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| Open AccessVariant 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 AccessOCT4 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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| Open AccessBioengineered 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
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| Open AccessTranscriptional profiling of mESC-derived tendon and fibrocartilage cell fate switch
The transcriptional regulators underlying the induction and differentiation of dense connective tissues remain largely unknown. Here the authors generate tendon and fibrocartilage cells from mouse embryonic stem cells and apply scRNA-seq to identify molecular regulation of the cell fate switch between these lineages.
- Deepak A. Kaji
- , Angela M. Montero
- & Alice H. Huang
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| Open AccessSS18 regulates pluripotent-somatic transition through phase separation
Emerging evidence suggests that exit from pluripotency is a regulated, rather than passive process. Here the authors identify a requirement for SS18-mediated Brg/Brahma-associated factors (BAF) chromatin remodeling complex assembly during exit from pluripotency, and that SS18 promotes BAF assembly through liquidliquid phase separation.
- Junqi Kuang
- , Ziwei Zhai
- & Duanqing Pei
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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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| Open AccessGeneration of mature compact ventricular cardiomyocytes from human pluripotent stem cells
Cardiomyocytes of heart ventricles consist of subpopulations of trabecular and compact subtypes. Here the authors describe the generation of structurally, metabolically and functionally mature compact ventricular cardiomyocytes as well as mature atrial cardiomyocytes from human pluripotent stem cells.
- Shunsuke Funakoshi
- , Ian Fernandes
- & Gordon Keller
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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 AccessWidespread reorganisation of pluripotent factor binding and gene regulatory interactions between human pluripotent states
The role of transcriptional enhancers and 3D chromatin organisation in coordinating the transition from naive to primed pluripotency remains poorly understood. Here the authors generate a high-resolution atlas of gene regulatory interactions, chromatin profiles and transcription factor occupancy in naive and primed human pluripotent stem cells to provide insights into these developmental processes.
- Peter Chovanec
- , Amanda J. Collier
- & Peter J. Rugg-Gunn
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| Open AccessDissection of two routes to naïve pluripotency using different kinase inhibitors
Naïve pluripotency can be stabilized through different pharmacological approaches. Here, the authors profile temporal changes of protein phosphorylation, proteome and metabolome as mESCs transition to the naïve state in response to two pharmacological treatments, revealing general and treatment-specific processes.
- Ana Martinez-Val
- , Cian J. Lynch
- & Javier Munoz
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Article
| Open AccessThe deubiquitinase Usp9x regulates PRC2-mediated chromatin reprogramming during mouse development
During development, H3K27me3 is reallocated from large domains in preimplantation embryos to mark promoters of developmental genes. Here the authors show that the deubiquitinase Usp9x interacts with, deubiquitinates and stabilizes PRC2 and provide evidence that a Usp9x-PRC2 regulatory axis is critical at peri-implantation.
- Trisha A. Macrae
- & Miguel Ramalho-Santos
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| Open AccessBlastocyst complementation using Prdm14-deficient rats enables efficient germline transmission and generation of functional mouse spermatids in rats
The uptake of donor pluripotent stem cells (PSCs) in hosts of different species and subsequent germline transmission is very inefficient. Here, the authors show, using Prdm14 gene depleted rat host blastocysts to remove functional sperm, that germline transmission from donor rat or mouse PSCs is possible.
- Toshihiro Kobayashi
- , Teppei Goto
- & Masumi Hirabayashi
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| Open AccessStrand-specific single-cell methylomics reveals distinct modes of DNA demethylation dynamics during early mammalian development
Erasure of DNA methylation from the parental genomes is critical to reset the methylome of differentiated gametes to pluripotent cells in the blastocyst. Here, the authors present a high-throughput single-cell method that enables strand-specific quantification of DNA methylation and identify distinct modes of DNA demethylation dynamics during early mammalian development.
- Maya Sen
- , Dylan Mooijman
- & Alexander van Oudenaarden
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| Open AccessWnt/Beta-catenin/Esrrb signalling controls the tissue-scale reorganization and maintenance of the pluripotent lineage during murine embryonic diapause
Embryonic diapause is a state of dormancy with poorly understood mechanisms of embryo intrinsic regulation. Here, the authors show that murine diapause is a dynamic process, where tissue-scale reorganization of the pluripotent lineage is controlled in an autocrine manner by the Wnt/b-catenin/Esrrb signalling cascade.
- Rui Fan
- , Yung Su Kim
- & Ivan Bedzhov
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Article
| Open AccessAn embryonic stem cell-specific heterochromatin state promotes core histone exchange in the absence of DNA accessibility
Nucleosome turnover concomitant with incorporation of the histone variant H3.3 is a hallmark of regulatory regions in the animal genome. Here, the authors demonstrate that fast histone turnover and H3.3 incorporation defines a dynamic heterochromatin state in pluripotent stem cells.
- Carmen Navarro
- , Jing Lyu
- & Simon J. Elsässer
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Article
| Open AccessFunctional role of Tet-mediated RNA hydroxymethylcytosine in mouse ES cells and during differentiation
TET mediated RNA-hydroxymethylation (5hmC) has been detected in mammals, but its physiological role remains unclear. Here the authors map 5hmC during embryonic stem cell (ESC) differentiation and find that Tet-mediated RNA hydroxymethylation reduces the stability of crucial pluripotency related transcripts.
- Jie Lan
- , Nicholas Rajan
- & François Fuks
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| Open AccessIdentifying proteins bound to native mitotic ESC chromosomes reveals chromatin repressors are important for compaction
Epigenetic information is transmitted from mother to daughter cells through mitosis. Here, the authors isolate native chromosomes from metaphase-arrested cells and perform LC-MS/MS to identify chromosome-bound proteins in pluripotent stem cells during mitosis and reveal that PRC2, DNA methylation and Mecp2 are required to maintain chromosome compaction.
- Dounia Djeghloul
- , Bhavik Patel
- & Amanda G. Fisher
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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 AccessIdentification of distinct loci for de novo DNA methylation by DNMT3A and DNMT3B during mammalian development
De novo DNA methylation is carried out by DNMT3A and DNMT3B, but the distinct functions of these two enzymes is poorly understood. Here the authors present a comprehensive, genome-wide identification of target sites for de novo DNA methylation by the DNMT3A and DNMT3B in mouse ES cells and embryos, identifying unique de novo DNA methylation target sites for both DNMT3 enzymes.
- Masaki Yagi
- , Mio Kabata
- & Yasuhiro Yamada
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Article
| Open AccessThe Perlman syndrome DIS3L2 exoribonuclease safeguards endoplasmic reticulum-targeted mRNA translation and calcium ion homeostasis
The DIS3L2 exonuclease degrades aberrant 7SL RNAs tagged by an oligouridine 3′-tail. Here the authors analyze DIS3L2 knockout mouse embryonic stem cells and suggest that DIS3L2-mediated quality control of 7SL RNA is important for ER-mediated translation and calcium ion homeostasis.
- Mehdi Pirouz
- , Chih-Hao Wang
- & Richard I. Gregory
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Article
| Open AccessSingle cell transcriptomics identifies stem cell-derived graft composition in a model of Parkinson’s disease
What happens to cells on engrafting into the brain in animal models to treat Parkinson’s disease is unclear. Here, the authors use scRNA-seq to examine ventral midbrain (VM)-patterned human embryonic stem cells after functional maturation in a pre-clinical rat model for Parkinson’s disease and identify perivascular-like cells.
- Katarína Tiklová
- , Sara Nolbrant
- & Malin Parmar
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| Open AccessUnique properties of a subset of human pluripotent stem cells with high capacity for self-renewal
Human pluripotent cells (hPSCs) in standard culture are similar to mouse epiblast cells, but heterogeneity within hPSC cultures complicates comparisons. Here the authors show that a subpopulation of hPSCs enriched for self-renewal capacity have distinct cell cycle, metabolic, DNA methylation, and ATAC-seq profiles.
- Kevin X. Lau
- , Elizabeth A. Mason
- & Martin F. Pera
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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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| Open AccessIdentification of cell surface markers and establishment of monolayer differentiation to retinal pigment epithelial cells
Whilst pigmentation has been used to identify retinal pigment epithelial (RPE) cells, surface markers for these cells remain unclear. Here, the authors define surface markers for the RPE including CD140b, which help produce hPSC-derived RPE cells at a large scale following a robust, direct and scalable monolayer differentiation protocol.
- Alvaro Plaza Reyes
- , Sandra Petrus-Reurer
- & Fredrik Lanner
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| Open AccessLow rates of mutation in clinical grade human pluripotent stem cells under different culture conditions
Mutations in human pluripotent stem cells (PSC) and whether any form during culture prior to use in a human clinical context are a concern. Here, the authors use hPSCs derived to cGMP standards and show they have low mutation rates after culture, noting this decreases on culturing in low (5%) oxygen conditions.
- Oliver Thompson
- , Ferdinand von Meyenn
- & Peter W. Andrews
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Article
| Open AccessPhosphoproteomics identifies a bimodal EPHA2 receptor switch that promotes embryonic stem cell differentiation
Fgf4 is a critical signal driving embryonic stem cell (ESC) exit from pluripotency and differentiation. Here the authors identify EPHA2 as a target of FGF4 signalling in ESCs, and show that EPHA2-EFNA1 signalling promotes pluripotent gene expression and suppresses commitment through repression of ERK1/2 activation.
- Rosalia Fernandez-Alonso
- , Francisco Bustos
- & Greg M. Findlay
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| Open AccessDynamic CpG methylation delineates subregions within super-enhancers selectively decommissioned at the exit from naive pluripotency
Clusters of enhancers, called super-enhancers (SEs), control the expression of cell identity genes. Here, the authors identify two types of enhancer units within SEs in ESCs, characterised by distinctive CpG methylation dynamics, and find that ESRRB regulates the enhancer units decommissioned at exit from naive pluripotency.
- Emma Bell
- , Edward W. Curry
- & Véronique Azuara
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Article
| Open AccessIGF1-mediated human embryonic stem cell self-renewal recapitulates the embryonic niche
The signals regulating the establishment and maintenance of the pluripotent epiblast in human embryos are unclear. Here, the authors use a bioinformatics approach to identify the role of IGF1 in human embryo development, and from this, propose a culture medium with IGF1 together with Activin to sustain hESCs in the absence of FGF.
- Sissy E. Wamaitha
- , Katarzyna J. Grybel
- & Kathy K. Niakan
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Article
| Open AccessThe in vivo genetic program of murine primordial lung epithelial progenitors
The identity of the earliest murine in vivo lung epithelial progenitors (marked by NKX2-1 expression) is unclear. Here, the authors use single-cell RNA sequencing to define the genetic program of these lung primordial progenitors, which will improve in vitro lung specification of pluripotent stem cells.
- Laertis Ikonomou
- , Michael J. Herriges
- & Darrell N. Kotton
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Article
| Open AccessJMJD3 and UTX determine fidelity and lineage specification of human neural progenitor cells
Neurogenesis is an ordered transition from pluriptotent cells to neural precursor cells (NPCs) to neurons. Here the authors show that loss of the lysine demethylases JMJD3 and UTX leads reduced DNA accessibility at neurogenesis loci in human NPCs, and that the chromatin remodeller BAF can rescue differentiation defects.
- Yongli Shan
- , Yanqi Zhang
- & Guangjin Pan
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Article
| Open AccessTRIM66 reads unmodified H3R2K4 and H3K56ac to respond to DNA damage in embryonic stem cells
TRIM66 protein has an N-terminal tripartite motif and a C-terminal PHD Bromodomain. Here the authors show the specific histone modification recognition of TRIM66-PHD-Bromodomain through crystallography and biochemistry assay, and further reveal that TRIM66 recognition of certain histone modification is important for DNA damage repair in ESCs.
- Jiajing Chen
- , Zikang Wang
- & Yunyu Shi
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Article
| Open AccessNext-generation unnatural monosaccharides reveal that ESRRB O-GlcNAcylation regulates pluripotency of mouse embryonic stem cells
Per-O-acetylated unnatural monosaccharides are popular tools for glycan labeling in live cells but can undergo unwanted side reactions with cysteines. Here, the authors develop unnatural sugars in a partially esterified form that are inert towards cysteines, and use them to probe O-GlcNAcylation in mESCs.
- Yi Hao
- , Xinqi Fan
- & Xing Chen
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Article
| Open AccessE2F4 regulates transcriptional activation in mouse embryonic stem cells independently of the RB family
E2F transcription factors are regulators of cell division and cell fate decisions. Here the authors show that E2F4 is important for proliferation and survival of mouse ESCs, independent of the RB family, and that E2F4 interacts with chromatin regulators associated with gene activation.
- Jenny Hsu
- , Julia Arand
- & Julien Sage
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Article
| Open AccessEnhancer accessibility and CTCF occupancy underlie asymmetric TAD architecture and cell type specific genome topology
Eukaryotic genomes fold into topologically associated domains (TAD). Here the authors characterise a TAD regulatory architecture underlying lineage-specific gene regulation, finding that stripe TADs are associated with poised and active chromatin landscapes and linked to the cells functional state.
- Christopher Barrington
- , Dimitra Georgopoulou
- & Suzana Hadjur
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| Open AccessDynamics of genome reorganization during human cardiogenesis reveal an RBM20-dependent splicing factory
The spatial organization of the genome plays an important but unclearly defined role in gene regulation. Here, the authors integrate Hi-C, RNA-seq and ATAC-seq data to map cardiogenesis from pluripotent stem cells and describe an RBM20-dependent splicing factory assembling the TTN locus with other RBM20 targets.
- Alessandro Bertero
- , Paul A. Fields
- & Charles E. Murry
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Article
| Open AccessUSP8 maintains embryonic stem cell stemness via deubiquitination of EPG5
Autophagy is implicated in self-renewal of stem cells, including embryonic stem cells (ES cells). Here the authors demonstrate EPG5 is highly expressed in ES cells, and its deubiquitylation by USP8 stimulates its interaction with LC3 to promote autophagy and maintenance of stemness.
- Haifeng Gu
- , Xingxing Shi
- & Tongbiao Zhao
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Article
| Open AccessA TRIM71 binding long noncoding RNA Trincr1 represses FGF/ERK signaling in embryonic stem cells
FGF signaling through ERK is known to promote the differentiation of embryonic stem cells (ES cells). Here, the authors demonstrate that the lncRNA Trincr1 binds and represses TRIM71 in ES cells, leading to downregulation of SHCBP1 protein, the reduction of FGF/ERK signaling and the promotion of self-renewal.
- Ya-Pu Li
- , Fei-Fei Duan
- & Yangming Wang
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Article
| Open AccessSMARCAD1 ATPase activity is required to silence endogenous retroviruses in embryonic stem cells
Tight regulation of retrotransposons such as endogenous retroviruses (ERVs) is essential for genome and transcriptome integrity. Here, the authors show that the ATPase function of the chromatin remodeler SMARCAD1 facilitates the binding of KAP1 to ERVs and is required for their repression in embryonic stem cells.
- Parysatis Sachs
- , Dong Ding
- & Jacqueline E. Mermoud
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Article
| Open AccessOrganoid-derived C-Kit+/SSEA4− human retinal progenitor cells promote a protective retinal microenvironment during transplantation in rodents
Stem cell transplantation to treat retinal degeneration could be limited by the degenerative microenvironment. Here, the authors show that C-Kit+/SSEA4– progenitor cells enriched from human embryonic stem cell derived retinal organoids protect retinal structure, suppress microglial activation, gliosis and inflammation.
- Ting Zou
- , Lixiong Gao
- & Zheng Qin Yin
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Article
| Open AccessThe molecular logic of Nanog-induced self-renewal in mouse embryonic stem cells
Transcription factor (TF) networks are essential for the molecular identity of each cell type. Here, the authors show that TF Nanog utilises multiple molecular strategies to enhance embryonic stem cell self-renewal, which include regulation of chromatin accessibility in the presence of LIF or maintenance of H3K27me3 at developmental regulators in its absence.
- Victor Heurtier
- , Nick Owens
- & Pablo Navarro
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Article
| Open AccessPrecisely controlling endogenous protein dosage in hPSCs and derivatives to model FOXG1 syndrome
Altered dosage of developmental regulators such as transcription factors can result in disorders, such as FOXG1 syndrome. Here, the authors demonstrate the utility of SMASh technology for modulating protein dosage by modeling FOXG1 syndrome using human pluripotent stem cell-derived neurons and neural organoids.
- Wenliang Zhu
- , Boya Zhang
- & Baoyang Hu
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Article
| Open AccessImplantation initiation of self-assembled embryo-like structures generated using three types of mouse blastocyst-derived stem cells
The precise cellular patterning and decisions of early embryogenesis have been hard to mimic in vitro. Here, the authors culture murine embryonic and trophoblast stem cells together with extra-embryonic endoderm stem cells to form embryo-like structures (ETX-embryoids), which can initiate an implantation response.
- Shaopeng Zhang
- , Tianzhi Chen
- & Jianyong Han
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Article
| Open AccessTransposable elements are regulated by context-specific patterns of chromatin marks in mouse embryonic stem cells
Transposable elements (TEs) fulfill essential but poorly understood roles in genome organization and gene expression control. Here the authors show that the regulation of TEs occurs through overlapping epigenetic mechanisms that control the expression and chromatin signatures at TEs.
- Jiangping He
- , Xiuling Fu
- & Andrew P. Hutchins
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Article
| Open AccessHoney bee Royalactin unlocks conserved pluripotency pathway in mammals
Royal jelly is the queen-maker for the honey bee that also has effects on longevity, fertility, and regeneration in mammals. Here the authors provide evidence that its major protein component Royalactin, and the mammalian structural analog Regina, maintain pluripotency in mouse ESCs by activating a ground-state pluripotency-like gene network.
- Derrick C. Wan
- , Stefanie L. Morgan
- & Kevin C. Wang
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Article
| Open AccessMTCH2-mediated mitochondrial fusion drives exit from naïve pluripotency in embryonic stem cells
Reprogramming of mitochondria metabolism occurs during naïve to primed pluripotency differentiation in mouse embryonic stem cells (ESCs). Here the authors show that mitochondrial MTCH2 regulates mitochondrial fusion and that this fusion is required for naïve to primed pluripotency conversion
- Amir Bahat
- , Andres Goldman
- & Atan Gross
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Article
| Open AccessA hPSC-based platform to discover gene-environment interactions that impact human β-cell and dopamine neuron survival
Diseases such as diabetes and Parkinson's manifest based on interactions between genes and environment. Here, the authors find among a panel of cell types that propargite, a common pesticide, induces pancreatic β-cell and dopamine neuron death and that loss of the gene GSTT1 confers hypersensitivity.
- Ting Zhou
- , Tae Wan Kim
- & Shuibing Chen
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Article
| Open AccessA distinct isoform of ZNF207 controls self-renewal and pluripotency of human embryonic stem cells
Self-renewal and pluripotency of human embryonic stem cells (hESCs) depends upon the function of the transcription factor OCT4. Here, the authors identified proteins associated with the OCT4 enhancer, notably ZNF207 that maintains both pluripotency and differentiation towards ectoderm through isoform switching.
- Fang Fang
- , Ninuo Xia
- & Renee A. Reijo Pera
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Article
| Open AccessPrecardiac organoids form two heart fields via Bmp/Wnt signaling
The heart arises from distinct progenitor cells of both the first and second heart fields (FHF and SHF). Here, the authors generated precardiac organoids from mouse and human pluripotent cells and show that FHF and SHF cells form similarly to their in vivo counterparts in response to BMP and Wnt signalling, respectively.
- Peter Andersen
- , Emmanouil Tampakakis
- & Chulan Kwon
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Article
| Open AccessNucleoporin 107, 62 and 153 mediate Kcnq1ot1 imprinted domain regulation in extraembryonic endoderm stem cells
Genomic imprinting restricts transcription to predominantly one parental allele. Here the authors perform a screen for epigenetic factors involved in paternal allelic silencing at the Kcnq1ot1 imprinted domain in mouse extraembryonic endoderm stem cells and characterize a role for specific nucleoporins in mediating Kcnq1ot1 imprinted regulation.
- Saqib S. Sachani
- , Lauren S. Landschoot
- & Mellissa R. W. Mann