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| Open AccessCellular reprogramming as a tool to model human aging in a dish
The development of human cellular models of aging that surpass the limitations of animal models of aging is urgent. Here, the authors explore the opportunities and limitations of cellular reprogramming to create reliable aging in vitro models and their potential for the discovery of anti-aging compounds.
- Patricia R. Pitrez
- , Luis M. Monteiro
- & Lino Ferreira
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Article
| Open AccessCellular reprogramming in vivo initiated by SOX4 pioneer factor activity
Upon physiological injury, hepatocytes transdifferentiate into biliary epithelial cells, a process involving molecular rewiring. Here, authors show that Sox4 organizes the early steps, acting as a pioneer factor to decommission hepatocyte enhancers and open chromatin around biliary genes.
- Takeshi Katsuda
- , Jonathan H. Sussman
- & Ben Z. Stanger
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Article
| Open AccessInterplay between coding and non-coding regulation drives the Arabidopsis seed-to-seedling transition
Seed germination in plants is a tightly controlled process relying on translation of stored RNAs. Here, Tremblay et al. show that nascent transcriptome and epigenome reprogramming are detected from initial stages of germination.
- Benjamin J. M. Tremblay
- , Cristina P. Santini
- & Julia I. Qüesta
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Article
| Open AccessCommon and divergent gene regulatory networks control injury-induced and developmental neurogenesis in zebrafish retina
The molecular mechanisms controlling injury-dependent neuronal regeneration are largely unknown. Here, the authors use integrated multiomic analysis to characterize gene regulatory networks controlling injury-induced neurogenesis in zebrafish retina
- Pin Lyu
- , Maria Iribarne
- & Seth Blackshaw
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Article
| Open AccessPAX3-FOXO1 dictates myogenic reprogramming and rhabdomyosarcoma identity in endothelial progenitors
Histologically, PAX3-FOXO1 (P3F) fusion-positive rhabdomyosarcoma (FP-RMS) resembles muscles cells, however, its cell-of-origin is less clear. Here, the authors demonstrate that P3F expression induces endothelial cells reprogramming into functional myogenic stem cells, driving the formation of FP-RMS in mouse models.
- Madeline B. Searcy
- , Randolph K. Larsen IV
- & Mark E. Hatley
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Article
| Open AccessSpecies-specific metabolic reprogramming in human and mouse microglia during inflammatory pathway induction
The innate immune cells undergo metabolic reprogramming upon inflammation. Here, the authors report that both mouse and human microglia display a metabolic reprogramming in the presence of a TLR4 activation, however species-specific enzymes are responsible for this process.
- Angélica María Sabogal-Guáqueta
- , Alejandro Marmolejo-Garza
- & Amalia Dolga
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Article
| Open AccessAscl1 and Ngn2 convert mouse embryonic stem cells to neurons via functionally distinct paths
Expression of transcription factors can convert one cell type to another beyond developmental paths. Here, the authors show that cells can take two mechanistically distinct paths in the same transition paradigm when driven by the similar proneural factors Ascl1 and Ngn2.
- Gintautas Vainorius
- , Maria Novatchkova
- & Ulrich Elling
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Article
| 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 AccessPluripotency-independent induction of human trophoblast stem cells from fibroblasts
In this work Naama et al. describe and deeply characterize a direct approach to produce human induced trophoblast stem cells from fibroblasts and show that it produces superior hiTSCs when compared to OSKM-hiTSCs.
- Moriyah Naama
- , Moran Rahamim
- & Yosef Buganim
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Article
| Open AccessThe NuRD complex cooperates with SALL4 to orchestrate reprogramming
Somatic reprogramming involves both transcriptional and epigenetic resetting, but we don’t yet fully understand this process. Here they show that Jdp2, Glis1, Esrrb, and Sall4 can mediate reprogramming by recruiting the NuRD complex to close chromatin, highlighting a potential role in cell fate control.
- Bo Wang
- , Chen Li
- & Duanqing Pei
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Article
| Open AccessCellular population dynamics shape the route to human pluripotency
The contribution of cell-extrinsic factors during cellular reprogramming to human induced pluripotent stem cells has long been overlooked. Here, the authors show functional protein communication between reprogramming intermediates and the re-shaping of a permissive extracellular environment.
- Francesco Panariello
- , Onelia Gagliano
- & Nicola Elvassore
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Article
| Open AccessFarrerol directly activates the deubiqutinase UCHL3 to promote DNA repair and reprogramming when mediated by somatic cell nuclear transfer
Here the authors find that farrerol directly binds to UCHL3 and activates its deubiquitinase activity, and that farrerol promotes development of SCNT embryos by enhancing HR repair and restoring epigenetic networks in a UCHL3-dependent manner.
- Weina Zhang
- , Mingzhu Wang
- & Ying Jiang
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Article
| Open AccessConserved transcription factors promote cell fate stability and restrict reprogramming potential in differentiated cells
Transdifferentiation has been proposed as an approach for regenerative medicine, but the mechanisms that safeguard cell identity are not well established. Here they identify transcription factors that oppose transdifferentiation and show that knockdown of these genes improves recovery after myocardial infarction.
- Maria A. Missinato
- , Sean Murphy
- & Alexandre R. Colas
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Article
| Open AccessLSM1-mediated Major Satellite RNA decay is required for nonequilibrium histone H3.3 incorporation into parental pronuclei
Asymmetric histone modifications in parental pronuclei displays epigenetic regulation. Here the authors reveal the role of LSM1-mediated Major Satellite RNA decay in the H3 variant incorporation and modifications in male pronucleus.
- Jiang Zhu
- , Kang Chen
- & Lan Kang
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Article
| Open AccessGenetic and pharmacologic inhibition of ALDH1A3 as a treatment of β-cell failure
β-cell dedifferentiation is a key feature of type 2 diabetes. Here, the authors show evidence of re-differentiation of de-differentiated β-cells and identify ALDH1A3 as a key player in this process, proposing inhibition of ALDH1A3 as a treatment method for β-cell dysfunction in diabetes.
- Jinsook Son
- , Wen Du
- & Domenico Accili
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Article
| Open AccessB1 SINE-binding ZFP266 impedes mouse iPSC generation through suppression of chromatin opening mediated by reprogramming factors
Induced pluripotent stem cell (iPSC) reprogramming is inherently inefficient. Here the authors identify 24 reprogramming roadblock genes through a CRISPR/Cas9-mediated genome-wide knockout screen including a KRAB-ZFP Zfp266, knockout of which consistently enhances murine iPSC generation.
- Daniel F. Kaemena
- , Masahito Yoshihara
- & Keisuke Kaji
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Article
| Open AccessRetrotransposon instability dominates the acquired mutation landscape of mouse induced pluripotent stem cells
Retrotransposons are mobile genetic elements normally repressed by DNA methylation in differentiated cells. Here, the authors show that DNA hypomethylation in mouse induced pluripotent stem cells allows retrotransposons to jump, but this can be blocked with a reverse transcriptase inhibitor.
- Patricia Gerdes
- , Sue Mei Lim
- & Geoffrey J. Faulkner
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Article
| Open AccessIL6 supports long-term expansion of hepatocytes in vitro
Hepatocytes are very difficult to expand in vitro. Here the authors discover that IL6 promotes long-term expansion (>30 passages) of primary mouse hepatocytes in vitro by converting the cells into hepatic progenitor cells, which maintain full capacity of differentiation into hepatocytes.
- Ren Guo
- , Mengmeng Jiang
- & Xin Xie
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Article
| Open AccessImprinting fidelity in mouse iPSCs depends on sex of donor cell and medium formulation
Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) is associated with epigenetic alterations. Here the authors assess DNA methylation in detail in multiple female and male mouse iPSC lines generated with different protocols and find that defects depend on the sex of donor cells and can be partially mitigated by Vitamin C.
- Maria Arez
- , Melanie Eckersley-Maslin
- & Simão Teixeira da Rocha
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Article
| Open AccessPregnancy-induced maternal microchimerism shapes neurodevelopment and behavior in mice
During pregnancy, maternal cells are transferred to the fetus, where they can reach the developing brain. In this study, the authors demonstrate that these maternal cells play an important role in neurodevelopment.
- Steven Schepanski
- , Mattia Chini
- & Petra C. Arck
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Article
| Open AccessComparative parallel multi-omics analysis during the induction of pluripotent and trophectoderm states
Ectopic transcription factor expression can reprogram mouse fibroblasts to pluripotent or trophoblast stem cells. Here the authors apply multi-omics analyses to the induction of pluripotency and trophoblast stem cell state from fibroblasts, comparing these with the changes in transcriptome of early embryonic cells.
- Mohammad Jaber
- , Ahmed Radwan
- & Yosef Buganim
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Article
| 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 AccessBMP4 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 AccessExpression of the transcription factor PU.1 induces the generation of microglia-like cells in human cortical organoids
The study of human microglia function in health and disease is limited by the availability of sound models. Here, the authors develop a method to generate functional microglia in human cortical organoids and investigate the role of human microglia during amyloid beta1-42- induced inflammation.
- Bilal Cakir
- , Yoshiaki Tanaka
- & In-Hyun Park
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Article
| Open AccessInduction of Rosette-to-Lumen stage embryoids using reprogramming paradigms in ESCs
Synthetic embryo models have arisen as an approach to probe early development in vitro, facilitating the study of difficult to access stages. Here the authors present a simple system for generating embryo-like structures that resemble peri-implantation mouse embryos.
- Jan Langkabel
- , Arik Horne
- & Hubert Schorle
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Article
| Open AccessComparative epigenetic analysis of tumour initiating cells and syngeneic EPSC-derived neural stem cells in glioblastoma
The identification of patient-specific disease mechanisms and druggable targets is crucial for precision medicine in glioblastoma. Here, the authors show that comparing patients-matched glioma-initiating cells with neural stem cells enables the discovery of patient-specific mechanisms of disease and the identification of effective drugs
- Claire Vinel
- , Gabriel Rosser
- & Silvia Marino
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Article
| Open AccessStemBond 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 AccessLiquid condensation of reprogramming factor KLF4 with DNA provides a mechanism for chromatin organization
KLF4, OCT4, SOX2 and MYC cooperate to reorganize chromatin during somatic cell reprogramming. Here the authors show that KLF4 forms a liquid-like biomolecular condensate that recruits OCT4 and SOX2, and that condensation of the isolated KLF4 DNA binding domain with DNA is enhanced by CpG methylation
- Rajesh Sharma
- , Kyoung-Jae Choi
- & Josephine C. Ferreon
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Article
| Open AccessDMRT1-mediated reprogramming drives development of cancer resembling human germ cell tumors with features of totipotency
The mechanisms by which in vivo expression of the Yamanaka transcription factors (OSKM) renders somatic cells permissive for differentiation remain unclear. Here, the authors show that in vivo reprogramming using OSKM generates germ cell tumors and drives acquisition of totipotency-like features in somatic cells through DMRT1.
- Jumpei Taguchi
- , Hirofumi Shibata
- & Yasuhiro Yamada
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Article
| Open AccessVertically transferred maternal immune cells promote neonatal immunity against early life infections
Maternal immune cells seed into the foetus during mammalian pregnancy, yet the functional role of these cells is unclear. Here the authors show that maternal immune cells in foetal bone marrow stimulate immune development, subsequently reducing the risk or severity of infections in newborns.
- Ina Annelies Stelzer
- , Christopher Urbschat
- & Petra Clara Arck
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Article
| Open AccessYAP1 nuclear efflux and transcriptional reprograming follow membrane diminution upon VSV-G-induced cell fusion
Cells in many tissues fuse into syncytia acquiring new functions. By investigating whether physical remodelling promotes differentiation, here, the authors show that plasma membrane diminution post-fusion causes transient nutrient stress that inhibits YAP1 activity and may reduce proliferation-promoting transcription.
- Daniel Feliciano
- , Carolyn M. Ott
- & Jennifer Lippincott-Schwartz
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Article
| Open AccessChromosome compartments on the inactive X guide TAD formation independently of transcription during X-reactivation
Both A/B compartments and TADs are thought to be absent from the inactive X chromosome, but to be re-established with transcriptional reactivation and chromatin opening during X-reactivation. Here, the authors characterise gene reactivation, chromatin opening and chromosome topology during X-reactivation, observe A/B-like compartments on the inactive X that guide TAD formation independently of transcription during X-reactivation.
- Moritz Bauer
- , Enrique Vidal
- & Bernhard Payer
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Article
| Open AccessA computer-guided design tool to increase the efficiency of cellular conversions
Transcription factor over-expression-based cellular conversion methods often endure low conversion efficiency. Here the authors show how to increase conversion efficiency by combining a computational method for prioritizing more efficient TF combinations with a transposon-based genomic integration system for delivery.
- Sascha Jung
- , Evan Appleton
- & Antonio del Sol
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Article
| Open AccessInduced organoids derived from patients with ulcerative colitis recapitulate colitic reactivity
Although ulcerative colitis (UC) is a major type of inflammatory bowel disease, attempts to model it fully have fallen short. Here the authors use patient-derived iPS cells to develop a UC organoid model that recapitulates disease histological and functional features, and confirm the role of CXCL8/CXCR1 in pathogenesis.
- Samaneh K. Sarvestani
- , Steven Signs
- & Emina H. Huang
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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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Article
| Open AccessTp63-expressing adult epithelial stem cells cross lineages boundaries revealing latent hairy skin competence
Adult stem cells are thought to be fate restricted to lineages distinct to their tissue of origin. Here, the authors demonstrate that Tp63 expressing epithelial stem cells from several disparate tissues can respond to skin morphogenetic signals and contribute to hair follicles, sebaceous glands and/or epidermis.
- Stéphanie Claudinot
- , Jun-Ichi Sakabe
- & Yann Barrandon
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Article
| Open AccessDirect reprogramming of human umbilical vein- and peripheral blood-derived endothelial cells into hepatic progenitor cells
The conditions to induce human hepatic progenitor cells from other cell types are unclear. Here, the authors reprogram human endothelial cells to hepatic progenitor cells by expressing FOXA3, HNF1A and HNF6, capable of giving rise to hepatocytes and cholangiocytes that reconstitute damaged liver tissues on transplantation.
- Hiroki Inada
- , Miyako Udono
- & Atsushi Suzuki
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Article
| Open AccessJMJD3 acts in tandem with KLF4 to facilitate reprogramming to pluripotency
Previous work suggested that histone demethylase JMJD3 is detrimental to somatic cell reprogramming. Here, the authors show that while JMJD3 has a context-independent detrimental effect on early stages of reprogramming, during late stages it activates epithelial and pluripotency genes together with Klf4.
- Yinghua Huang
- , Hui Zhang
- & Baoming Qin
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Article
| 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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Article
| 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 AccessLoss of H3K27me3 imprinting in the Sfmbt2 miRNA cluster causes enlargement of cloned mouse placentas
Somatic cell nuclear transfer (SCNT) frequently results in abnormal placenta development in cloned mice. Here the authors show that loss of histone methylation (H3K27me3) imprinting in clustered Sfmbt2 miRNAs contributes to SCNT placenta defect.
- Kimiko Inoue
- , Narumi Ogonuki
- & Atsuo Ogura
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Article
| Open AccessChromatin architecture reorganization in murine somatic cell nuclear transfer embryos
The organisation of chromatin in somatic cell nuclear transfer (SCNT) embryos remains poorly understood. Here, the authors examine higher order chromatin structures of mouse SCNT embryos and provide insights into chromatin architecture reorganisation during SCNT embryo development.
- Mo Chen
- , Qianshu Zhu
- & Shaorong Gao
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Article
| Open AccessTransient non-integrative expression of nuclear reprogramming factors promotes multifaceted amelioration of aging in human cells
Aging involves gradual loss of tissue function, and transcription factor (TF) expression can ameliorate this in progeroid mice. Here the authors show that transient TF expression reverses age-associated epigenetic marks, inflammatory profiles and restores regenerative potential in naturally aged human cells.
- Tapash Jay Sarkar
- , Marco Quarta
- & Vittorio Sebastiano
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Article
| Open AccessGenetic aberrations in iPSCs are introduced by a transient G1/S cell cycle checkpoint deficiency
Point mutations have been found in induced pluripotent stem cells (iPSCs) but when they arise is unclear. Here, the authors show that a G1/S cell cycle checkpoint deficiency transiently occurs early in genome reprogramming, suggesting a common developmental pathway between iPSC and tumorigenesis, and generate genetic burden-free human iPSCs.
- Ryoko Araki
- , Yuko Hoki
- & Masumi Abe
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Article
| Open AccessRenewed proliferation in adult mouse cochlea and regeneration of hair cells
The adult mammalian inner ear cells cannot regenerate nor proliferate. Here, the authors show that co-activation of Myc and NOTCH pathways can stimulate proliferation of inner ear sensory epithelial cells, which can be induced to become hair cell-like cells in vitro and in vivo.
- Yilai Shu
- , Wenyan Li
- & Zheng-Yi Chen
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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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Article
| Open AccessCell-type dependent enhancer binding of the EWS/ATF1 fusion gene in clear cell sarcomas
The EWS-ATF1 fusion gene causes clear cell sarcoma (CCS). Here, the authors show that the downstream effects of EWS-ATF1 expression are strictly context dependent, and reveal the cell of origin for CCS to be Tppp3-expressing cells in peripheral nerves.
- Shingo Komura
- , Kenji Ito
- & Yasuhiro Yamada
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Article
| Open AccessPluripotency reprogramming by competent and incompetent POU factors uncovers temporal dependency for Oct4 and Sox2
Oct4, along with Sox2 and Klf4 can induce pluripotency, but structurally similar factors like Oct6 cannot. Here, using pluripotency competent and incompetent factors, the authors show that Sox2 plays a dominant role in facilitating chromatin opening at Oct4 bound DNA early during reprogramming to pluripotency.
- Vikas Malik
- , Laura V. Glaser
- & Ralf Jauch
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Article
| Open AccessTargeted removal of epigenetic barriers during transcriptional reprogramming
Master transcription factors dominantly direct cell fate and barriers ensuring their tissue specific silencing are not clearly defined. Here, the authors demonstrate that inefficient targeted transactivation of Sox1 in neural progenitor cells is surmountable through targeted promoter demethylation using dCas9-Tet1.
- Valentin Baumann
- , Maximilian Wiesbeck
- & Stefan H. Stricker