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Journal Cover Cell
  [SJR: 28.188]   [H-I: 616]   [836 followers]  Follow
    
   Full-text available via subscription Subscription journal
   ISSN (Print) 0092-8674 - ISSN (Online) 1097-4172
   Published by Elsevier Homepage  [3043 journals]
  • The Coming Peptide Tidal Wave
    • Abstract: Publication date: 19 October 2017
      Source:Cell, Volume 171, Issue 3
      Author(s): Robert P. Kruger


      PubDate: 2017-10-19T19:34:49Z
       
  • FUS Zigzags Its Way to Cross Beta
    • Abstract: Publication date: 19 October 2017
      Source:Cell, Volume 171, Issue 3
      Author(s): Alex S. Holehouse, Rohit V. Pappu
      The low-complexity domain (LCD) of the FUS protein forms concentration-dependent assemblies, including liquid droplets and fibril-based hydrogels. The molecular structures of FUS within different assemblies and their functional relevance are subjects of intense debate. Murray et al. report an atomic-level structural model for FUS LCD fibrils that answers some questions and raises new ones.
      Teaser The low-complexity domain (LCD) of the FUS protein forms concentration-dependent assemblies, including liquid droplets and fibril-based hydrogels. The molecular structures of FUS within different assemblies and their functional relevance are subjects of intense debate. Murray et al. report an atomic-level structural model for FUS LCD fibrils that answers some questions and raises new ones.

      PubDate: 2017-10-19T19:34:49Z
       
  • Transforming Lipoxygenases: PE-Specific Enzymes in Disguise
    • Abstract: Publication date: 19 October 2017
      Source:Cell, Volume 171, Issue 3
      Author(s): Ling F. Ye, Brent R. Stockwell
      In this issue of Cell, Wenzel et al. solve a long-standing mystery regarding how damage to cell membranes occurs during ferroptosis, an iron-dependent form of regulated cell death. They found that lipoxygenases are like Transformer toys, being converted from one enzyme type to another in the presence of the protein PEBP1.
      Teaser In this issue of Cell, Wenzel et al. solve a long-standing mystery regarding how damage to cell membranes occurs during ferroptosis, an iron-dependent form of regulated cell death. They found that lipoxygenases are like Transformer toys, being converted from one enzyme type to another in the presence of the protein PEBP1.

      PubDate: 2017-10-19T19:34:49Z
       
  • Friends in Low Places: Intestinal Commensals Limit Colitis through
           Molecular Mimicry
    • Abstract: Publication date: 19 October 2017
      Source:Cell, Volume 171, Issue 3
      Author(s): D. Garrett Brown, June L. Round
      Inflammatory bowel disease is thought to arise from inappropriate inflammation to gut bacteria, yet mechanisms preventing these responses remain elusive. In this issue of Cell, Nanjundappa et al. report that Bacteroides share an epitope with a pancreas-specific peptide that induces protective CD8+ T cells, identifying molecular mimicry as a mechanism to enforce tolerance in the gut.
      Teaser Inflammatory bowel disease is thought to arise from inappropriate inflammation to gut bacteria, yet mechanisms preventing these responses remain elusive. In this issue of Cell, Nanjundappa et al. report that Bacteroides share an epitope with a pancreas-specific peptide that induces protective CD8+ T cells, identifying molecular mimicry as a mechanism to enforce tolerance in the gut.

      PubDate: 2017-10-19T19:34:49Z
       
  • Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer
    • Abstract: Publication date: 19 October 2017
      Source:Cell, Volume 171, Issue 3
      Author(s): A. Gordon Robertson, Jaegil Kim, Hikmat Al-Ahmadie, Joaquim Bellmunt, Guangwu Guo, Andrew D. Cherniack, Toshinori Hinoue, Peter W. Laird, Katherine A. Hoadley, Rehan Akbani, Mauro A.A. Castro, Ewan A. Gibb, Rupa S. Kanchi, Dmitry A. Gordenin, Sachet A. Shukla, Francisco Sanchez-Vega, Donna E. Hansel, Bogdan A. Czerniak, Victor E. Reuter, Xiaoping Su, Benilton de Sa Carvalho, Vinicius S. Chagas, Karen L. Mungall, Sara Sadeghi, Chandra Sekhar Pedamallu, Yiling Lu, Leszek J. Klimczak, Jiexin Zhang, Caleb Choo, Akinyemi I. Ojesina, Susan Bullman, Kristen M. Leraas, Tara M. Lichtenberg, Catherine J. Wu, Nicholaus Schultz, Gad Getz, Matthew Meyerson, Gordon B. Mills, David J. McConkey, John N. Weinstein, David J. Kwiatkowski, Seth P. Lerner
      We report a comprehensive analysis of 412 muscle-invasive bladder cancers characterized by multiple TCGA analytical platforms. Fifty-eight genes were significantly mutated, and the overall mutational load was associated with APOBEC-signature mutagenesis. Clustering by mutation signature identified a high-mutation subset with 75% 5-year survival. mRNA expression clustering refined prior clustering analyses and identified a poor-survival “neuronal” subtype in which the majority of tumors lacked small cell or neuroendocrine histology. Clustering by mRNA, long non-coding RNA (lncRNA), and miRNA expression converged to identify subsets with differential epithelial-mesenchymal transition status, carcinoma in situ scores, histologic features, and survival. Our analyses identified 5 expression subtypes that may stratify response to different treatments.
      Graphical abstract image Teaser A multiplatform analysis of 412 muscle-invasive bladder cancer patients provides insights into mutational profiles with prognostic value and establishes a framework associating distinct tumor subtypes with clinical options.

      PubDate: 2017-10-19T19:34:49Z
       
  • Multiscale 3D Genome Rewiring during Mouse Neural Development
    • Abstract: Publication date: 19 October 2017
      Source:Cell, Volume 171, Issue 3
      Author(s): Boyan Bonev, Netta Mendelson Cohen, Quentin Szabo, Lauriane Fritsch, Giorgio L. Papadopoulos, Yaniv Lubling, Xiaole Xu, Xiaodan Lv, Jean-Philippe Hugnot, Amos Tanay, Giacomo Cavalli
      Chromosome conformation capture technologies have revealed important insights into genome folding. Yet, how spatial genome architecture is related to gene expression and cell fate remains unclear. We comprehensively mapped 3D chromatin organization during mouse neural differentiation in vitro and in vivo, generating the highest-resolution Hi-C maps available to date. We found that transcription is correlated with chromatin insulation and long-range interactions, but dCas9-mediated activation is insufficient for creating TAD boundaries de novo. Additionally, we discovered long-range contacts between gene bodies of exon-rich, active genes in all cell types. During neural differentiation, contacts between active TADs become less pronounced while inactive TADs interact more strongly. An extensive Polycomb network in stem cells is disrupted, while dynamic interactions between neural transcription factors appear in vivo. Finally, cell type-specific enhancer-promoter contacts are established concomitant to gene expression. This work shows that multiple factors influence the dynamics of chromatin interactions in development.
      Graphical abstract image Teaser An ultrahigh resolution Hi-C map of mouse neural differentiation yields insights into the multiple factors that influence the dynamics of chromatin interactions during development.

      PubDate: 2017-10-19T19:34:49Z
       
  • Structural Basis for a Safety-Belt Mechanism That Anchors Condensin to
           Chromosomes
    • Abstract: Publication date: 19 October 2017
      Source:Cell, Volume 171, Issue 3
      Author(s): Marc Kschonsak, Fabian Merkel, Shveta Bisht, Jutta Metz, Vladimir Rybin, Markus Hassler, Christian H. Haering
      Condensin protein complexes coordinate the formation of mitotic chromosomes and thereby ensure the successful segregation of replicated genomes. Insights into how condensin complexes bind to chromosomes and alter their topology are essential for understanding the molecular principles behind the large-scale chromatin rearrangements that take place during cell divisions. Here, we identify a direct DNA-binding site in the eukaryotic condensin complex, which is formed by its Ycg1Cnd3 HEAT-repeat and Brn1Cnd2 kleisin subunits. DNA co-crystal structures reveal a conserved, positively charged groove that accommodates the DNA double helix. A peptide loop of the kleisin subunit encircles the bound DNA and, like a safety belt, prevents its dissociation. Firm closure of the kleisin loop around DNA is essential for the association of condensin complexes with chromosomes and their DNA-stimulated ATPase activity. Our data suggest a sophisticated molecular basis for anchoring condensin complexes to chromosomes that enables the formation of large-sized chromatin loops.
      Graphical abstract image Teaser Condensin uses a peptide strap to anchor dsDNA to itself, providing a possible basis for DNA loop formation.

      PubDate: 2017-10-19T19:34:49Z
       
  • PEBP1 Wardens Ferroptosis by Enabling Lipoxygenase Generation of Lipid
           Death Signals
    • Abstract: Publication date: 19 October 2017
      Source:Cell, Volume 171, Issue 3
      Author(s): Sally E. Wenzel, Yulia Y. Tyurina, Jinming Zhao, Claudette M. St. Croix, Haider H. Dar, Gaowei Mao, Vladimir A. Tyurin, Tamil S. Anthonymuthu, Alexandr A. Kapralov, Andrew A. Amoscato, Karolina Mikulska-Ruminska, Indira H. Shrivastava, Elizabeth M. Kenny, Qin Yang, Joel C. Rosenbaum, Louis J. Sparvero, David R. Emlet, Xiaoyan Wen, Yoshinori Minami, Feng Qu, Simon C. Watkins, Theodore R. Holman, Andrew P. VanDemark, John A. Kellum, Ivet Bahar, Hülya Bayır, Valerian E. Kagan
      Ferroptosis is a form of programmed cell death that is pathogenic to several acute and chronic diseases and executed via oxygenation of polyunsaturated phosphatidylethanolamines (PE) by 15-lipoxygenases (15-LO) that normally use free polyunsaturated fatty acids as substrates. Mechanisms of the altered 15-LO substrate specificity are enigmatic. We sought a common ferroptosis regulator for 15LO. We discovered that PEBP1, a scaffold protein inhibitor of protein kinase cascades, complexes with two 15LO isoforms, 15LO1 and 15LO2, and changes their substrate competence to generate hydroperoxy-PE. Inadequate reduction of hydroperoxy-PE due to insufficiency or dysfunction of a selenoperoxidase, GPX4, leads to ferroptosis. We demonstrated the importance of PEBP1-dependent regulatory mechanisms of ferroptotic death in airway epithelial cells in asthma, kidney epithelial cells in renal failure, and cortical and hippocampal neurons in brain trauma. As master regulators of ferroptotic cell death with profound implications for human disease, PEBP1/15LO complexes represent a new target for drug discovery.
      Graphical abstract image Teaser The small scaffolding protein PEBP1 regulates ferroptotic cell death by binding with lipoxygenases and allowing them to generate lipid peroxides.

      PubDate: 2017-10-19T19:34:49Z
       
  • mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from
           Lysosomes and Use Protein as a Nutrient
    • Abstract: Publication date: 19 October 2017
      Source:Cell, Volume 171, Issue 3
      Author(s): Gregory A. Wyant, Monther Abu-Remaileh, Rachel L. Wolfson, Walter W. Chen, Elizaveta Freinkman, Laura V. Danai, Matthew G. Vander Heiden, David M. Sabatini
      The mTORC1 kinase is a master growth regulator that senses many environmental cues, including amino acids. Activation of mTORC1 by arginine requires SLC38A9, a poorly understood lysosomal membrane protein with homology to amino acid transporters. Here, we validate that SLC38A9 is an arginine sensor for the mTORC1 pathway, and we uncover an unexpectedly central role for SLC38A9 in amino acid homeostasis. SLC38A9 mediates the transport, in an arginine-regulated fashion, of many essential amino acids out of lysosomes, including leucine, which mTORC1 senses through the cytosolic Sestrin proteins. SLC38A9 is necessary for leucine generated via lysosomal proteolysis to exit lysosomes and activate mTORC1. Pancreatic cancer cells, which use macropinocytosed protein as a nutrient source, require SLC38A9 to form tumors. Thus, through SLC38A9, arginine serves as a lysosomal messenger that couples mTORC1 activation to the release from lysosomes of the essential amino acids needed to drive cell growth.
      Graphical abstract image Teaser SLC38A9 is an arginine-regulated transporter of major amino acids, including leucine, providing insights into the regulation of the mTORC pathway and its nutrient-sensing function.

      PubDate: 2017-10-19T19:34:49Z
       
  • A Gut Microbial Mimic that Hijacks Diabetogenic Autoreactivity to Suppress
           Colitis
    • Abstract: Publication date: 19 October 2017
      Source:Cell, Volume 171, Issue 3
      Author(s): Roopa Hebbandi Nanjundappa, Francesca Ronchi, Jinguo Wang, Xavier Clemente-Casares, Jun Yamanouchi, Channakeshava Sokke Umeshappa, Yang Yang, Jesús Blanco, Helena Bassolas-Molina, Azucena Salas, Hamza Khan, Robyn M. Slattery, Madeleine Wyss, Catherine Mooser, Andrew J. Macpherson, Laura K. Sycuro, Pau Serra, Derek M. McKay, Kathy D. McCoy, Pere Santamaria
      The gut microbiota contributes to the development of normal immunity but, when dysregulated, can promote autoimmunity through various non-antigen-specific effects on pathogenic and regulatory lymphocytes. Here, we show that an integrase expressed by several species of the gut microbial genus Bacteroides encodes a low-avidity mimotope of the pancreatic β cell autoantigen islet-specific glucose-6-phosphatase-catalytic-subunit-related protein (IGRP206-214). Studies in germ-free mice monocolonized with integrase-competent, integrase-deficient, and integrase-transgenic Bacteroides demonstrate that the microbial epitope promotes the recruitment of diabetogenic CD8+ T cells to the gut. There, these effectors suppress colitis by targeting microbial antigen-loaded, antigen-presenting cells in an integrin β7-, perforin-, and major histocompatibility complex class I-dependent manner. Like their murine counterparts, human peripheral blood T cells also recognize Bacteroides integrase. These data suggest that gut microbial antigen-specific cytotoxic T cells may have therapeutic value in inflammatory bowel disease and unearth molecular mimicry as a novel mechanism by which the gut microbiota can regulate normal immune homeostasis. PaperClip
      Graphical abstract image Teaser A microbiome-generated molecule that acts as a molecular mimic of a human disease-linked autoantigen is surprisingly protective against host colitis and may be more broadly involved in maintaining gut immune homeostasis.

      PubDate: 2017-10-19T19:34:49Z
       
  • EGFR Ligands Differentially Stabilize Receptor Dimers to Specify Signaling
           Kinetics
    • Abstract: Publication date: 19 October 2017
      Source:Cell, Volume 171, Issue 3
      Author(s): Daniel M. Freed, Nicholas J. Bessman, Anatoly Kiyatkin, Emanuel Salazar-Cavazos, Patrick O. Byrne, Jason O. Moore, Christopher C. Valley, Kathryn M. Ferguson, Daniel J. Leahy, Diane S. Lidke, Mark A. Lemmon
      Epidermal growth factor receptor (EGFR) regulates many crucial cellular programs, with seven different activating ligands shaping cell signaling in distinct ways. Using crystallography and other approaches, we show how the EGFR ligands epiregulin (EREG) and epigen (EPGN) stabilize different dimeric conformations of the EGFR extracellular region. As a consequence, EREG or EPGN induce less stable EGFR dimers than EGF—making them partial agonists of EGFR dimerization. Unexpectedly, this weakened dimerization elicits more sustained EGFR signaling than seen with EGF, provoking responses in breast cancer cells associated with differentiation rather than proliferation. Our results reveal how responses to different EGFR ligands are defined by receptor dimerization strength and signaling dynamics. These findings have broad implications for understanding receptor tyrosine kinase (RTK) signaling specificity. Our results also suggest parallels between partial and/or biased agonism in RTKs and G-protein-coupled receptors, as well as new therapeutic opportunities for correcting RTK signaling output.
      Graphical abstract image Teaser Receptor tyrosine kinases operate under principles of biased agonism to shape signaling outputs.

      PubDate: 2017-10-19T19:34:49Z
       
  • SnapShot: Angiopoietins and Their Functions
    • Abstract: Publication date: 19 October 2017
      Source:Cell, Volume 171, Issue 3
      Author(s): Pipsa Saharinen, Veli-Matti Leppänen, Kari Alitalo
      Angiopoietins signal through TIE receptors to control both developmental and homeostatic processes that can go awry in genetic diseases and cancer. This SnapShot illustrates key elements of angiopoietin signaling in normal and disease contexts.
      Teaser Angiopoietins signal through TIE receptors to control both developmental and homeostatic processes that can go awry in genetic diseases and cancer. This SnapShot illustrates key elements of angiopoietin signaling in normal and disease contexts.

      PubDate: 2017-10-19T19:34:49Z
       
  • Comprehensive Analysis of Hypermutation in Human Cancer
    • Abstract: Publication date: Available online 19 October 2017
      Source:Cell
      Author(s): Brittany B. Campbell, Nicholas Light, David Fabrizio, Matthew Zatzman, Fabio Fuligni, Richard de Borja, Scott Davidson, Melissa Edwards, Julia A. Elvin, Karl P. Hodel, Walter J. Zahurancik, Zucai Suo, Tatiana Lipman, Katharina Wimmer, Christian P. Kratz, Daniel C. Bowers, Theodore W. Laetsch, Gavin P. Dunn, Tanner M. Johanns, Matthew R. Grimmer, Ivan V. Smirnov, Valérie Larouche, David Samuel, Annika Bronsema, Michael Osborn, Duncan Stearns, Pichai Raman, Kristina A. Cole, Phillip B. Storm, Michal Yalon, Enrico Opocher, Gary Mason, Gregory A. Thomas, Magnus Sabel, Ben George, David S. Ziegler, Scott Lindhorst, Vanan Magimairajan Issai, Shlomi Constantini, Helen Toledano, Ronit Elhasid, Roula Farah, Rina Dvir, Peter Dirks, Annie Huang, Melissa A. Galati, Jiil Chung, Vijay Ramaswamy, Meredith S. Irwin, Melyssa Aronson, Carol Durno, Michael D. Taylor, Gideon Rechavi, John M. Maris, Eric Bouffet, Cynthia Hawkins, Joseph F. Costello, M. Stephen Meyn, Zachary F. Pursell, David Malkin, Uri Tabori, Adam Shlien
      We present an extensive assessment of mutation burden through sequencing analysis of >81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations. Hypermutation was detected in tumor types not previously associated with high mutation burden. Replication repair deficiency was a major contributing factor. We uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load. Unbiased clustering, based on mutational context, revealed clinically relevant subgroups regardless of the tumors’ tissue of origin, highlighting similarities in evolutionary dynamics leading to hypermutation. Mutagens, such as UV light, were implicated in unexpected cancers, including sarcomas and lung tumors. The order of mutational signatures identified previous treatment and germline replication repair deficiency, which improved management of patients and families. These data will inform tumor classification, genetic testing, and clinical trial design.
      Graphical abstract image Teaser A large-scale analysis of hypermutation in human cancers provides insights into tumor evolution dynamics and identifies clinically actionable mutation signatures.

      PubDate: 2017-10-19T19:34:49Z
       
  • Wild Mouse Gut Microbiota Promotes Host Fitness and Improves Disease
           Resistance
    • Abstract: Publication date: Available online 19 October 2017
      Source:Cell
      Author(s): Stephan P. Rosshart, Brian G. Vassallo, Davide Angeletti, Diane S. Hutchinson, Andrew P. Morgan, Kazuyo Takeda, Heather D. Hickman, John A. McCulloch, Jonathan H. Badger, Nadim J. Ajami, Giorgio Trinchieri, Fernando Pardo-Manuel de Villena, Jonathan W. Yewdell, Barbara Rehermann
      Laboratory mice, while paramount for understanding basic biological phenomena, are limited in modeling complex diseases of humans and other free-living mammals. Because the microbiome is a major factor in mammalian physiology, we aimed to identify a naturally evolved reference microbiome to better recapitulate physiological phenomena relevant in the natural world outside the laboratory. Among 21 distinct mouse populations worldwide, we identified a closely related wild relative to standard laboratory mouse strains. Its bacterial gut microbiome differed significantly from its laboratory mouse counterpart and was transferred to and maintained in laboratory mice over several generations. Laboratory mice reconstituted with natural microbiota exhibited reduced inflammation and increased survival following influenza virus infection and improved resistance against mutagen/inflammation-induced colorectal tumorigenesis. By demonstrating the host fitness-promoting traits of natural microbiota, our findings should enable the discovery of protective mechanisms relevant in the natural world and improve the modeling of complex diseases of free-living mammals.
      Graphical abstract image Teaser Characterization of a wild mice reference microbiome opens a window of opportunity to understand how the gut microbiota affects aspects of host physiology that are important in the natural world outside the laboratory.

      PubDate: 2017-10-19T19:34:49Z
       
  • Synthetic RNA-Based Immunomodulatory Gene Circuits for Cancer
           Immunotherapy
    • Abstract: Publication date: Available online 19 October 2017
      Source:Cell
      Author(s): Lior Nissim, Ming-Ru Wu, Erez Pery, Adina Binder-Nissim, Hiroshi I. Suzuki, Doron Stupp, Claudia Wehrspaun, Yuval Tabach, Phillip A. Sharp, Timothy K. Lu
      Despite its success in several clinical trials, cancer immunotherapy remains limited by the rarity of targetable tumor-specific antigens, tumor-mediated immune suppression, and toxicity triggered by systemic delivery of potent immunomodulators. Here, we present a proof-of-concept immunomodulatory gene circuit platform that enables tumor-specific expression of immunostimulators, which could potentially overcome these limitations. Our design comprised de novo synthetic cancer-specific promoters and, to enhance specificity, an RNA-based AND gate that generates combinatorial immunomodulatory outputs only when both promoters are mutually active. These outputs included an immunogenic cell-surface protein, a cytokine, a chemokine, and a checkpoint inhibitor antibody. The circuits triggered selective T cell-mediated killing of cancer cells, but not of normal cells, in vitro. In in vivo efficacy assays, lentiviral circuit delivery mediated significant tumor reduction and prolonged mouse survival. Our design could be adapted to drive additional immunomodulators, sense other cancers, and potentially treat other diseases that require precise immunological programming.
      Graphical abstract image Teaser An immunomodulatory gene circuit platform that enables tumor-specific expression of immunostimulators that permits selective T cell-mediated killing of cancer cells, but not of normal cells, is developed. This platform shows prolonged survival in a mouse cancer model and has the potential to be adapted to express a range of other immune regulators and to treat other cancer types.

      PubDate: 2017-10-19T19:34:49Z
       
  • The Human Knockout Gene CLYBL Connects Itaconate to Vitamin B12
    • Abstract: Publication date: Available online 19 October 2017
      Source:Cell
      Author(s): Hongying Shen, Gregory C. Campanello, Daniel Flicker, Zenon Grabarek, Junchi Hu, Cheng Luo, Ruma Banerjee, Vamsi K. Mootha
      CLYBL encodes a ubiquitously expressed mitochondrial enzyme, conserved across all vertebrates, whose cellular activity and pathway assignment are unknown. Its homozygous loss is tolerated in seemingly healthy individuals, with reduced circulating B12 levels being the only and consistent phenotype reported to date. Here, by combining enzymology, structural biology, and activity-based metabolomics, we report that CLYBL operates as a citramalyl-CoA lyase in mammalian cells. Cells lacking CLYBL accumulate citramalyl-CoA, an intermediate in the C5-dicarboxylate metabolic pathway that includes itaconate, a recently identified human anti-microbial metabolite and immunomodulator. We report that CLYBL loss leads to a cell-autonomous defect in the mitochondrial B12 metabolism and that itaconyl-CoA is a cofactor-inactivating, substrate-analog inhibitor of the mitochondrial B12-dependent methylmalonyl-CoA mutase (MUT). Our work de-orphans the function of human CLYBL and reveals that a consequence of exposure to the immunomodulatory metabolite itaconate is B12 inactivation.
      Graphical abstract image Teaser A “missing” human gene sheds light into how production of itaconate, an immunometabolite, may contribute to vitamin B12 deficiency.

      PubDate: 2017-10-19T19:34:49Z
       
  • Selective Inhibition of FOXO1 Activator/Repressor Balance Modulates
           Hepatic Glucose Handling
    • Abstract: Publication date: Available online 19 October 2017
      Source:Cell
      Author(s): Fanny Langlet, Rebecca A. Haeusler, Daniel Lindén, Elke Ericson, Tyrrell Norris, Anders Johansson, Joshua R. Cook, Kumiko Aizawa, Ling Wang, Christoph Buettner, Domenico Accili
      Insulin resistance is a hallmark of diabetes and an unmet clinical need. Insulin inhibits hepatic glucose production and promotes lipogenesis by suppressing FOXO1-dependent activation of G6pase and inhibition of glucokinase, respectively. The tight coupling of these events poses a dual conundrum: mechanistically, as the FOXO1 corepressor of glucokinase is unknown, and clinically, as inhibition of glucose production is predicted to increase lipogenesis. Here, we report that SIN3A is the insulin-sensitive FOXO1 corepressor of glucokinase. Genetic ablation of SIN3A abolishes nutrient regulation of glucokinase without affecting other FOXO1 target genes and lowers glycemia without concurrent steatosis. To extend this work, we executed a small-molecule screen and discovered selective inhibitors of FOXO-dependent glucose production devoid of lipogenic activity in hepatocytes. In addition to identifying a novel mode of insulin action, these data raise the possibility of developing selective modulators of unliganded transcription factors to dial out adverse effects of insulin sensitizers.
      Graphical abstract image Teaser The transcriptional output of FOXO1 can be selectively modulated in a way that might reduce adverse effects of insulin sensitizers.

      PubDate: 2017-10-19T19:34:49Z
       
  • A Genetic Tool to Track Protein Aggregates and Control Prion Inheritance
    • Abstract: Publication date: Available online 19 October 2017
      Source:Cell
      Author(s): Gregory A. Newby, Szilvia Kiriakov, Erinc Hallacli, Can Kayatekin, Peter Tsvetkov, Christopher P. Mancuso, J. Maeve Bonner, William R. Hesse, Sohini Chakrabortee, Anita L. Manogaran, Susan W. Liebman, Susan Lindquist, Ahmad S. Khalil
      Protein aggregation is a hallmark of many diseases but also underlies a wide range of positive cellular functions. This phenomenon has been difficult to study because of a lack of quantitative and high-throughput cellular tools. Here, we develop a synthetic genetic tool to sense and control protein aggregation. We apply the technology to yeast prions, developing sensors to track their aggregation states and employing prion fusions to encode synthetic memories in yeast cells. Utilizing high-throughput screens, we identify prion-curing mutants and engineer “anti-prion drives” that reverse the non-Mendelian inheritance pattern of prions and eliminate them from yeast populations. We extend our technology to yeast RNA-binding proteins (RBPs) by tracking their propensity to aggregate, searching for co-occurring aggregates, and uncovering a group of coalescing RBPs through screens enabled by our platform. Our work establishes a quantitative, high-throughput, and generalizable technology to study and control diverse protein aggregation processes in cells.
      Graphical abstract image Teaser Newby et al. developed a new tool for tracking and quantifying protein aggregation and prion inheritance in live cells.

      PubDate: 2017-10-19T19:34:49Z
       
  • Early-Life Gene Expression in Neurons Modulates Lasting Epigenetic States
    • Abstract: Publication date: Available online 19 October 2017
      Source:Cell
      Author(s): Hume Stroud, Susan C. Su, Sinisa Hrvatin, Alexander W. Greben, William Renthal, Lisa D. Boxer, M. Aurel Nagy, Daniel R. Hochbaum, Benyam Kinde, Harrison W. Gabel, Michael E. Greenberg
      In mammals, the environment plays a critical role in promoting the final steps in neuronal development during the early postnatal period. While epigenetic factors are thought to contribute to this process, the underlying molecular mechanisms remain poorly understood. Here, we show that in the brain during early life, the DNA methyltransferase DNMT3A transiently binds across transcribed regions of lowly expressed genes, and its binding specifies the pattern of DNA methylation at CA sequences (mCA) within these genes. We find that DNMT3A occupancy and mCA deposition within the transcribed regions of genes is negatively regulated by gene transcription and may be modified by early-life experience. Once deposited, mCA is bound by the methyl-DNA-binding protein MECP2 and functions in a rheostat-like manner to fine-tune the cell-type-specific transcription of genes that are critical for brain function.
      Graphical abstract image Teaser The deposition of repressive mCA marks by the methyltransferase DNMT3A across specific brain genes during early postnatal life is important for their regulation throughout life.

      PubDate: 2017-10-19T19:34:49Z
       
  • ILC1 Confer Early Host Protection at Initial Sites of Viral Infection
    • Abstract: Publication date: Available online 19 October 2017
      Source:Cell
      Author(s): Orr-El Weizman, Nicholas M. Adams, Iona Schuster, Chirag Krishna, Yuri Pritykin, Colleen Lau, Mariapia A. Degli-Esposti, Christina S. Leslie, Joseph C. Sun, Timothy E. O’Sullivan
      Infection is restrained by the concerted activation of tissue-resident and circulating immune cells. Whether tissue-resident lymphocytes confer early antiviral immunity at local sites of primary infection prior to the initiation of circulating responses is not well understood. Furthermore, the kinetics of initial antiviral responses at sites of infection remain unclear. Here, we show that tissue-resident type 1 innate lymphoid cells (ILC1) serve an essential early role in host immunity through rapid production of interferon (IFN)-γ following viral infection. Ablation of Zfp683-dependent liver ILC1 lead to increased viral load in the presence of intact adaptive and innate immune cells critical for mouse cytomegalovirus (MCMV) clearance. Swift production of interleukin (IL)-12 by tissue-resident XCR1+ conventional dendritic cells (cDC1) promoted ILC1 production of IFN-γ in a STAT4-dependent manner to limit early viral burden. Thus, ILC1 contribute an essential role in viral immunosurveillance at sites of initial infection in response to local cDC1-derived proinflammatory cytokines.
      Graphical abstract image Teaser Innate lymphoid cells have a non-redundant role as initial responders to viral infections.

      PubDate: 2017-10-19T19:34:49Z
       
  • Universal Patterns of Selection in Cancer and Somatic Tissues
    • Abstract: Publication date: Available online 19 October 2017
      Source:Cell
      Author(s): Iñigo Martincorena, Keiran M. Raine, Moritz Gerstung, Kevin J. Dawson, Kerstin Haase, Peter Van Loo, Helen Davies, Michael R. Stratton, Peter J. Campbell
      Cancer develops as a result of somatic mutation and clonal selection, but quantitative measures of selection in cancer evolution are lacking. We adapted methods from molecular evolution and applied them to 7,664 tumors across 29 cancer types. Unlike species evolution, positive selection outweighs negative selection during cancer development. On average, <1 coding base substitution/tumor is lost through negative selection, with purifying selection almost absent outside homozygous loss of essential genes. This allows exome-wide enumeration of all driver coding mutations, including outside known cancer genes. On average, tumors carry ∼4 coding substitutions under positive selection, ranging from <1/tumor in thyroid and testicular cancers to >10/tumor in endometrial and colorectal cancers. Half of driver substitutions occur in yet-to-be-discovered cancer genes. With increasing mutation burden, numbers of driver mutations increase, but not linearly. We systematically catalog cancer genes and show that genes vary extensively in what proportion of mutations are drivers versus passengers.
      Graphical abstract image Teaser Adapting an evolutionary genomics approach to cancer highlights a limited impact of negative selection on cancer genomes and significant variations in the proportion of coding driver mutations per tumor among different tumor types.

      PubDate: 2017-10-19T19:34:49Z
       
  • STING Senses Microbial Viability to Orchestrate Stress-Mediated Autophagy
           of the Endoplasmic Reticulum
    • Abstract: Publication date: Available online 19 October 2017
      Source:Cell
      Author(s): Julien Moretti, Soumit Roy, Dominique Bozec, Jennifer Martinez, Jessica R. Chapman, Beatrix Ueberheide, Dudley W. Lamming, Zhijian J. Chen, Tiffany Horng, Garabet Yeretssian, Douglas R. Green, J. Magarian Blander
      Constitutive cell-autonomous immunity in metazoans predates interferon-inducible immunity and comprises primordial innate defense. Phagocytes mobilize interferon-inducible responses upon engagement of well-characterized signaling pathways by pathogen-associated molecular patterns (PAMPs). The signals controlling deployment of constitutive cell-autonomous responses during infection have remained elusive. Vita-PAMPs denote microbial viability, signaling the danger of cellular exploitation by intracellular pathogens. We show that cyclic-di-adenosine monophosphate in live Gram-positive bacteria is a vita-PAMP, engaging the innate sensor stimulator of interferon genes (STING) to mediate endoplasmic reticulum (ER) stress. Subsequent inactivation of the mechanistic target of rapamycin mobilizes autophagy, which sequesters stressed ER membranes, resolves ER stress, and curtails phagocyte death. This vita-PAMP-induced ER-phagy additionally orchestrates an interferon response by localizing ER-resident STING to autophagosomes. Our findings identify stress-mediated ER-phagy as a cell-autonomous response mobilized by STING-dependent sensing of a specific vita-PAMP and elucidate how innate receptors engage multilayered homeostatic mechanisms to promote immunity and survival after infection.
      Graphical abstract image Teaser Detection of live bacteria through STING triggers ER-phagy and resolution of cellular stress, allowing cells to deal with the threat and remain viable and functional.

      PubDate: 2017-10-19T19:34:49Z
       
  • Mechanism of Transcription Anti-termination in Human Mitochondria
    • Abstract: Publication date: Available online 12 October 2017
      Source:Cell
      Author(s): Hauke S. Hillen, Andrey V. Parshin, Karen Agaronyan, Yaroslav I. Morozov, James J. Graber, Aleksandar Chernev, Kathrin Schwinghammer, Henning Urlaub, Michael Anikin, Patrick Cramer, Dmitry Temiakov
      In human mitochondria, transcription termination events at a G-quadruplex region near the replication origin are thought to drive replication of mtDNA by generation of an RNA primer. This process is suppressed by a key regulator of mtDNA—the transcription factor TEFM. We determined the structure of an anti-termination complex in which TEFM is bound to transcribing mtRNAP. The structure reveals interactions of the dimeric pseudonuclease core of TEFM with mobile structural elements in mtRNAP and the nucleic acid components of the elongation complex (EC). Binding of TEFM to the DNA forms a downstream “sliding clamp,” providing high processivity to the EC. TEFM also binds near the RNA exit channel to prevent formation of the RNA G-quadruplex structure required for termination and thus synthesis of the replication primer. Our data provide insights into target specificity of TEFM and mechanisms by which it regulates the switch between transcription and replication of mtDNA.
      Graphical abstract image Teaser Crystal structures of the human mitochondrial transcription factor TEFM with its C-terminal domain bound to a transcription elongation complex provide insights into the molecular basis of its roles in promoting elongation and preventing termination.

      PubDate: 2017-10-13T02:48:07Z
       
  • Natively Unfolded FG Repeats Stabilize the Structure of the Nuclear Pore
           Complex
    • Abstract: Publication date: Available online 12 October 2017
      Source:Cell
      Author(s): Evgeny Onischenko, Jeffrey H. Tang, Kasper R. Andersen, Kevin E. Knockenhauer, Pascal Vallotton, Carina P. Derrer, Annemarie Kralt, Christopher F. Mugler, Leon Y. Chan, Thomas U. Schwartz, Karsten Weis
      Nuclear pore complexes (NPCs) are ∼100 MDa transport channels assembled from multiple copies of ∼30 nucleoporins (Nups). One-third of these Nups contain phenylalanine-glycine (FG)-rich repeats, forming a diffusion barrier, which is selectively permeable for nuclear transport receptors that interact with these repeats. Here, we identify an additional function of FG repeats in the structure and biogenesis of the yeast NPC. We demonstrate that GLFG-containing FG repeats directly bind to multiple scaffold Nups in vitro and act as NPC-targeting determinants in vivo. Furthermore, we show that the GLFG repeats of Nup116 function in a redundant manner with Nup188, a nonessential scaffold Nup, to stabilize critical interactions within the NPC scaffold needed for late steps of NPC assembly. Our results reveal a previously unanticipated structural role for natively unfolded GLFG repeats as Velcro to link NPC subcomplexes and thus add a new layer of connections to current models of the NPC architecture.
      Graphical abstract image Teaser In addition to forming the permeability barrier, FG repeats in nucleoporins contribute structurally to nuclear pore biogenesis and function.

      PubDate: 2017-10-13T02:48:07Z
       
  • Genome-Nuclear Lamina Interactions Regulate Cardiac Stem Cell Lineage
           Restriction
    • Abstract: Publication date: Available online 12 October 2017
      Source:Cell
      Author(s): Andrey Poleshko, Parisha P. Shah, Mudit Gupta, Apoorva Babu, Michael P. Morley, Lauren J. Manderfield, Jamie L. Ifkovits, Damelys Calderon, Haig Aghajanian, Javier E. Sierra-Pagán, Zheng Sun, Qiaohong Wang, Li Li, Nicole C. Dubois, Edward E. Morrisey, Mitchell A. Lazar, Cheryl L. Smith, Jonathan A. Epstein, Rajan Jain
      Progenitor cells differentiate into specialized cell types through coordinated expression of lineage-specific genes and modification of complex chromatin configurations. We demonstrate that a histone deacetylase (Hdac3) organizes heterochromatin at the nuclear lamina during cardiac progenitor lineage restriction. Specification of cardiomyocytes is associated with reorganization of peripheral heterochromatin, and independent of deacetylase activity, Hdac3 tethers peripheral heterochromatin containing lineage-relevant genes to the nuclear lamina. Deletion of Hdac3 in cardiac progenitor cells releases genomic regions from the nuclear periphery, leading to precocious cardiac gene expression and differentiation into cardiomyocytes; in contrast, restricting Hdac3 to the nuclear periphery rescues myogenesis in progenitors otherwise lacking Hdac3. Our results suggest that availability of genomic regions for activation by lineage-specific factors is regulated in part through dynamic chromatin-nuclear lamina interactions and that competence of a progenitor cell to respond to differentiation signals may depend upon coordinated movement of responding gene loci away from the nuclear periphery.
      Graphical abstract image Teaser Nuclear architecture provides a distinct layer of gene regulation during development, coordinating cell fate determination through changes in chromatin accessibility that are mediated by chromatin-nuclear lamina interactions.

      PubDate: 2017-10-13T02:48:07Z
       
  • Oxysterol Restraint of Cholesterol Synthesis Prevents AIM2 Inflammasome
           Activation
    • Abstract: Publication date: Available online 12 October 2017
      Source:Cell
      Author(s): Eric V. Dang, Jeffrey G. McDonald, David W. Russell, Jason G. Cyster
      Type I interferon restrains interleukin-1β (IL-1β)-driven inflammation in macrophages by upregulating cholesterol-25-hydroxylase (Ch25h) and repressing SREBP transcription factors. However, the molecular links between lipid metabolism and IL-1β production remain obscure. Here, we demonstrate that production of 25-hydroxycholesterol (25-HC) by macrophages is required to prevent inflammasome activation by the DNA sensor protein absent in melanoma 2 (AIM2). We find that in response to bacterial infection or lipopolysaccharide (LPS) stimulation, macrophages upregulate Ch25h to maintain repression of SREBP2 activation and cholesterol synthesis. Increasing macrophage cholesterol content is sufficient to trigger IL-1β release in a crystal-independent but AIM2-dependent manner. Ch25h deficiency results in cholesterol-dependent reduced mitochondrial respiratory capacity and release of mitochondrial DNA into the cytosol. AIM2 deficiency rescues the increased inflammasome activity observed in Ch25h −/−. Therefore, activated macrophages utilize 25-HC in an anti-inflammatory circuit that maintains mitochondrial integrity and prevents spurious AIM2 inflammasome activation.
      Graphical abstract image Teaser Cholesterol overload directly triggers mitochondrial DNA release and activation of the AIM2 inflammasome in activated macrophages.

      PubDate: 2017-10-13T02:48:07Z
       
  • Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab
    • Abstract: Publication date: Available online 12 October 2017
      Source:Cell
      Author(s): Nadeem Riaz, Jonathan J. Havel, Vladimir Makarov, Alexis Desrichard, Walter J. Urba, Jennifer S. Sims, F. Stephen Hodi, Salvador Martín-Algarra, Rajarsi Mandal, William H. Sharfman, Shailender Bhatia, Wen-Jen Hwu, Thomas F. Gajewski, Craig L. Slingluff, Diego Chowell, Sviatoslav M. Kendall, Han Chang, Rachna Shah, Fengshen Kuo, Luc G.T. Morris, John-William Sidhom, Jonathan P. Schneck, Christine E. Horak, Nils Weinhold, Timothy A. Chan
      The mechanisms by which immune checkpoint blockade modulates tumor evolution during therapy are unclear. We assessed genomic changes in tumors from 68 patients with advanced melanoma, who progressed on ipilimumab or were ipilimumab-naive, before and after nivolumab initiation (CA209-038 study). Tumors were analyzed by whole-exome, transcriptome, and/or T cell receptor (TCR) sequencing. In responding patients, mutation and neoantigen load were reduced from baseline, and analysis of intratumoral heterogeneity during therapy demonstrated differential clonal evolution within tumors and putative selection against neoantigenic mutations on-therapy. Transcriptome analyses before and during nivolumab therapy revealed increases in distinct immune cell subsets, activation of specific transcriptional networks, and upregulation of immune checkpoint genes that were more pronounced in patients with response. Temporal changes in intratumoral TCR repertoire revealed expansion of T cell clones in the setting of neoantigen loss. Comprehensive genomic profiling data in this study provide insight into nivolumab's mechanism of action.
      Graphical abstract image Teaser Mutation burden decreases with successful checkpoint blockade therapy in patients with melanoma, suggesting that selection against mutant neoepitopes may be a critical mechanism of action of Nivolumab.

      PubDate: 2017-10-13T02:48:07Z
       
  • Assembly and Function of Heterotypic Ubiquitin Chains in Cell-Cycle and
           Protein Quality Control
    • Abstract: Publication date: Available online 12 October 2017
      Source:Cell
      Author(s): Richard G. Yau, Kerstin Doerner, Erick R. Castellanos, Diane L. Haakonsen, Achim Werner, Nan Wang, X. William Yang, Nadia Martinez-Martin, Marissa L. Matsumoto, Vishva M. Dixit, Michael Rape
      Posttranslational modification with ubiquitin chains controls cell fate in all eukaryotes. Depending on the connectivity between subunits, different ubiquitin chain types trigger distinct outputs, as seen with K48- and K63-linked conjugates that drive protein degradation or complex assembly, respectively. Recent biochemical analyses also suggested roles for mixed or branched ubiquitin chains, yet without a method to monitor endogenous conjugates, the physiological significance of heterotypic polymers remained poorly understood. Here, we engineered a bispecific antibody to detect K11/K48-linked chains and identified mitotic regulators, misfolded nascent polypeptides, and pathological Huntingtin variants as their endogenous substrates. We show that K11/K48-linked chains are synthesized and processed by essential ubiquitin ligases and effectors that are mutated across neurodegenerative diseases; accordingly, these conjugates promote rapid proteasomal clearance of aggregation-prone proteins. By revealing key roles of K11/K48-linked chains in cell-cycle and quality control, we establish heterotypic ubiquitin conjugates as important carriers of biological information.
      Graphical abstract image Teaser Bispecific antibodies reveal the presence and function of heterotypic ubiquitin chains containing K11 and K48 linkages in cell-cycle regulation and protein quality control.

      PubDate: 2017-10-13T02:48:07Z
       
  • The DNA Inflammasome in Human Myeloid Cells Is Initiated by a STING-Cell
           Death Program Upstream of NLRP3
    • Abstract: Publication date: Available online 12 October 2017
      Source:Cell
      Author(s): Moritz M. Gaidt, Thomas S. Ebert, Dhruv Chauhan, Katharina Ramshorn, Francesca Pinci, Sarah Zuber, Fionan O’Duill, Jonathan L. Schmid-Burgk, Florian Hoss, Raymund Buhmann, Georg Wittmann, Eicke Latz, Marion Subklewe, Veit Hornung
      Detection of cytosolic DNA constitutes a central event in the context of numerous infectious and sterile inflammatory conditions. Recent studies have uncovered a bipartite mode of cytosolic DNA recognition, in which the cGAS-STING axis triggers antiviral immunity, whereas AIM2 triggers inflammasome activation. Here, we show that AIM2 is dispensable for DNA-mediated inflammasome activation in human myeloid cells. Instead, detection of cytosolic DNA by the cGAS-STING axis induces a cell death program initiating potassium efflux upstream of NLRP3. Forward genetics identified regulators of lysosomal trafficking to modulate this cell death program, and subsequent studies revealed that activated STING traffics to the lysosome, where it triggers membrane permeabilization and thus lysosomal cell death (LCD). Importantly, the cGAS-STING-NLRP3 pathway constitutes the default inflammasome response during viral and bacterial infections in human myeloid cells. We conclude that targeting the cGAS-STING-LCD-NLRP3 pathway will ameliorate pathology in inflammatory conditions that are associated with cytosolic DNA sensing.
      Graphical abstract image Teaser In humans, a cGAS-STING-lysosomal cell death-NLRP3 pathway is responsible for the inflammasome response to bacterial and viral DNA with AIM2 being dispensable.

      PubDate: 2017-10-13T02:48:07Z
       
  • Chemical Proteomics Identifies Druggable Vulnerabilities in a Genetically
           Defined Cancer
    • Abstract: Publication date: Available online 28 September 2017
      Source:Cell
      Author(s): Liron Bar-Peled, Esther K. Kemper, Radu M. Suciu, Ekaterina V. Vinogradova, Keriann M. Backus, Benjamin D. Horning, Thomas A. Paul, Taka-Aki Ichu, Robert U. Svensson, Jose Olucha, Max W. Chang, Bernard P. Kok, Zhou Zhu, Nathan T. Ihle, Melissa M. Dix, Ping Jiang, Matthew M. Hayward, Enrique Saez, Reuben J. Shaw, Benjamin F. Cravatt
      The transcription factor NRF2 is a master regulator of the cellular antioxidant response, and it is often genetically activated in non-small-cell lung cancers (NSCLCs) by, for instance, mutations in the negative regulator KEAP1. While direct pharmacological inhibition of NRF2 has proven challenging, its aberrant activation rewires biochemical networks in cancer cells that may create special vulnerabilities. Here, we use chemical proteomics to map druggable proteins that are selectively expressed in KEAP1-mutant NSCLC cells. Principal among these is NR0B1, an atypical orphan nuclear receptor that we show engages in a multimeric protein complex to regulate the transcriptional output of KEAP1-mutant NSCLC cells. We further identify small molecules that covalently target a conserved cysteine within the NR0B1 protein interaction domain, and we demonstrate that these compounds disrupt NR0B1 complexes and impair the anchorage-independent growth of KEAP1-mutant cancer cells. Our findings designate NR0B1 as a druggable transcriptional regulator that supports NRF2-dependent lung cancers.
      Graphical abstract image Teaser Combining chemical proteomics and functional analysis identifies druggable cysteines in NRF2-regulated proteins that contribute to KEAP1-mutant cancer cell growth.

      PubDate: 2017-10-05T15:53:36Z
       
  • Temporal Control of Mammalian Cortical Neurogenesis by m6A Methylation
    • Abstract: Publication date: Available online 28 September 2017
      Source:Cell
      Author(s): Ki-Jun Yoon, Francisca Rojas Ringeling, Caroline Vissers, Fadi Jacob, Michael Pokrass, Dennisse Jimenez-Cyrus, Yijing Su, Nam-Shik Kim, Yunhua Zhu, Lily Zheng, Sunghan Kim, Xinyuan Wang, Louis C. Doré, Peng Jin, Sergi Regot, Xiaoxi Zhuang, Stefan Canzar, Chuan He, Guo-li Ming, Hongjun Song
      N6-methyladenosine (m6A), installed by the Mettl3/Mettl14 methyltransferase complex, is the most prevalent internal mRNA modification. Whether m6A regulates mammalian brain development is unknown. Here, we show that m6A depletion by Mettl14 knockout in embryonic mouse brains prolongs the cell cycle of radial glia cells and extends cortical neurogenesis into postnatal stages. m6A depletion by Mettl3 knockdown also leads to a prolonged cell cycle and maintenance of radial glia cells. m6A sequencing of embryonic mouse cortex reveals enrichment of mRNAs related to transcription factors, neurogenesis, the cell cycle, and neuronal differentiation, and m6A tagging promotes their decay. Further analysis uncovers previously unappreciated transcriptional prepatterning in cortical neural stem cells. m6A signaling also regulates human cortical neurogenesis in forebrain organoids. Comparison of m6A-mRNA landscapes between mouse and human cortical neurogenesis reveals enrichment of human-specific m6A tagging of transcripts related to brain-disorder risk genes. Our study identifies an epitranscriptomic mechanism in heightened transcriptional coordination during mammalian cortical neurogenesis.
      Graphical abstract image Teaser m6A-dependent mRNA decay is critical for proper transcriptional prepatterning in mammalian cortical neurogenesis.

      PubDate: 2017-10-05T15:53:36Z
       
  • A Population Representation of Absolute Light Intensity in the Mammalian
           Retina
    • Abstract: Publication date: Available online 28 September 2017
      Source:Cell
      Author(s): Elliott Scott Milner, Michael Tri Hoang Do
      Environmental illumination spans many log units of intensity and is tracked for essential functions that include regulation of the circadian clock, arousal state, and hormone levels. Little is known about the neural representation of light intensity and how it covers the necessary range. This question became accessible with the discovery of mammalian photoreceptors that are required for intensity-driven functions, the M1 ipRGCs. The spike outputs of M1s are thought to uniformly track intensity over a wide range. We provide a different understanding: individual cells operate over a narrow range, but the population covers irradiances from moonlight to full daylight. The range of most M1s is limited by depolarization block, which is generally considered pathological but is produced intrinsically by these cells. The dynamics of block allow the population to code stimulus intensity with flexibility and efficiency. Moreover, although spikes are distorted by block, they are regularized during axonal propagation.
      Graphical abstract image Teaser M1 photoreceptors sense environmental light intensity, but individual cells have ambiguous outputs and limited ranges. Differential tuning across cells, arising from intrinsic depolarization block and varied sensitivity, allows them to divide labor and code a broad range of intensities collectively.

      PubDate: 2017-10-05T15:53:36Z
       
  • Parvalbumin and Somatostatin Interneurons Control Different Space-Coding
           Networks in the Medial Entorhinal Cortex
    • Abstract: Publication date: Available online 28 September 2017
      Source:Cell
      Author(s): Chenglin Miao, Qichen Cao, May-Britt Moser, Edvard I. Moser
      The medial entorhinal cortex (MEC) contains several discrete classes of GABAergic interneurons, but their specific contributions to spatial pattern formation in this area remain elusive. We employed a pharmacogenetic approach to silence either parvalbumin (PV)- or somatostatin (SOM)-expressing interneurons while MEC cells were recorded in freely moving mice. PV-cell silencing antagonized the hexagonally patterned spatial selectivity of grid cells, especially in layer II of MEC. The impairment was accompanied by reduced speed modulation in colocalized speed cells. Silencing SOM cells, in contrast, had no impact on grid cells or speed cells but instead decreased the spatial selectivity of cells with discrete aperiodic firing fields. Border cells and head direction cells were not affected by either intervention. The findings point to distinct roles for PV and SOM interneurons in the local dynamics underlying periodic and aperiodic firing in spatially modulated cells of the MEC.
      Graphical abstract image Teaser Two distinct sub-classes of inhibitory interneurons modulate different forms of spatial representation in the medial entorhinal cortex.

      PubDate: 2017-10-05T15:53:36Z
       
  • Genomic Patterns of De Novo Mutation in Simplex Autism
    • Abstract: Publication date: Available online 28 September 2017
      Source:Cell
      Author(s): Tychele N. Turner, Bradley P. Coe, Diane E. Dickel, Kendra Hoekzema, Bradley J. Nelson, Michael C. Zody, Zev N. Kronenberg, Fereydoun Hormozdiari, Archana Raja, Len A. Pennacchio, Robert B. Darnell, Evan E. Eichler
      To further our understanding of the genetic etiology of autism, we generated and analyzed genome sequence data from 516 idiopathic autism families (2,064 individuals). This resource includes >59 million single-nucleotide variants (SNVs) and 9,212 private copy number variants (CNVs), of which 133,992 and 88 are de novo mutations (DNMs), respectively. We estimate a mutation rate of ∼1.5 × 10−8 SNVs per site per generation with a significantly higher mutation rate in repetitive DNA. Comparing probands and unaffected siblings, we observe several DNM trends. Probands carry more gene-disruptive CNVs and SNVs, resulting in severe missense mutations and mapping to predicted fetal brain promoters and embryonic stem cell enhancers. These differences become more pronounced for autism genes (p = 1.8 × 10−3, OR = 2.2). Patients are more likely to carry multiple coding and noncoding DNMs in different genes, which are enriched for expression in striatal neurons (p = 3 × 10−3), suggesting a path forward for genetically characterizing more complex cases of autism.
      Graphical abstract image Teaser Genomic analysis of 516 families with an autistic child and an unaffected sibling suggests that simplex autism results from de novo mutation and is oligogenic.

      PubDate: 2017-10-05T15:53:36Z
       
  • A New Model T on the Horizon'
    • Abstract: Publication date: 21 September 2017
      Source:Cell, Volume 171, Issue 1
      Author(s): Xiaohong Helena Yang


      PubDate: 2017-09-21T17:36:03Z
       
  • The Pyrenoid: An Overlooked Organelle Comes out of Age
    • Abstract: Publication date: 21 September 2017
      Source:Cell, Volume 171, Issue 1
      Author(s): Jean-David Rochaix
      The pyrenoid is a membrane-less organelle that exists in various photosynthetic organisms, such as algae, and wherein most global CO2 fixation occurs. Two papers from the Jonikas lab in this issue of Cell provide new insights into the structure, protein composition, and dynamics of this important organelle.
      Teaser The pyrenoid is a membrane-less organelle that exists in various photosynthetic organisms, such as algae, and wherein most global CO2 fixation occurs. Two papers from the Jonikas lab in this issue of Cell provide new insights into the structure, protein composition, and dynamics of this important organelle.

      PubDate: 2017-09-21T17:36:03Z
       
  • Prion-like Domains Program Ewing’s Sarcoma
    • Abstract: Publication date: 21 September 2017
      Source:Cell, Volume 171, Issue 1
      Author(s): James Shorter
      Prion-like domains have emerged as important drivers of neurodegenerative disease. Now, Boulay et al. establish that the translocated prion-like domain of the oncogenic EWS-FLI1 fusion protein enables phase-separation events, which inappropriately recruit chromatin-remodeling factors to elicit the aberrant transcriptional programs underlying Ewing’s sarcoma.
      Teaser Prion-like domains have emerged as important drivers of neurodegenerative disease. Now, Boulay et al. establish that the translocated prion-like domain of the oncogenic EWS-FLI1 fusion protein enables phase-separation events, which inappropriately recruit chromatin-remodeling factors to elicit the aberrant transcriptional programs underlying Ewing’s sarcoma.

      PubDate: 2017-09-21T17:36:03Z
       
  • Huntingtin Fibrils Poke Membranes
    • Abstract: Publication date: 21 September 2017
      Source:Cell, Volume 171, Issue 1
      Author(s): Pedro Guedes-Dias, Erika L.F. Holzbaur
      A hallmark of Huntington’s disease is the presence of intracellular aggregates of mutant huntingtin, the pathological significance of which has long been debated. Using cryo-electron tomography, Bauerlein et al. reveal the fibrillary structure of huntingtin aggregates in situ and show that huntingtin fibrils interact with the endoplasmic reticulum, distorting its morphology and dynamics.
      Teaser A hallmark of Huntington’s disease is the presence of intracellular aggregates of mutant huntingtin, the pathological significance of which has long been debated. Using cryo-electron tomography, Bauerlein et al. reveal the fibrillary structure of huntingtin aggregates in situ and show that huntingtin fibrils interact with the endoplasmic reticulum, distorting its morphology and dynamics.

      PubDate: 2017-09-21T17:36:03Z
       
  • Genome Regulation by Polycomb and Trithorax: 70 Years and Counting
    • Abstract: Publication date: 21 September 2017
      Source:Cell, Volume 171, Issue 1
      Author(s): Bernd Schuettengruber, Henri-Marc Bourbon, Luciano Di Croce, Giacomo Cavalli
      Polycomb (PcG) and Trithorax (TrxG) group proteins are evolutionarily conserved chromatin-modifying factors originally identified as part of an epigenetic cellular memory system that maintains repressed or active gene expression states. Recently, they have been shown to globally control a plethora of cellular processes. This functional diversity is achieved by their ability to regulate chromatin at multiple levels, ranging from modifying local chromatin structure to orchestrating the three-dimensional organization of the genome. Understanding this system is a fascinating challenge of critical relevance for biology and medicine, since misexpression or mutation of multiple PcG components, as well as of TrxG members of the COMPASS family and of the SWI/SNF complex, is implicated in cancer and other diseases.
      Teaser Polycomb and Trithorax group proteins are chromatin-modifying factors that regulate a plethora of cellular processes, from modifying local chromatin structure to orchestrating the three-dimensional organization of the genome.

      PubDate: 2017-09-21T17:36:03Z
       
  • Reconstructing Prehistoric African Population Structure
    • Abstract: Publication date: 21 September 2017
      Source:Cell, Volume 171, Issue 1
      Author(s): Pontus Skoglund, Jessica C. Thompson, Mary E. Prendergast, Alissa Mittnik, Kendra Sirak, Mateja Hajdinjak, Tasneem Salie, Nadin Rohland, Swapan Mallick, Alexander Peltzer, Anja Heinze, Iñigo Olalde, Matthew Ferry, Eadaoin Harney, Megan Michel, Kristin Stewardson, Jessica I. Cerezo-Román, Chrissy Chiumia, Alison Crowther, Elizabeth Gomani-Chindebvu, Agness O. Gidna, Katherine M. Grillo, I. Taneli Helenius, Garrett Hellenthal, Richard Helm, Mark Horton, Saioa López, Audax Z.P. Mabulla, John Parkington, Ceri Shipton, Mark G. Thomas, Ruth Tibesasa, Menno Welling, Vanessa M. Hayes, Douglas J. Kennett, Raj Ramesar, Matthias Meyer, Svante Pääbo, Nick Patterson, Alan G. Morris, Nicole Boivin, Ron Pinhasi, Johannes Krause, David Reich
      We assembled genome-wide data from 16 prehistoric Africans. We show that the anciently divergent lineage that comprises the primary ancestry of the southern African San had a wider distribution in the past, contributing approximately two-thirds of the ancestry of Malawi hunter-gatherers ∼8,100–2,500 years ago and approximately one-third of the ancestry of Tanzanian hunter-gatherers ∼1,400 years ago. We document how the spread of farmers from western Africa involved complete replacement of local hunter-gatherers in some regions, and we track the spread of herders by showing that the population of a ∼3,100-year-old pastoralist from Tanzania contributed ancestry to people from northeastern to southern Africa, including a ∼1,200-year-old southern African pastoralist. The deepest diversifications of African lineages were complex, involving either repeated gene flow among geographically disparate groups or a lineage more deeply diverging than that of the San contributing more to some western African populations than to others. We finally leverage ancient genomes to document episodes of natural selection in southern African populations. PaperClip
      Graphical abstract image Teaser The prehistory of African populations is explored by genome-wide analysis of 16 human remains providing insight into ancestral lineages, admixture, and genomic adaptations.

      PubDate: 2017-09-21T17:36:03Z
       
  • The Kinetochore Receptor for the Cohesin Loading Complex
    • Abstract: Publication date: 21 September 2017
      Source:Cell, Volume 171, Issue 1
      Author(s): Stephen M. Hinshaw, Vasso Makrantoni, Stephen C. Harrison, Adèle L. Marston
      The ring-shaped cohesin complex brings together distant DNA domains to maintain, express, and segregate the genome. Establishing specific chromosomal linkages depends on cohesin recruitment to defined loci. One such locus is the budding yeast centromere, which is a paradigm for targeted cohesin loading. The kinetochore, a multiprotein complex that connects centromeres to microtubules, drives the recruitment of high levels of cohesin to link sister chromatids together. We have exploited this system to determine the mechanism of specific cohesin recruitment. We show that phosphorylation of the Ctf19 kinetochore protein by a conserved kinase, DDK, provides a binding site for the Scc2/4 cohesin loading complex, thereby directing cohesin loading to centromeres. A similar mechanism targets cohesin to chromosomes in vertebrates. These findings represent a complete molecular description of targeted cohesin loading, a phenomenon with wide-ranging importance in chromosome segregation and, in multicellular organisms, transcription regulation.
      Graphical abstract image Teaser The mechanism by which cohesin is recruited and loaded in yeast and vertebrates is elucidated with implications for our understanding of chromosome segregation.

      PubDate: 2017-09-21T17:36:03Z
       
  • Transcriptional Architecture of Synaptic Communication Delineates
           GABAergic Neuron Identity
    • Abstract: Publication date: Available online 21 September 2017
      Source:Cell
      Author(s): Anirban Paul, Megan Crow, Ricardo Raudales, Miao He, Jesse Gillis, Z. Josh Huang
      Understanding the organizational logic of neural circuits requires deciphering the biological basis of neuronal diversity and identity, but there is no consensus on how neuron types should be defined. We analyzed single-cell transcriptomes of a set of anatomically and physiologically characterized cortical GABAergic neurons and conducted a computational genomic screen for transcriptional profiles that distinguish them from one another. We discovered that cardinal GABAergic neuron types are delineated by a transcriptional architecture that encodes their synaptic communication patterns. This architecture comprises 6 categories of ∼40 gene families, including cell-adhesion molecules, transmitter-modulator receptors, ion channels, signaling proteins, neuropeptides and vesicular release components, and transcription factors. Combinatorial expression of select members across families shapes a multi-layered molecular scaffold along the cell membrane that may customize synaptic connectivity patterns and input-output signaling properties. This molecular genetic framework of neuronal identity integrates cell phenotypes along multiple axes and provides a foundation for discovering and classifying neuron types.
      Graphical abstract image Teaser GABAergic neuron types are distinguished by a transcriptional architecture that encodes their synaptic communication patterns.

      PubDate: 2017-09-21T17:36:03Z
       
  • Structure of FUS Protein Fibrils and Its Relevance to Self-Assembly and
           Phase Separation of Low-Complexity Domains
    • Abstract: Publication date: Available online 21 September 2017
      Source:Cell
      Author(s): Dylan T. Murray, Masato Kato, Yi Lin, Kent R. Thurber, Ivan Hung, Steven L. McKnight, Robert Tycko
      Polymerization and phase separation of proteins containing low-complexity (LC) domains are important factors in gene expression, mRNA processing and trafficking, and localization of translation. We have used solid-state nuclear magnetic resonance methods to characterize the molecular structure of self-assembling fibrils formed by the LC domain of the fused in sarcoma (FUS) RNA-binding protein. From the 214-residue LC domain of FUS (FUS-LC), a segment of only 57 residues forms the fibril core, while other segments remain dynamically disordered. Unlike pathogenic amyloid fibrils, FUS-LC fibrils lack hydrophobic interactions within the core and are not polymorphic at the molecular structural level. Phosphorylation of core-forming residues by DNA-dependent protein kinase blocks binding of soluble FUS-LC to FUS-LC hydrogels and dissolves phase-separated, liquid-like FUS-LC droplets. These studies offer a structural basis for understanding LC domain self-assembly, phase separation, and regulation by post-translational modification.
      Graphical abstract image Teaser Solid-state NMR of FUS fibrils provides structural insight into phase separation of low-complexity domains and its regulation by post-translational modification.

      PubDate: 2017-09-21T17:36:03Z
       
  • Excitable Dynamics and Yap-Dependent Mechanical Cues Drive the
           Segmentation Clock
    • Abstract: Publication date: Available online 21 September 2017
      Source:Cell
      Author(s): Alexis Hubaud, Ido Regev, L. Mahadevan, Olivier Pourquié
      The periodic segmentation of the vertebrate body axis into somites, and later vertebrae, relies on a genetic oscillator (the segmentation clock) driving the rhythmic activity of signaling pathways in the presomitic mesoderm (PSM). To understand whether oscillations are an intrinsic property of individual cells or represent a population-level phenomenon, we established culture conditions for stable oscillations at the cellular level. This system was used to demonstrate that oscillations are a collective property of PSM cells that can be actively triggered in vitro by a dynamical quorum sensing signal involving Yap and Notch signaling. Manipulation of Yap-dependent mechanical cues is sufficient to predictably switch isolated PSM cells from a quiescent to an oscillatory state in vitro, a behavior reminiscent of excitability in other systems. Together, our work argues that the segmentation clock behaves as an excitable system, introducing a broader paradigm to study such dynamics in vertebrate morphogenesis.
      Graphical abstract image Teaser YAP and Notch collaborate to control collective cellular oscillations during somitogenesis.

      PubDate: 2017-09-21T17:36:03Z
       
  • Age-Dependent Alterations in Meiotic Recombination Cause Chromosome
           Segregation Errors in Spermatocytes
    • Abstract: Publication date: Available online 21 September 2017
      Source:Cell
      Author(s): Maciej J. Zelazowski, Maria Sandoval, Lakshmi Paniker, Holly M. Hamilton, Jiaying Han, Mikalah A. Gribbell, Rhea Kang, Francesca Cole
      Faithful chromosome segregation in meiosis requires crossover (CO) recombination, which is regulated to ensure at least one CO per homolog pair. We investigate the failure to ensure COs in juvenile male mice. By monitoring recombination genome-wide using cytological assays and at hotspots using molecular assays, we show that juvenile mouse spermatocytes have fewer COs relative to adults. Analysis of recombination in the absence of MLH3 provides evidence for greater utilization in juveniles of pathways involving structure-selective nucleases and alternative complexes, which can act upon precursors to generate noncrossovers (NCOs) at the expense of COs. We propose that some designated CO sites fail to mature efficiently in juveniles owing to inappropriate activity of these alternative repair pathways, leading to chromosome mis-segregation. We also find lower MutLγ focus density in juvenile human spermatocytes, suggesting that weaker CO maturation efficiency may explain why younger men have a higher risk of fathering children with Down syndrome.
      Graphical abstract image Teaser A lower incidence of efficient meiotic crossover recombination in young males is attributed to the preferred utilization of pathways involving structure-selective nucleases and alternative complexes that generate noncrossovers at the expense of crossovers.

      PubDate: 2017-09-21T17:36:03Z
       
  • Artists Create Puzzles, Scientists Solve Them
    • Abstract: Publication date: Available online 6 September 2017
      Source:Cell
      Author(s): Joseph L. Goldstein
      The Spanish artist Diego Velázquez created a puzzle-painting 360 years ago that to this day remains unsolved, but still mystifies and intrigues. Unlike artists who get their thrills by creating puzzles that stimulate the imagination, scientists get their kicks by solving puzzles that advance biomedical research.
      Teaser The Spanish artist Diego Velázquez created a puzzle-painting 360 years ago that to this day remains unsolved, but still mystifies and intrigues. Unlike artists who get their thrills by creating puzzles that stimulate the imagination, scientists get their kicks by solving puzzles that advance biomedical research.

      PubDate: 2017-09-10T01:10:30Z
       
  • TOR, the Gateway to Cellular Metabolism, Cell Growth, and Disease
    • Abstract: Publication date: Available online 6 September 2017
      Source:Cell
      Author(s): John Blenis
      Michael N. Hall is this year’s recipient of the Lasker Basic Medical Research Award for the identification of the target of rapamycin, TOR. TOR is a master regulator of the cell’s growth and metabolic state, and its dysregulation contributes to a variety of diseases, including diabetes, obesity, neurodegenerative disorders, aging, and cancer, making the TOR pathway an attractive therapeutic target.
      Teaser Michael N. Hall is this year’s recipient of the Lasker Basic Medical Research Award for the identification of the target of rapamycin, TOR. TOR is a master regulator of the cell’s growth and metabolic state, and its dysregulation contributes to a variety of diseases, including diabetes, obesity, neurodegenerative disorders, aging, and cancer, making the TOR pathway an attractive therapeutic target.

      PubDate: 2017-09-10T01:10:30Z
       
  • Two Basic Scientists Walk into a Translational Space
    • Abstract: Publication date: Available online 6 September 2017
      Source:Cell
      When John Schiller first joined Douglas Lowy’s lab at the National Cancer Institute of the NIH, he could have not predicted that their common interest in the molecular biology of oncogenes would set them in path for discoveries that ultimately enabled the development of a vaccine for the human papillomavirus, which causes the majority of cervical cancers worldwide. John and Doug, the recipients of the 2017 Lasker-DeBakey Clinical Award, have joined Cell editor João Monteiro in a Conversation about science, public health, and the joys and challenges of being basic scientists in a translational space. Annotated excerpts from this conversation are presented below.
      Teaser When John Schiller first joined Douglas Lowy’s lab at the National Cancer Institute of the NIH, he could have not predicted that their common interest in the molecular biology of oncogenes would set them in path for discoveries that ultimately enabled the development of a vaccine for the human papillomavirus, which causes the majority of cervical cancers worldwide. John and Doug, the recipients of the 2017 Lasker-DeBakey Clinical Award, have joined Cell editor Joao Monteiro in a Conversation about science, public health, and the joys and challenges of being basic scientists in a translational space. Annotated excerpts from this conversation are presented below.

      PubDate: 2017-09-10T01:10:30Z
       
  • A Prize for Cancer Prevention
    • Abstract: Publication date: Available online 6 September 2017
      Source:Cell
      Author(s): Harold Varmus
      This year’s Lasker-DeBakey Prize for Clinical Research to Douglas Lowy and John Schiller celebrates the science behind one of the greatest advances in the history of cancer research: the development of vaccines that prevent infection and thus prevent tumor induction by pathogenic strains of human papilloma virus (HPV).
      Teaser This year’s Lasker-DeBakey Prize for Clinical Research to Douglas Lowy and John Schiller celebrates the science behind one of the greatest advances in the history of cancer research: the development of vaccines that prevent infection and thus prevent tumor induction by pathogenic strains of human papilloma virus (HPV).

      PubDate: 2017-09-10T01:10:30Z
       
  • An Amazing Turn of Events
    • Abstract: Publication date: Available online 6 September 2017
      Source:Cell
      Author(s): Michael N. Hall
      Teaser How the master regulator of cell growth, TOR, came to be identified and understood, from the perspective of its discoverer, Michael N. Hall.

      PubDate: 2017-09-10T01:10:30Z
       
 
 
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