. Hargreaves
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Article
| Open AccessBMI1 enables interspecies chimerism with human pluripotent stem cells
Conventional human pluripotent stem cells (hPSCs) fail to contribute to interspecies chimaeras when injected into mouse blastocysts. Here the authors show that forced expression of BMI1 overcomes apoptosis of hPSCs in blastocysts of mouse, rabbit and pig allowing them to contribute to chimaeras.
- Ke Huang
- , Yanling Zhu
- & Guangjin Pan
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Article
| Open AccessP53 and mTOR signalling determine fitness selection through cell competition during early mouse embryonic development
During embryo development, cell fitness determines survival but how this is regulated is unclear. Here, the authors show that in early embryonic development and stem cells exiting the naive state, cells sense the fitness of their neighbours and trigger p53 to repress mTOR to eliminate a third of cells.
- Sarah Bowling
- , Aida Di Gregorio
- & Tristan A. Rodríguez
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Article
| Open AccessKlf4 glutamylation is required for cell reprogramming and early embryonic development in mice
Embryonic stem cell pluripotency depends upon precise regulation by a core transcription network. Here the authors show that polyglutamylation mediated stabilization of the transcription factor Klf4 by TTLL1 and TTLL4 promotes reprogramming, pluripotency and preimplantation embryonic development.
- Buqing Ye
- , Benyu Liu
- & Zusen Fan
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Article
| Open AccessRASSF1A uncouples Wnt from Hippo signalling and promotes YAP mediated differentiation via p73
In development, the switch from pluripotency to differentiation is important but it is often unclear how it is regulated. Here, the authors show that the tumour suppressor RASSF1A mediates this switch by promoting YAP-p73 transcription, which in turn enables differentiation.
- Angelos Papaspyropoulos
- , Leanne Bradley
- & Eric O’Neill
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Article
| Open AccessParallel derivation of isogenic human primed and naive induced pluripotent stem cells
Derivation of human induced pluripotent stem cells (hiPSCs) produces primed hiPSCs that can in turn be converted to naive hiPSCs. Here, the authors directly reprogram somatic cells to form both naive and primed isogenic hiPSCs and confirm the similarity of naive hiPSCs to their in vivo counterparts.
- Stéphanie Kilens
- , Dimitri Meistermann
- & Matthew L. Albert
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Article
| Open AccessA post-transcriptional program coordinated by CSDE1 prevents intrinsic neural differentiation of human embryonic stem cells
Unlike transcriptional regulation of hESC identity, little is known post-transcriptionally. Here, the authors show that the RNA binding protein CSDE1 regulates core components of hESC identity, neurectoderm commitment and neurogenesis to maintain pluripotency and prevent neural differentiation.
- Hyun Ju Lee
- , Deniz Bartsch
- & David Vilchez
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Article
| Open AccessPRC2 specifies ectoderm lineages and maintains pluripotency in primed but not naïve ESCs
Polycomb repressive complex 2 (PRC2) plays an essential role in development by modifying chromatin but what this means at a cellular level is unclear. Here, the authors show that ablation of PRC2 genes in human embryonic stem cells and in mice results in changes in pluripotency and the primed state of cells.
- Yongli Shan
- , Zechuan Liang
- & Guangjin Pan
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Article
| Open AccessAsynchronous fate decisions by single cells collectively ensure consistent lineage composition in the mouse blastocyst
Early embryonic cell fate and lineage specification is tightly regulated in the preimplantation mammalian embryo. Here, the authors quantitatively examine the ratio of epiblast to primitive endoderm lineages in the blastocyst and show composition of the inner cell mass is conserved, independent of its size.
- Néstor Saiz
- , Kiah M. Williams
- & Anna-Katerina Hadjantonakis
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Article
| Open AccessNetrin-1 regulates somatic cell reprogramming and pluripotency maintenance
Reprogramming holds great promise for regenerative medicine but the molecular mechanisms governing the generation of induced pluripotent stem cells remain unclear. Here, the authors reveal functions for the axonal guidance cue Netrin-1 in constraining apoptosis at the early stage of reprogramming and in established pluripotent cells.
- Duygu Ozmadenci
- , Olivier Féraud
- & Fabrice Lavial
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Small RNA changes en route to distinct cellular states of induced pluripotency
Somatic cell reprogramming can induce distinct pluripotent states. Here the authors perform time-resolved small RNA expression profiling during the reprogramming of mouse embryonic fibroblasts and observe that distinct miRNA milieus characterise alternate states of pluripotency.
- Jennifer L. Clancy
- , Hardip R. Patel
- & Thomas Preiss
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| Open AccessAn epigenomic roadmap to induced pluripotency reveals DNA methylation as a reprogramming modulator
Somatic cell reprogramming can induce distinct pluripotent states. Here the authors perform time-resolved whole-genome bisulfite sequencing during the reprogramming of mouse embryonic fibroblasts and report dynamic global DNA methylation changes.
- Dong-Sung Lee
- , Jong-Yeon Shin
- & Jeong-Sun Seo
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Lineage-restricted function of the pluripotency factor NANOG in stratified epithelia
The transcription factor Nanog regulates self-renewal in pluripotent stem cells and cancer stem cells. Here the authors show that Nanog is expressed in mouse adult stratified epithelia, and its overexpression increases proliferation and aneuploidy and activates pathways associated to mitosis.
- Daniela Piazzolla
- , Adelaida R. Palla
- & Manuel Serrano
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Induction of pluripotency in human somatic cells via a transient state resembling primitive streak-like mesendoderm
The mesendoderm is located in the embryonic primitive streak's anterior region, which is specified by the transcription factor FOXH1. Here, the authors show that human fibroblasts transit through a mesendoderm-like state during reprogramming into pluripotent cells, and that expression of FOXH1 enhances reprogramming efficiency.
- Kazutoshi Takahashi
- , Koji Tanabe
- & Shinya Yamanaka
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Article |
Snail1-dependent control of embryonic stem cell pluripotency and lineage commitment
Factors inducing epithelial to mesenchymal transition, such as the transcriptional repressor Snail1, have been implicated in cancer stem cell development and function. Here Lin et al.report that endogenous Snail1 is not required for embryonic stem cell pluripotency and self-renewal, but rather regulates Wnt-induced epiblast differentiation.
- Yongshun Lin
- , Xiao-Yan Li
- & Stephen J. Weiss
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MacroH2A histone variants act as a barrier upon reprogramming towards pluripotency
Chromatin templates can act as barriers against cellular reprogramming. Gaspar-Maia and colleagues use mouse models deficient in the histone variants macroH2A1 and macroH2A2, and find that macroH2A functions as an epigenetic barrier against induced pluripotency by silencing Utx target genes.
- Alexandre Gaspar-Maia
- , Zulekha A. Qadeer
- & Emily Bernstein
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Reprogramming to pluripotency is an ancient trait of vertebrate Oct4 and Pou2 proteins
The mammalian transcription factors Oct4 and Pou2 are implicated in germ cell pluripotency induction and maintenance. Tapia and colleagues find that axolotl Pou2 and Oct4 reprogram mouse and human fibroblasts to a pluripotent state, suggesting ancestral Oct4 and Pou2 gene function is evolutionarily conserved.
- Natalia Tapia
- , Peter Reinhardt
- & Hans R. Schöler
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Article
| Open AccessEndogenous Wnt signalling in human embryonic stem cells generates an equilibrium of distinct lineage-specified progenitors
Human embryonic stem cell cultures are morphologically heterogeneous. Here, differences in Wnt signalling are shown to contribute to this heterogeneity, cells containing high levels of Wnt form endodermal and cardiac cells, whereas cells with low Wnt form neuroectodermal cells, when differentiation is induced.
- Timothy A. Blauwkamp
- , Shelly Nigam
- & Roel Nusse
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Article
| Open AccessJAK/STAT3 signalling is sufficient and dominant over antagonistic cues for the establishment of naive pluripotency
Culture conditions are critical for the successful induction of pluripotent stem cells and define whether cells are primed or naïve. Here, activation of JAK/STAT3 signalling is shown to be sufficient and dominant over antagonistic cues to enable the induction of a naïve pluripotent state in stem cells.
- Anouk L. van Oosten
- , Yael Costa
- & José C.R. Silva