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The EMBO Journal
Number of Followers: 58  
 
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ISSN (Print) 0261-4189 - ISSN (Online) 1460-2075
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  • The Nucleosome Remodelling and Deacetylation complex suppresses
           transcriptional noise during lineage commitment

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      Authors: Burgold, T; Barber, M, Kloet, S, Cramard, J, Gharbi, S, Floyd, R, Kinoshita, M, Ralser, M, Vermeulen, M, Reynolds, N, Dietmann, S, Hendrich, B.
      Abstract: Multiprotein chromatin remodelling complexes show remarkable conservation of function amongst metazoans, even though components present in invertebrates are often found as multiple paralogous proteins in vertebrate complexes. In some cases, these paralogues specify distinct biochemical and/or functional activities in vertebrate cells. Here, we set out to define the biochemical and functional diversity encoded by one such group of proteins within the mammalian Nucleosome Remodelling and Deacetylation (NuRD) complex: Mta1, Mta2 and Mta3. We find that, in contrast to what has been described in somatic cells, MTA proteins are not mutually exclusive within embryonic stem (ES) cell NuRD and, despite subtle differences in chromatin binding and biochemical interactions, serve largely redundant functions. ES cells lacking all three MTA proteins exhibit complete NuRD loss of function and are viable, allowing us to identify a previously unreported function for NuRD in reducing transcriptional noise, which is essential for maintaining a proper differentiation trajectory during early stages of lineage commitment.
      Keywords: Development & Differentiation, Stem Cells, Transcription
      PubDate: 2019-06-17T00:05:23-07:00
      DOI: 10.15252/embj.2018100788
      Issue No: Vol. 38, No. 12 (2019)
       
  • Live-cell imaging reveals the interplay between transcription factors,
           nucleosomes, and bursting

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      Authors: Donovan, B. T; Huynh, A, Ball, D. A, Patel, H. P, Poirier, M. G, Larson, D. R, Ferguson, M. L, Lenstra, T. L.
      Abstract: Transcription factors show rapid and reversible binding to chromatin in living cells, and transcription occurs in sporadic bursts, but how these phenomena are related is unknown. Using a combination of in vitro and in vivo single-molecule imaging approaches, we directly correlated binding of the Gal4 transcription factor with the transcriptional bursting kinetics of the Gal4 target genes GAL3 and GAL10 in living yeast cells. We find that Gal4 dwell time sets the transcriptional burst size. Gal4 dwell time depends on the affinity of the binding site and is reduced by orders of magnitude by nucleosomes. Using a novel imaging platform called orbital tracking, we simultaneously tracked transcription factor binding and transcription at one locus, revealing the timing and correlation between Gal4 binding and transcription. Collectively, our data support a model in which multiple RNA polymerases initiate transcription during one burst as long as the transcription factor is bound to DNA, and bursts terminate upon transcription factor dissociation.
      Keywords: Transcription
      PubDate: 2019-06-17T00:05:23-07:00
      DOI: 10.15252/embj.2018100809
      Issue No: Vol. 38, No. 12 (2019)
       
  • 3D model for CAR-mediated cytotoxicity using patient-derived colorectal
           cancer organoids

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      Authors: Schnalzger, T. E; de Groot, M. H, Zhang, C, Mosa, M. H, Michels, B. E, Röder, J, Darvishi, T, Wels, W. S, Farin, H. F.
      Abstract: Immunotherapy using chimeric antigen receptor (CAR)-engineered lymphocytes has shown impressive results in leukemia. However, for solid tumors such as colorectal cancer (CRC), new preclinical models are needed that allow to test CAR-mediated cytotoxicity in a tissue-like environment. Here, we developed a platform to study CAR cell cytotoxicity against 3-dimensional (3D) patient-derived colon organoids. Luciferase-based measurement served as a quantitative read-out for target cell viability. Additionally, we set up a confocal live imaging protocol to monitor effector cell recruitment and cytolytic activity at a single organoid level. As proof of principle, we demonstrated efficient targeting in diverse organoid models using CAR-engineered NK-92 cells directed toward a ubiquitous epithelial antigen (EPCAM). Tumor antigen-specific cytotoxicity was studied with CAR-NK-92 cells targeting organoids expressing EGFRvIII, a neoantigen found in several cancers. Finally, we tested a novel CAR strategy targeting FRIZZLED receptors that show increased expression in a subgroup of CRC tumors. Here, comparative killing assays with normal organoids failed to show tumor-specific activity. Taken together, we report a sensitive in vitro platform to evaluate CAR efficacy and tumor specificity in a personalized manner.
      Keywords: Cancer, Immunology, Methods & Resources
      PubDate: 2019-06-17T00:05:23-07:00
      DOI: 10.15252/embj.2018100928
      Issue No: Vol. 38, No. 12 (2019)
       
  • Epigenetic aberrations in human pluripotent stem cells

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      Authors: Bar, S; Benvenisty, N.
      Abstract: Human pluripotent stem cells (hPSCs) are being increasingly utilized worldwide in investigating human development, and modeling and discovering therapies for a wide range of diseases as well as a source for cellular therapy. Yet, since the first isolation of human embryonic stem cells (hESCs) 20 years ago, followed by the successful reprogramming of human-induced pluripotent stem cells (hiPSCs) 10 years later, various studies shed light on abnormalities that sometimes accumulate in these cells in vitro. Whereas genetic aberrations are well documented, epigenetic alterations are not as thoroughly discussed. In this review, we highlight frequent epigenetic aberrations found in hPSCs, including alterations in DNA methylation patterns, parental imprinting, and X chromosome inactivation. We discuss the potential origins of these abnormalities in hESCs and hiPSCs, survey the different methods for detecting them, and elaborate on their potential consequences for the different utilities of hPSCs.
      Keywords: Chromatin, Epigenetics, Genomics & Functional Genomics, Development & Differentiation, Stem Cells
      PubDate: 2019-06-17T00:05:23-07:00
      DOI: 10.15252/embj.2018101033
      Issue No: Vol. 38, No. 12 (2019)
       
  • Expression of endogenous retroviruses reflects increased usage of atypical
           enhancers in T cells

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      Authors: Azebi, S; Batsche, E, Michel, F, Kornobis, E, Muchardt, C.
      Abstract: Several autoimmune diseases including multiple sclerosis (MS) cause increased transcription of endogenous retroviruses (HERVs) normally repressed by heterochromatin. In parallel, HERV-derived sequences were reported to drive gene expression. Here, we have examined a possible link between promoter and enhancer divergent transcription and the production of HERV transcripts. We find that HERV-derived sequences are in general counter-selected at regulatory regions, a counter-selection that is strongest in brain tissues while very moderate in stem cells. By exposing T cells to the pesticide dieldrin, we further found that a series of HERV-driven enhancers otherwise active only at stem cell stages can be reactivated by stress. This in part relies on peptidylarginine deiminase activity, possibly participating in the reawakening of silenced enhancers. Likewise, usage of HERV-driven enhancers was increased in myelin-reactive T cells from patients with MS, correlating with activation of nearby genes at several sites. Altogether, we propose that HERV-driven enhancers constitute a reservoir of auxiliary enhancers transiently induced by stress while chronically active in diseases like MS.
      Keywords: Chromatin, Epigenetics, Genomics & Functional Genomics, Molecular Biology of Disease
      PubDate: 2019-06-17T00:05:23-07:00
      DOI: 10.15252/embj.2018101107
      Issue No: Vol. 38, No. 12 (2019)
       
  • Nutrient-sensitive transcription factors TFEB and TFE3 couple autophagy
           and metabolism to the peripheral clock

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      Authors: Pastore, N; Vainshtein, A, Herz, N. J, Huynh, T, Brunetti, L, Klisch, T. J, Mutarelli, M, Annunziata, P, Kinouchi, K, Brunetti-Pierri, N, Sassone-Corsi, P, Ballabio, A.
      Abstract: Autophagy and energy metabolism are known to follow a circadian pattern. However, it is unclear whether autophagy and the circadian clock are coordinated by common control mechanisms. Here, we show that the oscillation of autophagy genes is dependent on the nutrient-sensitive activation of TFEB and TFE3, key regulators of autophagy, lysosomal biogenesis, and cell homeostasis. TFEB and TFE3 display a circadian activation over the 24-h cycle and are responsible for the rhythmic induction of genes involved in autophagy during the light phase. Genetic ablation of TFEB and TFE3 in mice results in deregulated autophagy over the diurnal cycle and altered gene expression causing abnormal circadian wheel-running behavior. In addition, TFEB and TFE3 directly regulate the expression of Rev-erbα (Nr1d1), a transcriptional repressor component of the core clock machinery also involved in the regulation of whole-body metabolism and autophagy. Comparative analysis of the cistromes of TFEB/TFE3 and REV-ERBα showed an extensive overlap of their binding sites, particularly in genes involved in autophagy and metabolic functions. These data reveal a direct link between nutrient and clock-dependent regulation of gene expression shedding a new light on the crosstalk between autophagy, metabolism, and circadian cycles.
      Keywords: Autophagy & Cell Death, Metabolism, Transcription
      PubDate: 2019-06-17T00:05:23-07:00
      DOI: 10.15252/embj.2018101347
      Issue No: Vol. 38, No. 12 (2019)
       
  • Anoctamin 8 tethers endoplasmic reticulum and plasma membrane for assembly
           of Ca2+ signaling complexes at the ER/PM compartment

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      Authors: Jha, A; Chung, W. Y, Vachel, L, Maleth, J, Lake, S, Zhang, G, Ahuja, M, Muallem, S.
      Abstract: Communication and material transfer between membranes and organelles take place at membrane contact sites (MCSs). MCSs between the ER and PM, the ER/PM junctions, are the sites where the ER Ca2+ sensor STIM1 and the PM Ca2+ influx channel Orai1 cluster. MCSs are formed by tether proteins that bridge the opposing membranes, but the identity and role of these tethers in receptor-evoked Ca2+ signaling is not well understood. Here, we identified Anoctamin 8 (ANO8) as a key tether in the formation of the ER/PM junctions that is essential for STIM1-STIM1 interaction and STIM1-Orai1 interaction and channel activation at a ER/PM PI(4,5)P2-rich compartment. Moreover, ANO8 assembles all core Ca2+ signaling proteins: Orai1, PMCA, STIM1, IP3 receptors, and SERCA2 at the ER/PM junctions to mediate a novel form of Orai1 channel inactivation by markedly facilitating SERCA2-mediated Ca2+ influx into the ER. This controls the efficiency of receptor-stimulated Ca2+ signaling, Ca2+ oscillations, and duration of Orai1 activity to prevent Ca2+ toxicity. These findings reveal the central role of MCSs in determining efficiency and fidelity of cell signaling.
      Keywords: Membrane & Intracellular Transport, Signal Transduction
      PubDate: 2019-06-17T00:05:23-07:00
      DOI: 10.15252/embj.2018101452
      Issue No: Vol. 38, No. 12 (2019)
       
  • Extracellular interface between APP and Nicastrin regulates A{beta} length
           and response to {gamma}-secretase modulators

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      Authors: Petit, D; Hitzenberger, M, Lismont, S, Zoltowska, K. M, Ryan, N. S, Mercken, M, Bischoff, F, Zacharias, M, Chavez-Gutierrez, L.
      Abstract: -Secretase complexes (GSECs) are multimeric membrane proteases involved in a variety of physiological processes and linked to Alzheimer's disease (AD). Presenilin (PSEN, catalytic subunit), Nicastrin (NCT), Presenilin Enhancer 2 (PEN-2), and Anterior Pharynx Defective 1 (APH1) are the essential subunits of GSECs. Mutations in PSEN and the Amyloid Precursor Protein (APP) cause early-onset AD. GSECs successively cut APP to generate amyloid-β (Aβ) peptides of various lengths. AD-causing mutations destabilize GSEC-APP/Aβn interactions and thus enhance the production of longer Aβs, which elicit neurotoxic events underlying pathogenesis. Here, we investigated the molecular strategies that anchor GSEC and APP/Aβn during the sequential proteolysis. Our studies reveal that a direct interaction between NCT ectodomain and APPC99 influences the stability of GSEC-Aβn assemblies and thereby modulates Aβ length. The data suggest a potential link between single-nucleotide variants in NCSTN and AD risk. Furthermore, our work indicates that an extracellular interface between the protease (NCT, PSEN) and the substrate (APP) represents the target for compounds (GSMs) modulating Aβ length. Our findings may guide future rationale-based drug discovery efforts.
      Keywords: Molecular Biology of Disease, Neuroscience, Post-translational Modifications, Proteolysis & Proteomics
      PubDate: 2019-06-17T00:05:23-07:00
      DOI: 10.15252/embj.2019101494
      Issue No: Vol. 38, No. 12 (2019)
       
  • Bronchioalveolar stem cells are a main source for regeneration of distal
           lung epithelia in vivo

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      Authors: Salwig, I; Spitznagel, B, Vazquez-Armendariz, A. I, Khalooghi, K, Guenther, S, Herold, S, Szibor, M, Braun, T.
      Abstract: Bronchioalveolar stem cells (BASCs) are a potential source for lung regeneration, but direct in vivo evidence for a multipotential lineage contribution during homeostasis and disease is critically missing, since specific genetic labeling of BASCs has not been possible. We developed a novel cell tracing approach based on intein-mediated assembly of newly engineered split-effectors, allowing selective targeting of dual-marker expressing BASCs in the mouse lung. RNA sequencing of isolated BASCs demonstrates that BASCs show a distinct transcriptional profile, characterized by co-expression of bronchiolar and alveolar epithelial genes. We found that BASCs generate the majority of distal lung airway cells after bronchiolar damage but only moderately contribute to cellular turnover under homeostatic conditions. Importantly, DTA-mediated ablation of BASCs compromised proper regeneration of distal airways. The study defines BASCs as crucial components of the lung repair machinery and provides a paradigmatic example for the detection and manipulation of stem cells that cannot be recognized by a single marker alone.
      Keywords: Development & Differentiation, Immunology, Stem Cells
      PubDate: 2019-06-17T00:05:23-07:00
      DOI: 10.15252/embj.2019102099
      Issue No: Vol. 38, No. 12 (2019)
       
  • BASC-ing in the glow: bronchioalveolar stem cells get their place in the
           lung

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      Authors: Basil, M. C; Morrisey, E. E.
      Abstract: Lung epithelial progenitor cell populations fulfill the needs of this complex facultative regenerative organ when exposed to insult and contribute to repair in either the airway or alveolar compartments. The presence of a cell that can populate both epithelia had been proposed previously but has remained elusive. In this issue, Salwig et al (2019) provide compelling, genetic evidence that supports a growing narrative—a rare population of bronchioalveolar stem cells (BASCs) that can contribute to both airway and alveolar epithelium in the distal murine lung.
      Keywords: Development & Differentiation, Immunology, Stem Cells
      PubDate: 2019-06-17T00:05:23-07:00
      DOI: 10.15252/embj.2019102344
      Issue No: Vol. 38, No. 12 (2019)
       
  • Autophagy: clocking in for the night shift

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      Authors: Brooks, R. C; Dang, C. V.
      Abstract: Daily rhythms of biological activity, such as cycles of sleep–wake and feeding–fasting, are coupled to cell-autonomous circadian clocks to synchronize organismal food intake with cellular bioenergetics. Food intake during wake stimulates biosynthesis followed by rest periods of autophagy, which degrades damaged macromolecules and recycles them as nutrients to enhance fitness. In this issue of The EMBO Journal, Pastore et al discovered that regulators of autophagy, TFEB and TFE3, are activated during the rest phase and ultimately drive the expression of Rev-erbα, a component of the core circadian molecular clock, coupling autophagy and the clock.
      Keywords: Autophagy & Cell Death, Metabolism, Molecular Biology of Disease
      PubDate: 2019-06-17T00:05:23-07:00
      DOI: 10.15252/embj.2019102434
      Issue No: Vol. 38, No. 12 (2019)
       
  • Retraction: "CITRX thioredoxin interacts with the tomato Cf-9 resistance
           protein and negatively regulates defence"

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      Authors: Rivas, S; Rougon-Cardoso, A, Smoker, M, Schauser, L, Yoshioka, H, Jones, J. D.
      PubDate: 2019-06-17T00:05:23-07:00
      DOI: 10.15252/embj.2019102435
      Issue No: Vol. 38, No. 12 (2019)
       
 
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