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Article
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Quiescence 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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Article
| Open Access
Sox9 regulates alternative splicing and pancreatic beta cell function
Sox9 is a well-known transcriptional regulator of embryonic pancreas and endocrine cell development. Here, the authors show that loss of Sox9 in mature beta cells disrupts alternative splicing patterns and impairs insulin secretion, with significant implications for cellular function.
- Sapna Puri
- , Hasna Maachi
- & Matthias Hebrok
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Article
| Open Access
Role of UPF1-LIN28A interaction during early differentiation of pluripotent stem cells
UPF1 and LIN28A are RNA-binding proteins involved in post-transcriptional regulation and cell differentiation. Here, authors report that they interact with each other via specific domains and regulate ectodermal specialization of human pluripotent stem cells.
- Seungwon Jung
- , Seung Hwan Ko
- & Jungwook Hwang
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Article
| Open Access
Modeling cardiac fibroblast heterogeneity from human pluripotent stem cell-derived epicardial cells
Cardiac fibroblasts play an essential role in heart development. Here Fernandes et al. describe a human pluripotent stem cell-derived epicardial organoid system to investigate the role of fibroblasts in cardiovascular development and disease.
- Ian Fernandes
- , Shunsuke Funakoshi
- & Gordon Keller
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Article
| Open Access
Generation of three-dimensional meat-like tissue from stable pig epiblast stem cells
Cultured meat technology promises to alleviate protein shortages, but still faces many challenges. Here, the authors achieve serum-free myogenic differentiation of porcine pre-gastrulation epiblast stem cells and generate meat-like tissue via edible plant-based scaffolds without any animal compounds.
- Gaoxiang Zhu
- , Dengfeng Gao
- & Jianyong Han
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Article
| Open Access
Functional dissection of PRC1 subunits RYBP and YAF2 during neural differentiation of embryonic stem cells
RYBP and YAF2 are a pair of paralog subunits of variant PRC1. Here, authors show that RYBP decrease but YAF2 increase during mESC neural differentiation, and that they are not redundant but function differentially in regulating this differentiation.
- Yanjiang Liu
- , Gongcheng Hu
- & Hongjie Yao
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Article
| Open Access
Optogenetic control of YAP reveals a dynamic communication code for stem cell fate and proliferation
The transcriptional regulator YAP controls cellular decisions such as proliferation, differentiation, and pluripotency. Here, the authors show a concentration-dependent and temporal communication code for YAP that enables cells to choose between these programs.
- Kirstin Meyer
- , Nicholas C. Lammers
- & Orion D. Weiner
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Article
| Open Access
Demethylase-independent roles of LSD1 in regulating enhancers and cell fate transition
Here the authors describe the catalytic-independent role of LSD1 in regulating gene expression and cellular differentiation and a mechanism by which the LSD1-P300 axis contributes to the regulation of enhancers and cell fate.
- Cheng Zeng
- , Jiwei Chen
- & Kaixiang Cao
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Article
| Open Access
Fluorescent protein lifetimes report densities and phases of nuclear condensates during embryonic stem-cell differentiation
Fluorescent proteins can report on many cellular variables. Here, authors develop a method for reporting high local densities, and use it to show that density distribution of heterochromatin in mouse embryonic stem cells are not in a liquid phase.
- Khalil Joron
- , Juliane Oliveira Viegas
- & Eitan Lerner
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Article
| Open Access
Plakoglobin 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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Article
| Open Access
Genome-wide screening in pluripotent cells identifies Mtf1 as a suppressor of mutant huntingtin toxicity
Huntington’s disease is caused by mutation in the HTT gene. Here, the authors screen for suppressors of mutant HTT-induced toxicity, identifying Mtf1. Mtf1 reduced oxidative stress and cell death in stem cells, and motor defects and protein aggregates in mouse models.
- Giorgia Maria Ferlazzo
- , Anna Maria Gambetta
- & Graziano Martello
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Article
| Open Access
LIS1 RNA-binding orchestrates the mechanosensitive properties of embryonic stem cells in AGO2-dependent and independent ways
LIS1 protein is important for brain development and stem cells’ survival. Here the authors show that LIS1 binds RNA and interact with RNA-binding proteins regulating the physical properties of mouse embryonic stem cells.
- Aditya Kshirsagar
- , Svetlana Maslov Doroshev
- & Orly Reiner
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Article
| Open Access
Apicobasal RNA asymmetries regulate cell fate in the early mouse embryo
How do cells of the preimplantation mouse embryo make decisions? Here the authors discovered that the spatial sorting of mRNAs, tRNA, rRNAs and organelles lead to localized translation, conducive for cell fate allocation and embryonic development.
- Azelle Hawdon
- , Niall D. Geoghegan
- & Jennifer Zenker
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Article
| Open Access
The Wnt/TCF7L1 transcriptional repressor axis drives primitive endoderm formation by antagonizing naive and formative pluripotency
Signal transduction and gene expression regulation via downstream transcription factors shape the early mammalian embryo. Here the authors show that Wnt/TCF7L1 transcriptional repressive activity is required for primitive endoderm lineage formation.
- Paraskevi Athanasouli
- , Martina Balli
- & Frederic Lluis
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| Open Access
ZBTB12 is a molecular barrier to dedifferentiation in human pluripotent stem cells
The metastability of stem cells requires a mechanism for actively blocking dedifferentiation to achieve successful differentiation. Here the authors show that ZBTB12 serves as a molecular barrier to dedifferentiation by repressing a primate-specific retrotransposon, HERVH.
- Dasol Han
- , Guojing Liu
- & Jiwon Jang
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Article
| Open Access
RSL24D1 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 Access
DNMT3B supports meso-endoderm differentiation from mouse embryonic stem cells
DNMT3B-dependent DNA methylation provides epigenetic priming at epiblast stage by methylating enhancers of ectodermal genes to ensure proper differentiation toward mesoendoderm tissues.
- Andrea Lauria
- , Guohua Meng
- & Salvatore Oliviero
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Perspective
| Open Access
Molecular versatility during pluripotency progression
During development the embryo must balance lineage specification against the preservation of plasticity using a limited molecular toolkit. In this Perspective, the authors propose Molecular Versatility as a paradigm for grouping molecular mechanisms that are repurposed through development to exert distinct functions.
- Giacomo Furlan
- , Aurélia Huyghe
- & Fabrice Lavial
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Article
| Open Access
Primate-specific transposable elements shape transcriptional networks during human development
The human genome harbors more than 4.5 million transposable element (TE)-derived insertions, the result of recurrent waves of invasion and internal propagation. Here they show that TEs belonging to evolutionarily recent subfamilies go on to regulate later stages of human embryonic development, notably conditioning the expression of genes involved in gastrulation and early organogenesis.
- Julien Pontis
- , Cyril Pulver
- & Didier Trono
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| Open Access
CHD7 regulates otic lineage specification and hair cell differentiation in human inner ear organoids
Mutations in the chromatin remodeler CHD7 cause CHARGE syndrome, affecting development of several organs including the inner ear. Here, the authors recapitulated pathogenesis of this disease with human inner ear organoids and found that CHD7 is indispensable for proper otic lineage specification and hair cell differentiation.
- Jing Nie
- , Yoshitomo Ueda
- & Eri Hashino
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| Open Access
CK2-mediated phosphorylation of SUZ12 promotes PRC2 function by stabilizing enzyme active site
Here the authors identify SUZ12 as a cellular substate of casein kinase 2 (CK2), and show this phosphorylation changes the active site structure of Polycomb repressive complex 2 (PRC2) and promotes PRC2 function in cell identity maintenance during stem cell differentiation.
- Lihu Gong
- , Xiuli Liu
- & Xin Liu
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Article
| Open Access
Exploration of nuclear body-enhanced sumoylation reveals that PML represses 2-cell features of embryonic stem cells
Here the authors identify novel PML-partners and demonstrate that PML NBs control their sumoylation and that PML-controlled sumoylation of transcriptional regulators maintains the embryonic stem cell transcriptome and transposable element silencing.
- Sarah Tessier
- , Omar Ferhi
- & Valérie Lallemand-Breitenbach
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Article
| Open Access
Evolutionary 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 Access
ZnT8 loss-of-function accelerates functional maturation of hESC-derived β cells and resists metabolic stress in diabetes
Immature function and fragility hinder application of hESC-derived β cells (SC-β cell) for diabetes cell therapy. Here, the authors identify ZnT8 as a gene editing target to enhance the insulin secretion and cell survival under metabolic stress by abolishing zinc transport in SC-β cells.
- Qing Ma
- , Yini Xiao
- & Weida Li
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Article
| Open Access
A Nodal enhanced micropeptide NEMEP regulates glucose uptake during mesendoderm differentiation of embryonic stem cells
Fu et al. identify the highly conserved, transmembrane micropeptide, NEMEP, as a direct target of Nodal signaling, essential for mesendoderm differentiation. NEMEP interacts with the glucose transporters GLUT1/GLUT3 and promotes glucose uptake.
- Haipeng Fu
- , Tingyu Wang
- & Qiaoran Xi
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Article
| Open Access
Dynamic 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 Access
G1/S restriction point coordinates phasic gene expression and cell differentiation
Somatic cells display phasic gene expression with compartmentalized gene expression during the cell cycle, while pluripotent cells lack phasic expression. Here, the authors describe a pathway linking microRNA regulation of the G1/S restriction point with phasic gene expression and cell differentiation during mammalian development.
- Brian DeVeale
- , Leqian Liu
- & Robert Blelloch
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Article
| Open Access
Satellite 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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Article
| Open Access
ZFP281-BRCA2 prevents R-loop accumulation during DNA replication
R-loops are prevalent in mammalian genomes and involved in many fundamental cellular processes. Here, Wang et al. report that ZFP281 cooperates with BRCA2 in preventing R-loop accumulation to facilitate DNA replication in embryonic stem cells.
- Yan Wang
- , Binbin Ma
- & Zhuojuan Luo
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Article
| Open Access
SMYD5 catalyzes histone H3 lysine 36 trimethylation at promoters
SETD2 methylates histone H3K36me3 in gene bodies in mammalian cells. Here the authors show H3K36me3 is also enriched at the promoter regions, and that this methylation is carried out by SMYD5, which is recruited by RNA polymerase II. They furthermore show SMYD5 is elevated in liver cancer and is correlated with changes in gene expression.
- Yanjun Zhang
- , Yuan Fang
- & Dong Fang
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Article
| Open Access
Cell 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 Access
The 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 Access
Cell cycle gene regulation dynamics revealed by RNA velocity and deep-learning
Single-cell RNA-sequencing technology gives access to cell cycle dynamics without externally perturbing the cell. Here the authors present DeepCycle,a robust deep learning method to infer the cell cycle state in single cells from scRNA-seq data.
- Andrea Riba
- , Attila Oravecz
- & Nacho Molina
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Article
| Open Access
BMP4 drives primed to naïve transition through PGC-like state
Multiple pluripotent states have been described in mouse and human stem cells. Here the authors describe trajectories during BMP4 induced primed to naïve transition, which bifurcates into naïve and trophoblast-like branches with a PGC-like intermediate at the naïve branch.
- Shengyong Yu
- , Chunhua Zhou
- & Jing Liu
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Article
| Open Access
Preventing erosion of X-chromosome inactivation in human embryonic stem cells
Cloutier et al. discover that human embryonic stem cells (hESCs) cultured with media containing inhibitors of GSK3 proteins undergo erosion of X-chromosome inactivation, which equalizes X-linked gene expression between females and males. The findings inform the faithful culture of hESCs.
- Marissa Cloutier
- , Surinder Kumar
- & Sundeep Kalantry
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Article
| Open Access
Differential effects of macrophage subtypes on SARS-CoV-2 infection in a human pluripotent stem cell-derived model
Model systems to study SARS-CoV-2 infection are required to better understand the immune response. Here the authors use a lung and macrophage co-culture system by differentiation of human pluripotent stem cells to better understand the phenotype and gene expression changes in host lung cells and macrophages after SARS-CoV-2 infection in vitro.
- Qizhou Lian
- , Kui Zhang
- & Huanhuan Joyce Chen
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Article
| Open Access
The nuclear receptor ERR cooperates with the cardiogenic factor GATA4 to orchestrate cardiomyocyte maturation
Mature cardiac muscle requires high mitochondrial ATP production and specialized contractile proteins. Here the authors demonstrate that cardiomyocyte-specific contractile maturation involves cooperation between the nuclear receptor ERRγ and cardiogenic transcription factor GATA4, but ERRγ controls metabolic genes independently.
- Tomoya Sakamoto
- , Kirill Batmanov
- & Daniel P. Kelly
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Article
| Open Access
Elastic dosage compensation by X-chromosome upregulation
The concerted dynamics of X-chromosome upregulation and X-chromosome inactivation, which collectively balance X-chromosome expression, are not well understood. Using allelic single-cell genomics, the authors characterize the dynamics of X-chromosome upregulation and inactivation along mouse embryonic and stem cell development, calling to question keys aspects of the established model of mammalian dosage compensation.
- Antonio Lentini
- , Huaitao Cheng
- & Björn Reinius
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Article
| Open Access
BAF complex-mediated chromatin relaxation is required for establishment of X chromosome inactivation
Female embryonic stem cells (ESCs) are the ideal model to study X chromosome inactivation (XCI) establishment; however, these cells are challenging to keep in culture. Here the authors create fluorescent ‘Xmas’ reporter mice as a renewable source of ESCs and show nucleosome remodelers Smarcc1 and Smarca4 create a nucleosome-free promoter region prior to the establishment of silencing.
- Andrew Keniry
- , Natasha Jansz
- & Marnie E. Blewitt
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Article
| Open Access
Ezh2 is essential for the generation of functional yolk sac derived erythro-myeloid progenitors
Yolk sac erythro-myeloid progenitors (EMPs) are critical for embryo viability and a major source of adult tissue-resident macrophages. Here, the authors show an essential stage-specific role for Ezh2 in modulating Wnt signaling during EMP generation.
- Wen Hao Neo
- , Yiran Meng
- & Georges Lacaud
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Article
| Open Access
Identifying regulators of parental imprinting by CRISPR/Cas9 screening in haploid human embryonic stem cells
Genetic imprinting ensures monoallelic gene expression critical for normal embryonic development. Here the authors take advantage of human haploid parthenogenic embryonic stem cells lacking paternal alleles to identify, by genome-wide screening, factors involved in the regulation of imprinted genes.
- Shiran Bar
- , Dan Vershkov
- & Nissim Benvenisty
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Article
| Open Access
Sequence logic at enhancers governs a dual mechanism of endodermal organ fate induction by FOXA pioneer factors
Enhancers for endodermal organs are primed at the chromatin level prior to lineage induction by FOXA pioneer transcription factors; how pervasive this is, is not well known. Here the authors show that only a small subset of organ-specific enhancers are bound and primed by FOXA prior to lineage induction, whereas the majority do not undergo chromatin priming and engage FOXA upon lineage induction.
- Ryan J. Geusz
- , Allen Wang
- & Maike Sander
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Article
| Open Access
StemBond hydrogels control the mechanical microenvironment for pluripotent stem cells
The independent control of substrate stiffness and tethering of extracellular matrix to substrates for mechanical signalling investigations remains challenging. Here the authors present StemBond hydrogels, with stable ECM tethering that can be varied independently of stiffness, and use these to modulate the function of mouse and human pluripotent stem cells.
- Céline Labouesse
- , Bao Xiu Tan
- & Kevin J. Chalut
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Article
| Open Access
Plexin-B2 orchestrates collective stem cell dynamics via actomyosin contractility, cytoskeletal tension and adhesion
Biomechanical mechanisms orchestrating stem cell dynamics in development remain unclear. Here the authors show that guidance receptor Plexin-B2 organizes actomyosin contractility, cytoskeletal tension and adhesion during multicellular development of human embryonic stem cells and neuroprogenitor cells.
- Chrystian Junqueira Alves
- , Rafael Dariolli
- & Roland H. Friedel
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Article
| Open Access
Joint single-cell multiomic analysis in Wnt3a induced asymmetric stem cell division
A localized Wnt3a signal has been shown to induce asymmetric division of mouse embryonic stem cells. Here the authors develop SET-seq, an approach to jointly profile epigenome and transcriptome in the same single cell and use it to provide mechanistic insights into the gene regulatory programs for maintaining and resetting stem cell fate during differentiation.
- Zhongxing Sun
- , Yin Tang
- & Dong Fang
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Article
| Open Access
Nuclear transporter Importin-13 plays a key role in the oxidative stress transcriptional response
Importin superfamily member IPO13 mediates nuclear transport bidirectionally. Here the authors delineate the transcriptome of wild-type and IPO13-knockout mouse embryonic stem cells, revealing IPO13’s key role in the oxidative stress response through targeted transport of specific transcription factors.
- K. A. Gajewska
- , H. Lescesen
- & D. A. Jans
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Article
| Open Access
Variant PCGF1-PRC1 links PRC2 recruitment with differentiation-associated transcriptional inactivation at target genes
Polycomb repressive complexes (PRC1 and PRC2) repress genes that are crucial for development via epigenetic modifications; however, their role in differentiation is not well known. Here the authors reveal that a PCGF1-containing PRC1 variant facilitates exit from pluripotency by downregulating target genes and recruiting PRC2.
- Hiroki Sugishita
- , Takashi Kondo
- & Haruhiko Koseki
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Article
| Open Access
OCT4 cooperates with distinct ATP-dependent chromatin remodelers in naïve and primed pluripotent states in human
Although the interactors of pluripotency factors have been identified in mouse embryonic stem cells (ESCs), their interactors in human ESCs remain unexplored. Here the authors map OCT4 protein interactions in naïve and primed human ESCs to find specific interactions with BAF subunits that promote an open chromatin architecture at blastocyst-associated genes and ectodermal genes, respectively.
- Xin Huang
- , Kyoung-mi Park
- & Thorold W. Theunissen
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Article
| Open Access
Bioengineered embryoids mimic post-implantation development in vitro
Previous approaches to derive embryoids either lack physiological morphology and signaling interactions, or are unconducive to model post-gastrulation development. Here the authors use a high-throughput approach to induce mouse embryonic stem cells into epiblast-like aggregates, which are then co-cultured with mouse trophoblast stem cell aggregates, to yield embryoids with axial morphogenesis and anterior development.
- Mehmet U. Girgin
- , Nicolas Broguiere
- & Matthias P. Lutolf
Differentiation shifts from a reversible to an irreversible heterochromatin state at the DM1 locus