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Journal Cover Cell
  [SJR: 28.188]   [H-I: 616]   [792 followers]  Follow
    
   Full-text available via subscription Subscription journal
   ISSN (Print) 0092-8674 - ISSN (Online) 1097-4172
   Published by Elsevier Homepage  [3043 journals]
  • Formidable Defenses In Utero
    • Abstract: Publication date: 10 August 2017
      Source:Cell, Volume 170, Issue 4
      Author(s): Catarina Sacristán
      Teaser A developing human embryo encounters a multitude of threatening scenarios in the womb. How does the fetus defend itself throughout gestation' A new study by McGovern et al. provides remarkable insight into maternal-fetal immunotolerance.

      PubDate: 2017-08-15T02:36:06Z
       
  • Keeping the Rhythm while Changing the Lyrics: Circadian Biology in Aging
    • Abstract: Publication date: 10 August 2017
      Source:Cell, Volume 170, Issue 4
      Author(s): Fumiyuki Hatanaka, Alejandro Ocampo, Juan Carlos Izpisua Belmonte
      Aging and circadian rhythms have been linked for decades, but their molecular interplay has remained obscure. Sato et al. and Solanas et al. now reveal that, while core clock components remain nearly unaltered, aging is associated with tissue-specific rewiring, which can be prevented by calorie restriction.
      Teaser Aging and circadian rhythms have been linked for decades, but their molecular interplay has remained obscure. Sato et al. and Solanas et al. now reveal that, while core clock components remain nearly unaltered, aging is associated with tissue-specific rewiring, which can be prevented by calorie restriction.

      PubDate: 2017-08-15T02:36:06Z
       
  • The MutAnts Are Here
    • Abstract: Publication date: 10 August 2017
      Source:Cell, Volume 170, Issue 4
      Author(s): Daniel A. Friedman, Deborah M. Gordon, Liqun Luo
      The development of CRISPR/Cas9-mediated gene knockout in two ant species opens a new window into exploring how social insects use olfactory cues to organize their collective behavior.
      Teaser The development of CRISPR/Cas9-mediated gene knockout in two ant species opens a new window into exploring how social insects use olfactory cues to organize their collective behavior.

      PubDate: 2017-08-15T02:36:06Z
       
  • Transcription-Replication Conflicts: Orientation Matters
    • Abstract: Publication date: 10 August 2017
      Source:Cell, Volume 170, Issue 4
      Author(s): Yea-Lih Lin, Philippe Pasero
      Interference between DNA replication and transcription represents a major source of genomic instability. In this issue of Cell, Lang et al. and Hamperl et al. show that head-on collisions, but not codirectional collisions, impede fork progression in bacteria and in human cells by promoting the formation of RNA-DNA hybrids known as R-loops.
      Teaser Interference between DNA replication and transcription represents a major source of genomic instability. In this issue of Cell, Lang et al. and Hamperl et al. show that head-on collisions, but not codirectional collisions, impede fork progression in bacteria and in human cells by promoting the formation of RNA-DNA hybrids known as R-loops.

      PubDate: 2017-08-15T02:36:06Z
       
  • The PI3K Pathway in Human Disease
    • Abstract: Publication date: 10 August 2017
      Source:Cell, Volume 170, Issue 4
      Author(s): David A. Fruman, Honyin Chiu, Benjamin D. Hopkins, Shubha Bagrodia, Lewis C. Cantley, Robert T. Abraham
      Phosphoinositide 3-kinase (PI3K) activity is stimulated by diverse oncogenes and growth factor receptors, and elevated PI3K signaling is considered a hallmark of cancer. Many PI3K pathway-targeted therapies have been tested in oncology trials, resulting in regulatory approval of one isoform-selective inhibitor (idelalisib) for treatment of certain blood cancers and a variety of other agents at different stages of development. In parallel to PI3K research by cancer biologists, investigations in other fields have uncovered exciting and often unpredicted roles for PI3K catalytic and regulatory subunits in normal cell function and in disease. Many of these functions impinge upon oncology by influencing the efficacy and toxicity of PI3K-targeted therapies. Here we provide a perspective on the roles of class I PI3Ks in the regulation of cellular metabolism and in immune system functions, two topics closely intertwined with cancer biology. We also discuss recent progress developing PI3K-targeted therapies for treatment of cancer and other diseases.
      Teaser As a central hub for cellular signaling, PI3K is an important regulator of cellular growth and function. This Review focuses on its basic signaling mechanisms as well as its role in metabolism and immune function in the context of cancer.

      PubDate: 2017-08-15T02:36:06Z
       
  • TREM2 Maintains Microglial Metabolic Fitness in Alzheimer’s Disease
    • Abstract: Publication date: 10 August 2017
      Source:Cell, Volume 170, Issue 4
      Author(s): Tyler K. Ulland, Wilbur M. Song, Stanley Ching-Cheng Huang, Jason D. Ulrich, Alexey Sergushichev, Wandy L. Beatty, Alexander A. Loboda, Yingyue Zhou, Nigel J. Cairns, Amal Kambal, Ekaterina Loginicheva, Susan Gilfillan, Marina Cella, Herbert W. Virgin, Emil R. Unanue, Yaming Wang, Maxim N. Artyomov, David M. Holtzman, Marco Colonna
      Elevated risk of developing Alzheimer’s disease (AD) is associated with hypomorphic variants of TREM2, a surface receptor required for microglial responses to neurodegeneration, including proliferation, survival, clustering, and phagocytosis. How TREM2 promotes such diverse responses is unknown. Here, we find that microglia in AD patients carrying TREM2 risk variants and TREM2-deficient mice with AD-like pathology have abundant autophagic vesicles, as do TREM2-deficient macrophages under growth-factor limitation or endoplasmic reticulum (ER) stress. Combined metabolomics and RNA sequencing (RNA-seq) linked this anomalous autophagy to defective mammalian target of rapamycin (mTOR) signaling, which affects ATP levels and biosynthetic pathways. Metabolic derailment and autophagy were offset in vitro through Dectin-1, a receptor that elicits TREM2-like intracellular signals, and cyclocreatine, a creatine analog that can supply ATP. Dietary cyclocreatine tempered autophagy, restored microglial clustering around plaques, and decreased plaque-adjacent neuronal dystrophy in TREM2-deficient mice with amyloid-β pathology. Thus, TREM2 enables microglial responses during AD by sustaining cellular energetic and biosynthetic metabolism.
      Graphical abstract image Teaser The Alzheimer’s disease risk factor TREM2 regulates microglial function through modulation of cellular biosynthetic metabolism.

      PubDate: 2017-08-15T02:36:06Z
       
  • Circadian Reprogramming in the Liver Identifies Metabolic Pathways of
           Aging
    • Abstract: Publication date: 10 August 2017
      Source:Cell, Volume 170, Issue 4
      Author(s): Shogo Sato, Guiomar Solanas, Francisca Oliveira Peixoto, Leonardo Bee, Aikaterini Symeonidi, Mark S. Schmidt, Charles Brenner, Selma Masri, Salvador Aznar Benitah, Paolo Sassone-Corsi
      The process of aging and circadian rhythms are intimately intertwined, but how peripheral clocks involved in metabolic homeostasis contribute to aging remains unknown. Importantly, caloric restriction (CR) extends lifespan in several organisms and rewires circadian metabolism. Using young versus old mice, fed ad libitum or under CR, we reveal reprogramming of the circadian transcriptome in the liver. These age-dependent changes occur in a highly tissue-specific manner, as demonstrated by comparing circadian gene expression in the liver versus epidermal and skeletal muscle stem cells. Moreover, de novo oscillating genes under CR show an enrichment in SIRT1 targets in the liver. This is accompanied by distinct circadian hepatic signatures in NAD+-related metabolites and cyclic global protein acetylation. Strikingly, this oscillation in acetylation is absent in old mice while CR robustly rescues global protein acetylation. Our findings indicate that the clock operates at the crossroad between protein acetylation, liver metabolism, and aging.
      Graphical abstract image Teaser Aging reprograms the circadian transcriptome in a highly tissue-specific manner

      PubDate: 2017-08-15T02:36:06Z
       
  • Aged Stem Cells Reprogram Their Daily Rhythmic Functions to Adapt to
           Stress
    • Abstract: Publication date: 10 August 2017
      Source:Cell, Volume 170, Issue 4
      Author(s): Guiomar Solanas, Francisca Oliveira Peixoto, Eusebio Perdiguero, Mercè Jardí, Vanessa Ruiz-Bonilla, Debayan Datta, Aikaterini Symeonidi, Andrés Castellanos, Patrick-Simon Welz, Juan Martín Caballero, Paolo Sassone-Corsi, Pura Muñoz-Cánoves, Salvador Aznar Benitah
      Normal homeostatic functions of adult stem cells have rhythmic daily oscillations that are believed to become arrhythmic during aging. Unexpectedly, we find that aged mice remain behaviorally circadian and that their epidermal and muscle stem cells retain a robustly rhythmic core circadian machinery. However, the oscillating transcriptome is extensively reprogrammed in aged stem cells, switching from genes involved in homeostasis to those involved in tissue-specific stresses, such as DNA damage or inefficient autophagy. Importantly, deletion of circadian clock components did not reproduce the hallmarks of this reprogramming, underscoring that rewiring, rather than arrhythmia, is associated with physiological aging. While age-associated rewiring of the oscillatory diurnal transcriptome is not recapitulated by a high-fat diet in young adult mice, it is significantly prevented by long-term caloric restriction in aged mice. Thus, stem cells rewire their diurnal timed functions to adapt to metabolic cues and to tissue-specific age-related traits.
      Graphical abstract image Teaser The daily rhythmic transcriptome is extensively reprogrammed in aged stem cells, switching from genes involved in homeostasis to those involved in tissue-specific stresses.

      PubDate: 2017-08-15T02:36:06Z
       
  • Cryo-EM Structure of the TOM Core Complex from Neurospora crassa
    • Abstract: Publication date: 10 August 2017
      Source:Cell, Volume 170, Issue 4
      Author(s): Thomas Bausewein, Deryck J. Mills, Julian D. Langer, Beate Nitschke, Stephan Nussberger, Werner Kühlbrandt
      The TOM complex is the main entry gate for protein precursors from the cytosol into mitochondria. We have determined the structure of the TOM core complex by cryoelectron microscopy (cryo-EM). The complex is a 148 kDa symmetrical dimer of ten membrane protein subunits that create a shallow funnel on the cytoplasmic membrane surface. In the core of the dimer, the β-barrels of the Tom40 pore form two identical preprotein conduits. Each Tom40 pore is surrounded by the transmembrane segments of the α-helical subunits Tom5, Tom6, and Tom7. Tom22, the central preprotein receptor, connects the two Tom40 pores at the dimer interface. Our structure offers detailed insights into the molecular architecture of the mitochondrial preprotein import machinery.
      Graphical abstract image Teaser Molecular structure of the TOM preprotein import complex exposes how the two pore assembly translocates proteins into the mitochondria.

      PubDate: 2017-08-15T02:36:06Z
       
  • orco Mutagenesis Causes Loss of Antennal Lobe Glomeruli and Impaired
           Social Behavior in Ants
    • Abstract: Publication date: 10 August 2017
      Source:Cell, Volume 170, Issue 4
      Author(s): Waring Trible, Leonora Olivos-Cisneros, Sean K. McKenzie, Jonathan Saragosti, Ni-Chen Chang, Benjamin J. Matthews, Peter R. Oxley, Daniel J.C. Kronauer
      Life inside ant colonies is orchestrated with diverse pheromones, but it is not clear how ants perceive these social signals. It has been proposed that pheromone perception in ants evolved via expansions in the numbers of odorant receptors (ORs) and antennal lobe glomeruli. Here, we generate the first mutant lines in the clonal raider ant, Ooceraea biroi, by disrupting orco, a gene required for the function of all ORs. We find that orco mutants exhibit severe deficiencies in social behavior and fitness, suggesting they are unable to perceive pheromones. Surprisingly, unlike in Drosophila melanogaster, orco mutant ants also lack most of the ∼500 antennal lobe glomeruli found in wild-type ants. These results illustrate that ORs are essential for ant social organization and raise the possibility that, similar to mammals, receptor function is required for the development and/or maintenance of the highly complex olfactory processing areas in the ant brain. Video
      Graphical abstract image Teaser Development of the first line of mutant ants, using CRISPR/Cas technology, reveals what happens inside of a colony when ants lose the ability to recognize odors.

      PubDate: 2017-08-15T02:36:06Z
       
  • An Engineered orco Mutation Produces Aberrant Social Behavior and
           Defective Neural Development in Ants
    • Abstract: Publication date: 10 August 2017
      Source:Cell, Volume 170, Issue 4
      Author(s): Hua Yan, Comzit Opachaloemphan, Giacomo Mancini, Huan Yang, Matthew Gallitto, Jakub Mlejnek, Alexandra Leibholz, Kevin Haight, Majid Ghaninia, Lucy Huo, Michael Perry, Jesse Slone, Xiaofan Zhou, Maria Traficante, Clint A. Penick, Kelly Dolezal, Kaustubh Gokhale, Kelsey Stevens, Ingrid Fetter-Pruneda, Roberto Bonasio, Laurence J. Zwiebel, Shelley L. Berger, Jürgen Liebig, Danny Reinberg, Claude Desplan
      Ants exhibit cooperative behaviors and advanced forms of sociality that depend on pheromone-mediated communication. Odorant receptor neurons (ORNs) express specific odorant receptors (ORs) encoded by a dramatically expanded gene family in ants. In most eusocial insects, only the queen can transmit genetic information, restricting genetic studies. In contrast, workers in Harpegnathos saltator ants can be converted into gamergates (pseudoqueens) that can found entire colonies. This feature facilitated CRISPR-Cas9 generation of germline mutations in orco, the gene that encodes the obligate co-receptor of all ORs. orco mutations should significantly impact olfaction. We demonstrate striking functions of Orco in odorant perception, reproductive physiology, and social behavior plasticity. Surprisingly, unlike in other insects, loss of OR functionality also dramatically impairs development of the antennal lobe to which ORNs project. Therefore, the development of genetics in Harpegnathos establishes this ant species as a model organism to study the complexity of eusociality.
      Graphical abstract image Teaser Development of the first line of mutant ants using CRISPR/Cas technology reveals what happens inside a colony when ants lose the ability to recognize odors.

      PubDate: 2017-08-15T02:36:06Z
       
  • The Neuropeptide Corazonin Controls Social Behavior and Caste Identity in
           Ants
    • Abstract: Publication date: 10 August 2017
      Source:Cell, Volume 170, Issue 4
      Author(s): Janko Gospocic, Emily J. Shields, Karl M. Glastad, Yanping Lin, Clint A. Penick, Hua Yan, Alexander S. Mikheyev, Timothy A. Linksvayer, Benjamin A. Garcia, Shelley L. Berger, Jürgen Liebig, Danny Reinberg, Roberto Bonasio
      Social insects are emerging models to study how gene regulation affects behavior because their colonies comprise individuals with the same genomes but greatly different behavioral repertoires. To investigate the molecular mechanisms that activate distinct behaviors in different castes, we exploit a natural behavioral plasticity in Harpegnathos saltator, where adult workers can transition to a reproductive, queen-like state called gamergate. Analysis of brain transcriptomes during the transition reveals that corazonin, a neuropeptide homologous to the vertebrate gonadotropin-releasing hormone, is downregulated as workers become gamergates. Corazonin is also preferentially expressed in workers and/or foragers from other social insect species. Injection of corazonin in transitioning Harpegnathos individuals suppresses expression of vitellogenin in the brain and stimulates worker-like hunting behaviors, while inhibiting gamergate behaviors, such as dueling and egg deposition. We propose that corazonin is a central regulator of caste identity and behavior in social insects.
      Graphical abstract image Teaser Corazonin controls behavioral transitions between ant workers and pseudo queens.

      PubDate: 2017-08-15T02:36:06Z
       
  • Transcription-Replication Conflict Orientation Modulates R-Loop Levels and
           Activates Distinct DNA Damage Responses
    • Abstract: Publication date: 10 August 2017
      Source:Cell, Volume 170, Issue 4
      Author(s): Stephan Hamperl, Michael J. Bocek, Joshua C. Saldivar, Tomek Swigut, Karlene A. Cimprich
      Conflicts between transcription and replication are a potent source of DNA damage. Co-transcriptional R-loops could aggravate such conflicts by creating an additional barrier to replication fork progression. Here, we use a defined episomal system to investigate how conflict orientation and R-loop formation influence genome stability in human cells. R-loops, but not normal transcription complexes, induce DNA breaks and orientation-specific DNA damage responses during conflicts with replication forks. Unexpectedly, the replisome acts as an orientation-dependent regulator of R-loop levels, reducing R-loops in the co-directional (CD) orientation but promoting their formation in the head-on (HO) orientation. Replication stress and deregulated origin firing increase the number of HO collisions leading to genome-destabilizing R-loops. Our findings connect DNA replication to R-loop homeostasis and suggest a mechanistic basis for genome instability resulting from deregulated DNA replication, observed in cancer and other disease states.
      Graphical abstract image Teaser Collisions between transcription and replication complexes activate distinct DNA damage responses depending on whether they meet head-on or are moving in the same direction.

      PubDate: 2017-08-15T02:36:06Z
       
  • Replication-Transcription Conflicts Generate R-Loops that Orchestrate
           Bacterial Stress Survival and Pathogenesis
    • Abstract: Publication date: 10 August 2017
      Source:Cell, Volume 170, Issue 4
      Author(s): Kevin S. Lang, Ashley N. Hall, Christopher N. Merrikh, Mark Ragheb, Hannah Tabakh, Alex J. Pollock, Joshua J. Woodward, Julia E. Dreifus, Houra Merrikh
      Replication-transcription collisions shape genomes, influence evolution, and promote genetic diseases. Although unclear why, head-on transcription (lagging strand genes) is especially disruptive to replication and promotes genomic instability. Here, we find that head-on collisions promote R-loop formation in Bacillus subtilis. We show that pervasive R-loop formation at head-on collision regions completely blocks replication, elevates mutagenesis, and inhibits gene expression. Accordingly, the activity of the R-loop processing enzyme RNase HIII at collision regions is crucial for stress survival in B. subtilis, as many stress response genes are head-on to replication. Remarkably, without RNase HIII, the ability of the intracellular pathogen Listeria monocytogenes to infect and replicate in hosts is weakened significantly, most likely because many virulence genes are head-on to replication. We conclude that the detrimental effects of head-on collisions stem primarily from excessive R-loop formation and that the resolution of these structures is critical for bacterial stress survival and pathogenesis.
      Graphical abstract image Teaser Head-on replication-transcription collisions lead to pervasive R-loop formation, which must be resolved for bacterial stress survival and pathogenesis.

      PubDate: 2017-08-15T02:36:06Z
       
  • Dual ifgMosaic: A Versatile Method for Multispectral and Combinatorial
           Mosaic Gene-Function Analysis
    • Abstract: Publication date: 10 August 2017
      Source:Cell, Volume 170, Issue 4
      Author(s): Samuel Pontes-Quero, Luis Heredia, Verónica Casquero-García, Macarena Fernández-Chacón, Wen Luo, Ana Hermoso, Mayank Bansal, Irene Garcia-Gonzalez, Maria S. Sanchez-Muñoz, Juan R. Perea, Adrian Galiana-Simal, Iker Rodriguez-Arabaolaza, Sergio Del Olmo-Cabrera, Susana F. Rocha, Luis M. Criado-Rodriguez, Giovanna Giovinazzo, Rui Benedito
      Improved methods for manipulating and analyzing gene function have provided a better understanding of how genes work during organ development and disease. Inducible functional genetic mosaics can be extraordinarily useful in the study of biological systems; however, this experimental approach is still rarely used in vertebrates. This is mainly due to technical difficulties in the assembly of large DNA constructs carrying multiple genes and regulatory elements and their targeting to the genome. In addition, mosaic phenotypic analysis, unlike classical single gene-function analysis, requires clear labeling and detection of multiple cell clones in the same tissue. Here, we describe several methods for the rapid generation of transgenic or gene-targeted mice and embryonic stem (ES) cell lines containing all the necessary elements for inducible, fluorescent, and functional genetic mosaic (ifgMosaic) analysis. This technology enables the interrogation of multiple and combinatorial gene function with high temporal and cellular resolution.
      Graphical abstract image Teaser Multiple strategies are developed to enable multispectral and combinatorial mosaic gene-function analysis in mice, allowing comparison of molecular phenotypes on a cell-by-cell basis.

      PubDate: 2017-08-15T02:36:06Z
       
  • Biology Gone Wild
    • Abstract: Publication date: 10 August 2017
      Source:Cell, Volume 170, Issue 4
      Author(s): Diana Crow


      PubDate: 2017-08-15T02:36:06Z
       
  • SnapShot: Cellular Senescence Pathways
    • Abstract: Publication date: 10 August 2017
      Source:Cell, Volume 170, Issue 4
      Author(s): Ricardo Iván Martínez-Zamudio, Lucas Robinson, Pierre-Francois Roux, Oliver Bischof
      Cellular senescence is a fundamental cell fate, playing important physiological and pathophysiological roles. This SnapShot focuses on major signaling pathways and transcriptional control mechanisms that consolidate the senescence phenotype.
      Teaser Cellular senescence is a fundamental cell fate, playing important physiological and pathophysiological roles. This SnapShot focuses on major signaling pathways and transcriptional control mechanisms that consolidate the senescence phenotype.

      PubDate: 2017-08-15T02:36:06Z
       
  • The Ground State and Evolution of Promoter Region Directionality
    • Abstract: Publication date: Available online 10 August 2017
      Source:Cell
      Author(s): Yi Jin, Umut Eser, Kevin Struhl, L. Stirling Churchman
      Eukaryotic promoter regions are frequently divergently transcribed in vivo, but it is unknown whether the resultant antisense RNAs are a mechanistic by-product of RNA polymerase II (Pol II) transcription or biologically meaningful. Here, we use a functional evolutionary approach that involves nascent transcript mapping in S. cerevisiae strains containing foreign yeast DNA. Promoter regions in foreign environments lose the directionality they have in their native species. Strikingly, fortuitous promoter regions arising in foreign DNA produce equal transcription in both directions, indicating that divergent transcription is a mechanistic feature that does not imply a function for these transcripts. Fortuitous promoter regions arising during evolution promote bidirectional transcription and over time are purged through mutation or retained to enable new functionality. Similarly, human transcription is more bidirectional at newly evolved enhancers and promoter regions. Thus, promoter regions are intrinsically bidirectional and are shaped by evolution to bias transcription toward coding versus non-coding RNAs.
      Graphical abstract image Teaser Promoter regions are intrinsically bidirectional and are shaped by evolution to bias transcription of coding transcripts, while suppressing non-coding antisense transcription.

      PubDate: 2017-08-15T02:36:06Z
       
  • Distinct Cellular Mechanisms Underlie Anti-CTLA-4 and Anti-PD-1 Checkpoint
           Blockade
    • Abstract: Publication date: Available online 10 August 2017
      Source:Cell
      Author(s): Spencer C. Wei, Jacob H. Levine, Alexandria P. Cogdill, Yang Zhao, Nana-Ama A.S. Anang, Miles C. Andrews, Padmanee Sharma, Jing Wang, Jennifer A. Wargo, Dana Pe’er, James P. Allison
      Immune-checkpoint blockade is able to achieve durable responses in a subset of patients; however, we lack a satisfying comprehension of the underlying mechanisms of anti-CTLA-4- and anti-PD-1-induced tumor rejection. To address these issues, we utilized mass cytometry to comprehensively profile the effects of checkpoint blockade on tumor immune infiltrates in human melanoma and murine tumor models. These analyses reveal a spectrum of tumor-infiltrating T cell populations that are highly similar between tumor models and indicate that checkpoint blockade targets only specific subsets of tumor-infiltrating T cell populations. Anti-PD-1 predominantly induces the expansion of specific tumor-infiltrating exhausted-like CD8 T cell subsets. In contrast, anti-CTLA-4 induces the expansion of an ICOS+ Th1-like CD4 effector population in addition to engaging specific subsets of exhausted-like CD8 T cells. Thus, our findings indicate that anti-CTLA-4 and anti-PD-1 checkpoint-blockade-induced immune responses are driven by distinct cellular mechanisms.
      Graphical abstract image Teaser Anti-CTLA-4 and anti-PD-1 checkpoint-blockade therapies target distinct tumor-infiltrating T cell populations to induce tumor rejection.

      PubDate: 2017-08-15T02:36:06Z
       
  • Golgi-Resident Gαo Promotes Protrusive Membrane Dynamics
    • Abstract: Publication date: Available online 10 August 2017
      Source:Cell
      Author(s): Gonzalo P. Solis, Oleksii Bilousov, Alexey Koval, Anne-Marie Lüchtenborg, Chen Lin, Vladimir L. Katanaev
      To form protrusions like neurites, cells must coordinate their induction and growth. The first requires cytoskeletal rearrangements at the plasma membrane (PM), the second requires directed material delivery from cell’s insides. We find that the Gαo-subunit of heterotrimeric G proteins localizes dually to PM and Golgi across phyla and cell types. The PM pool of Gαo induces, and the Golgi pool feeds, the growing protrusions by stimulated trafficking. Golgi-residing KDELR binds and activates monomeric Gαo, atypically for G protein-coupled receptors that normally act on heterotrimeric G proteins. Through multidimensional screenings identifying > 250 Gαo interactors, we pinpoint several basic cellular activities, including vesicular trafficking, as being regulated by Gαo. We further find small Golgi-residing GTPases Rab1 and Rab3 as direct effectors of Gαo. This KDELR → Gαo → Rab1/3 signaling axis is conserved from insects to mammals and controls material delivery from Golgi to PM in various cells and tissues.
      Graphical abstract image Teaser Gαo functions in vesicle trafficking independent of canonical G protein signaling.

      PubDate: 2017-08-15T02:36:06Z
       
  • Renal Sodium Gradient Orchestrates a Dynamic Antibacterial Defense Zone
    • Abstract: Publication date: Available online 10 August 2017
      Source:Cell
      Author(s): Miriam R. Berry, Rebeccah J. Mathews, John R. Ferdinand, Chenzhi Jing, Kevin W. Loudon, Elizabeth Wlodek, Thomas W. Dennison, Christoph Kuper, Wolfgang Neuhofer, Menna R. Clatworthy
      Lower urinary tract infections are among the most common human bacterial infections, but extension to the kidneys is rare. This has been attributed to mechanical forces, such as urine flow, that prevent the ascent of bladder microbes. Here, we show that the regional hypersalinity, required for the kidney’s urine-concentrating function, instructs epithelial cells to produce chemokines that localize monocyte-derived mononuclear phagocytes (MNPs) to the medulla. This hypersaline environment also increases the intrinsic bactericidal and neutrophil chemotactic activities of MNPs to generate a zone of defense. Because MNP positioning and function are dynamically regulated by the renal salt gradient, we find that patients with urinary concentrating defects are susceptible to kidney infection. Our work reveals a critical accessory role for the homeostatic function of a vital organ in optimizing tissue defense.
      Graphical abstract image Teaser Sodium gradient guides the migration of innate immune cells in the kidney during infections.

      PubDate: 2017-08-15T02:36:06Z
       
  • Elimination of Toxic Microsatellite Repeat Expansion RNA by RNA-Targeting
           Cas9
    • Abstract: Publication date: Available online 10 August 2017
      Source:Cell
      Author(s): Ranjan Batra, David A. Nelles, Elaine Pirie, Steven M. Blue, Ryan J. Marina, Harrison Wang, Isaac A. Chaim, James D. Thomas, Nigel Zhang, Vu Nguyen, Stefan Aigner, Sebastian Markmiller, Guangbin Xia, Kevin D. Corbett, Maurice S. Swanson, Gene W. Yeo
      Microsatellite repeat expansions in DNA produce pathogenic RNA species that cause dominantly inherited diseases such as myotonic dystrophy type 1 and 2 (DM1/2), Huntington’s disease, and C9orf72-linked amyotrophic lateral sclerosis (C9-ALS). Means to target these repetitive RNAs are required for diagnostic and therapeutic purposes. Here, we describe the development of a programmable CRISPR system capable of specifically visualizing and eliminating these toxic RNAs. We observe specific targeting and efficient elimination of microsatellite repeat expansion RNAs both when exogenously expressed and in patient cells. Importantly, RNA-targeting Cas9 (RCas9) reverses hallmark features of disease including elimination of RNA foci among all conditions studied (DM1, DM2, C9-ALS, polyglutamine diseases), reduction of polyglutamine protein products, relocalization of repeat-bound proteins to resemble healthy controls, and efficient reversal of DM1-associated splicing abnormalities in patient myotubes. Finally, we report a truncated RCas9 system compatible with adeno-associated viral packaging. This effort highlights the potential of RCas9 for human therapeutics.
      Graphical abstract image Teaser An RNA-targeting Cas9 system induces degradation of microsatellite repeat expansion RNAs, highlighting the potential of RNA-targeting CRISPR systems for therapeutic purposes.

      PubDate: 2017-08-15T02:36:06Z
       
  • Cryo-EM Structure of a Pre-catalytic Human Spliceosome Primed for
           Activation
    • Abstract: Publication date: Available online 3 August 2017
      Source:Cell
      Author(s): Karl Bertram, Dmitry E. Agafonov, Olexandr Dybkov, David Haselbach, Majety N. Leelaram, Cindy L. Will, Henning Urlaub, Berthold Kastner, Reinhard Lührmann, Holger Stark
      Little is known about the spliceosome’s structure before its extensive remodeling into a catalytically active complex. Here, we report a 3D cryo-EM structure of a pre-catalytic human spliceosomal B complex. The U2 snRNP-containing head domain is connected to the B complex main body via three main bridges. U4/U6.U5 tri-snRNP proteins, which are located in the main body, undergo significant rearrangements during tri-snRNP integration into the B complex. These include formation of a partially closed Prp8 conformation that creates, together with Dim1, a 5′ splice site (ss) binding pocket, displacement of Sad1, and rearrangement of Brr2 such that it contacts its U4/U6 substrate and is poised for the subsequent spliceosome activation step. The molecular organization of several B-specific proteins suggests that they are involved in negatively regulating Brr2, positioning the U6/5′ss helix, and stabilizing the B complex structure. Our results indicate significant differences between the early activation phase of human and yeast spliceosomes.
      Graphical abstract image Teaser Structure of the human spliceosome getting ready for action.

      PubDate: 2017-08-04T21:20:11Z
       
  • Multi-invasions Are Recombination Byproducts that Induce Chromosomal
           Rearrangements
    • Abstract: Publication date: Available online 3 August 2017
      Source:Cell
      Author(s): Aurèle Piazza, William Douglass Wright, Wolf-Dietrich Heyer
      Inaccurate repair of broken chromosomes generates structural variants that can fuel evolution and inflict pathology. We describe a novel rearrangement mechanism in which translocation between intact chromosomes is induced by a lesion on a third chromosome. This multi-invasion-induced rearrangement (MIR) stems from a homologous recombination byproduct, where a broken DNA end simultaneously invades two intact donors. No homology is required between the donors, and the intervening sequence from the invading molecule is inserted at the translocation site. MIR is stimulated by increasing homology length and spatial proximity of the donors and depends on the overlapping activities of the structure-selective endonucleases Mus81-Mms4, Slx1-Slx4, and Yen1. Conversely, the 3′-flap nuclease Rad1-Rad10 and enzymes known to disrupt recombination intermediates (Sgs1-Top3-Rmi1, Srs2, and Mph1) inhibit MIR. Resolution of MIR intermediates propagates secondary chromosome breaks that frequently cause additional rearrangements. MIR features have implications for the formation of simple and complex rearrangements underlying human pathologies.
      Graphical abstract image Teaser Translocation between two intact chromosomes can be induced by an independent lesion on a third chromosome.

      PubDate: 2017-08-04T21:20:11Z
       
  • Raphe Circuits on the Menu
    • Abstract: Publication date: 27 July 2017
      Source:Cell, Volume 170, Issue 3
      Author(s): Hui Yang, Scott M. Sternson
      The dorsal raphe nucleus (DRN) is an important brain area for body-weight regulation. In this issue of Cell, Nectow et al. uncover cell-type-specific neural circuitry and pharmacology for appetite control within the DRN.
      Teaser The dorsal raphe nucleus (DRN) is an important brain area for body-weight regulation. In this issue of Cell, Nectow et al. uncover cell-type-specific neural circuitry and pharmacology for appetite control within the DRN.

      PubDate: 2017-08-04T21:20:11Z
       
  • Drugs, Bugs, and Cancer: Fusobacterium nucleatum Promotes Chemoresistance
           in Colorectal Cancer
    • Abstract: Publication date: 27 July 2017
      Source:Cell, Volume 170, Issue 3
      Author(s): Azucena Ramos, Michael T. Hemann
      The tumor microenvironment has recently been shown to play decisive roles in chemotherapeutic response. In this issue of Cell, Yu et al. add to these findings by identifying the bacterium Fusobacterium nucleatum as a previously unrecognized chemoresistance mediator in colorectal cancer, thereby establishing the microbiota as a potential therapeutic target.
      Teaser The tumor microenvironment has recently been shown to play decisive roles in chemotherapeutic response. In this issue of Cell, Yu et al. add to these findings by identifying the bacterium Fusobacterium nucleatum as a previously unrecognized chemoresistance mediator in colorectal cancer, thereby establishing the microbiota as a potential therapeutic target.

      PubDate: 2017-08-04T21:20:11Z
       
  • How Ligands Illuminate GPCR Molecular Pharmacology
    • Abstract: Publication date: 27 July 2017
      Source:Cell, Volume 170, Issue 3
      Author(s): Daniel Wacker, Raymond C. Stevens, Bryan L. Roth
      G protein-coupled receptors (GPCRs), which are modulated by a variety of endogenous and synthetic ligands, represent the largest family of druggable targets in the human genome. Recent structural and molecular studies have both transformed and expanded classical concepts of receptor pharmacology and have begun to illuminate the distinct mechanisms by which structurally, chemically, and functionally diverse ligands modulate GPCR function. These molecular insights into ligand engagement and action have enabled new computational methods and accelerated the discovery of novel ligands and tool compounds, especially for understudied and orphan GPCRs. These advances promise to streamline the development of GPCR-targeted medications.
      Teaser Structural and computational approaches studying GPCR-ligand interactions are shaping fundamental principles in receptor signaling and uncovering new physiological functions for this protein family.

      PubDate: 2017-08-04T21:20:11Z
       
  • Identification of a Brainstem Circuit Controlling Feeding
    • Abstract: Publication date: 27 July 2017
      Source:Cell, Volume 170, Issue 3
      Author(s): Alexander R. Nectow, Marc Schneeberger, Hongxing Zhang, Bianca C. Field, Nicolas Renier, Estefania Azevedo, Bindiben Patel, Yupu Liang, Siddhartha Mitra, Marc Tessier-Lavigne, Ming-Hu Han, Jeffrey M. Friedman
      Hunger, driven by negative energy balance, elicits the search for and consumption of food. While this response is in part mediated by neurons in the hypothalamus, the role of specific cell types in other brain regions is less well defined. Here, we show that neurons in the dorsal raphe nucleus, expressing vesicular transporters for GABA or glutamate (hereafter, DRNVgat and DRNVGLUT3 neurons), are reciprocally activated by changes in energy balance and that modulating their activity has opposite effects on feeding—DRNVgat neurons increase, whereas DRNVGLUT3 neurons suppress, food intake. Furthermore, modulation of these neurons in obese (ob/ob) mice suppresses food intake and body weight and normalizes locomotor activity. Finally, using molecular profiling, we identify druggable targets in these neurons and show that local infusion of agonists for specific receptors on these neurons has potent effects on feeding. These data establish the DRN as an important node controlling energy balance. PaperClip
      Graphical abstract image Teaser A combination of brain mapping and molecular pharmacology approaches identifies specific neurons in the dorsal raphe nucleus as being important regulators of feeding behavior.

      PubDate: 2017-08-04T21:20:11Z
       
  • Alzheimer’s-Causing Mutations Shift Aβ Length by Destabilizing
           γ-Secretase-Aβn Interactions
    • Abstract: Publication date: 27 July 2017
      Source:Cell, Volume 170, Issue 3
      Author(s): Maria Szaruga, Bogdan Munteanu, Sam Lismont, Sarah Veugelen, Katrien Horré, Marc Mercken, Takaomi C. Saido, Natalie S. Ryan, Tatjana De Vos, Savvas N. Savvides, Rodrigo Gallardo, Joost Schymkowitz, Frederic Rousseau, Nick C. Fox, Carsten Hopf, Bart De Strooper, Lucía Chávez-Gutiérrez
      Alzheimer’s disease (AD)-linked mutations in Presenilins (PSEN) and the amyloid precursor protein (APP) lead to production of longer amyloidogenic Aβ peptides. The shift in Aβ length is fundamental to the disease; however, the underlying mechanism remains elusive. Here, we show that substrate shortening progressively destabilizes the consecutive enzyme-substrate (E-S) complexes that characterize the sequential γ-secretase processing of APP. Remarkably, pathogenic PSEN or APP mutations further destabilize labile E-S complexes and thereby promote generation of longer Aβ peptides. Similarly, destabilization of wild-type E-S complexes by temperature, compounds, or detergent promotes release of amyloidogenic Aβ. In contrast, E-Aβn stabilizers increase γ-secretase processivity. Our work presents a unifying model for how PSEN or APP mutations enhance amyloidogenic Aβ production, suggests that environmental factors may increase AD risk, and provides the theoretical basis for the development of γ-secretase/substrate stabilizing compounds for the prevention of AD.
      Graphical abstract image Teaser Sequential γ-secretase cuts on amyloid precursor protein (APP) generates progressively less stable enzyme-substrate (E-S) complexes. Alzheimer’s disease–causing mutations destabilize E-S complexes and thereby enhance amyloidogenic Aβ production.

      PubDate: 2017-08-04T21:20:11Z
       
  • Identification of Phosphorylation Codes for Arrestin Recruitment by G
           Protein-Coupled Receptors
    • Abstract: Publication date: 27 July 2017
      Source:Cell, Volume 170, Issue 3
      Author(s): X. Edward Zhou, Yuanzheng He, Parker W. de Waal, Xiang Gao, Yanyong Kang, Ned Van Eps, Yanting Yin, Kuntal Pal, Devrishi Goswami, Thomas A. White, Anton Barty, Naomi R. Latorraca, Henry N. Chapman, Wayne L. Hubbell, Ron O. Dror, Raymond C. Stevens, Vadim Cherezov, Vsevolod V. Gurevich, Patrick R. Griffin, Oliver P. Ernst, Karsten Melcher, H. Eric Xu
      G protein-coupled receptors (GPCRs) mediate diverse signaling in part through interaction with arrestins, whose binding promotes receptor internalization and signaling through G protein-independent pathways. High-affinity arrestin binding requires receptor phosphorylation, often at the receptor’s C-terminal tail. Here, we report an X-ray free electron laser (XFEL) crystal structure of the rhodopsin-arrestin complex, in which the phosphorylated C terminus of rhodopsin forms an extended intermolecular β sheet with the N-terminal β strands of arrestin. Phosphorylation was detected at rhodopsin C-terminal tail residues T336 and S338. These two phospho-residues, together with E341, form an extensive network of electrostatic interactions with three positively charged pockets in arrestin in a mode that resembles binding of the phosphorylated vasopressin-2 receptor tail to β-arrestin-1. Based on these observations, we derived and validated a set of phosphorylation codes that serve as a common mechanism for phosphorylation-dependent recruitment of arrestins by GPCRs.
      Graphical abstract image Teaser A crystal structure of a fully engaged rhodopsin-arrestin complex identifies phosphorylation codes as a common mechanism of arrestin recruitment by GPCRs.

      PubDate: 2017-08-04T21:20:11Z
       
  • Methyltransferase SETD2-Mediated Methylation of STAT1 Is Critical for
           Interferon Antiviral Activity
    • Abstract: Publication date: 27 July 2017
      Source:Cell, Volume 170, Issue 3
      Author(s): Kun Chen, Juan Liu, Shuxun Liu, Meng Xia, Xiaomin Zhang, Dan Han, Yingming Jiang, Chunmei Wang, Xuetao Cao
      Interferon-α (IFNα) signaling is essential for antiviral response via induction of IFN-stimulated genes (ISGs). Through a non-biased high-throughput RNAi screening of 711 known epigenetic modifiers in cellular models of IFNα-mediated inhibition of HBV replication, we identified methyltransferase SETD2 as a critical amplifier of IFNα-mediated antiviral immunity. Conditional knockout mice with hepatocyte-specific deletion of Setd2 exhibit enhanced HBV infection. Mechanistically, SETD2 directly mediates STAT1 methylation on lysine 525 via its methyltransferase activity, which reinforces IFN-activated STAT1 phosphorylation and antiviral cellular response. In addition, SETD2 selectively catalyzes the tri-methylation of H3K36 on promoters of some ISGs such as ISG15, leading to gene activation. Our study identifies STAT1 methylation on K525 catalyzed by the methyltransferase SETD2 as an essential signaling event for IFNα-dependent antiviral immunity and indicates potential of SETD2 in controlling viral infections.
      Graphical abstract image Teaser Multilayer epigenetic modulations of IFNα-dependent signaling responses by the methyltransferase SETD2 are essential for the amplification of antiviral immunity.

      PubDate: 2017-08-04T21:20:11Z
       
  • A Genetic Variant Associated with Five Vascular Diseases Is a Distal
           Regulator of Endothelin-1 Gene Expression
    • Abstract: Publication date: 27 July 2017
      Source:Cell, Volume 170, Issue 3
      Author(s): Rajat M. Gupta, Joseph Hadaya, Aditi Trehan, Seyedeh M. Zekavat, Carolina Roselli, Derek Klarin, Connor A. Emdin, Catharina R.E. Hilvering, Valerio Bianchi, Christian Mueller, Amit V. Khera, Russell J.H. Ryan, Jesse M. Engreitz, Robbyn Issner, Noam Shoresh, Charles B. Epstein, Wouter de Laat, Jonathan D. Brown, Renate B. Schnabel, Bradley E. Bernstein, Sekar Kathiresan
      Genome-wide association studies (GWASs) implicate the PHACTR1 locus (6p24) in risk for five vascular diseases, including coronary artery disease, migraine headache, cervical artery dissection, fibromuscular dysplasia, and hypertension. Through genetic fine mapping, we prioritized rs9349379, a common SNP in the third intron of the PHACTR1 gene, as the putative causal variant. Epigenomic data from human tissue revealed an enhancer signature at rs9349379 exclusively in aorta, suggesting a regulatory function for this SNP in the vasculature. CRISPR-edited stem cell-derived endothelial cells demonstrate rs9349379 regulates expression of endothelin 1 (EDN1), a gene located 600 kb upstream of PHACTR1. The known physiologic effects of EDN1 on the vasculature may explain the pattern of risk for the five associated diseases. Overall, these data illustrate the integration of genetic, phenotypic, and epigenetic analysis to identify the biologic mechanism by which a common, non-coding variant can distally regulate a gene and contribute to the pathogenesis of multiple vascular diseases.
      Graphical abstract image Teaser A common sequence variant that perturbs long-range enhancer interactions mediates risk for different vascular diseases.

      PubDate: 2017-08-04T21:20:11Z
       
  • Clustered Mutation Signatures Reveal that Error-Prone DNA Repair Targets
           Mutations to Active Genes
    • Abstract: Publication date: 27 July 2017
      Source:Cell, Volume 170, Issue 3
      Author(s): Fran Supek, Ben Lehner
      Many processes can cause the same nucleotide change in a genome, making the identification of the mechanisms causing mutations a difficult challenge. Here, we show that clustered mutations provide a more precise fingerprint of mutagenic processes. Of nine clustered mutation signatures identified from >1,000 tumor genomes, three relate to variable APOBEC activity and three are associated with tobacco smoking. An additional signature matches the spectrum of translesion DNA polymerase eta (POLH). In lymphoid cells, these mutations target promoters, consistent with AID-initiated somatic hypermutation. In solid tumors, however, they are associated with UV exposure and alcohol consumption and target the H3K36me3 chromatin of active genes in a mismatch repair (MMR)-dependent manner. These regions normally have a low mutation rate because error-free MMR also targets H3K36me3 chromatin. Carcinogens and error-prone repair therefore redistribute mutations to the more important regions of the genome, contributing a substantial mutation load in many tumors, including driver mutations.
      Graphical abstract image Teaser An analysis of clustered somatic mutations identifies error-prone DNA repair as a common source of mutations in active chromatin in human tumors.

      PubDate: 2017-08-04T21:20:11Z
       
  • Fusobacterium nucleatum Promotes Chemoresistance to Colorectal Cancer by
           Modulating Autophagy
    • Abstract: Publication date: 27 July 2017
      Source:Cell, Volume 170, Issue 3
      Author(s): TaChung Yu, Fangfang Guo, Yanan Yu, Tiantian Sun, Dan Ma, Jixuan Han, Yun Qian, Ilona Kryczek, Danfeng Sun, Nisha Nagarsheth, Yingxuan Chen, Haoyan Chen, Jie Hong, Weiping Zou, Jing-Yuan Fang
      Gut microbiota are linked to chronic inflammation and carcinogenesis. Chemotherapy failure is the major cause of recurrence and poor prognosis in colorectal cancer patients. Here, we investigated the contribution of gut microbiota to chemoresistance in patients with colorectal cancer. We found that Fusobacterium (F.) nucleatum was abundant in colorectal cancer tissues in patients with recurrence post chemotherapy, and was associated with patient clinicopathological characterisitcs. Furthermore, our bioinformatic and functional studies demonstrated that F. nucleatum promoted colorectal cancer resistance to chemotherapy. Mechanistically, F. nucleatum targeted TLR4 and MYD88 innate immune signaling and specific microRNAs to activate the autophagy pathway and alter colorectal cancer chemotherapeutic response. Thus, F. nucleatum orchestrates a molecular network of the Toll-like receptor, microRNAs, and autophagy to clinically, biologically, and mechanistically control colorectal cancer chemoresistance. Measuring and targeting F. nucleatum and its associated pathway will yield valuable insight into clinical management and may ameliorate colorectal cancer patient outcomes.
      Graphical abstract image Teaser Reducing a specific gut microbe in colorectal cancer patients may improve their response to chemotherapy and reduce cancer recurrence.

      PubDate: 2017-08-04T21:20:11Z
       
  • Defining a Cancer Dependency Map
    • Abstract: Publication date: 27 July 2017
      Source:Cell, Volume 170, Issue 3
      Author(s): Aviad Tsherniak, Francisca Vazquez, Phil G. Montgomery, Barbara A. Weir, Gregory Kryukov, Glenn S. Cowley, Stanley Gill, William F. Harrington, Sasha Pantel, John M. Krill-Burger, Robin M. Meyers, Levi Ali, Amy Goodale, Yenarae Lee, Guozhi Jiang, Jessica Hsiao, William F.J. Gerath, Sara Howell, Erin Merkel, Mahmoud Ghandi, Levi A. Garraway, David E. Root, Todd R. Golub, Jesse S. Boehm, William C. Hahn
      Most human epithelial tumors harbor numerous alterations, making it difficult to predict which genes are required for tumor survival. To systematically identify cancer dependencies, we analyzed 501 genome-scale loss-of-function screens performed in diverse human cancer cell lines. We developed DEMETER, an analytical framework that segregates on- from off-target effects of RNAi. 769 genes were differentially required in subsets of these cell lines at a threshold of six SDs from the mean. We found predictive models for 426 dependencies (55%) by nonlinear regression modeling considering 66,646 molecular features. Many dependencies fall into a limited number of classes, and unexpectedly, in 82% of models, the top biomarkers were expression based. We demonstrated the basis behind one such predictive model linking hypermethylation of the UBB ubiquitin gene to a dependency on UBC. Together, these observations provide a foundation for a cancer dependency map that facilitates the prioritization of therapeutic targets.
      Graphical abstract image Teaser A large-scale analysis of 501 cancer cell lines reveals new vulnerabilities that will help prioritize therapeutic targets

      PubDate: 2017-08-04T21:20:11Z
       
  • Project DRIVE: A Compendium of Cancer Dependencies and Synthetic Lethal
           Relationships Uncovered by Large-Scale, Deep RNAi Screening
    • Abstract: Publication date: 27 July 2017
      Source:Cell, Volume 170, Issue 3
      Author(s): E. Robert McDonald, Antoine de Weck, Michael R. Schlabach, Eric Billy, Konstantinos J. Mavrakis, Gregory R. Hoffman, Dhiren Belur, Deborah Castelletti, Elizabeth Frias, Kalyani Gampa, Javad Golji, Iris Kao, Li Li, Philippe Megel, Thomas A. Perkins, Nadire Ramadan, David A. Ruddy, Serena J. Silver, Sosathya Sovath, Mark Stump, Odile Weber, Roland Widmer, Jianjun Yu, Kristine Yu, Yingzi Yue, Dorothee Abramowski, Elizabeth Ackley, Rosemary Barrett, Joel Berger, Julie L. Bernard, Rebecca Billig, Saskia M. Brachmann, Frank Buxton, Roger Caothien, Justina X. Caushi, Franklin S. Chung, Marta Cortés-Cros, Rosalie S. deBeaumont, Clara Delaunay, Aurore Desplat, William Duong, Donald A. Dwoske, Richard S. Eldridge, Ali Farsidjani, Fei Feng, JiaJia Feng, Daisy Flemming, William Forrester, Giorgio G. Galli, Zhenhai Gao, François Gauter, Veronica Gibaja, Kristy Haas, Marc Hattenberger, Tami Hood, Kristen E. Hurov, Zainab Jagani, Mathias Jenal, Jennifer A. Johnson, Michael D. Jones, Avnish Kapoor, Joshua Korn, Jilin Liu, Qiumei Liu, Shumei Liu, Yue Liu, Alice T. Loo, Kaitlin J. Macchi, Typhaine Martin, Gregory McAllister, Amandine Meyer, Sandra Mollé, Raymond A. Pagliarini, Tanushree Phadke, Brian Repko, Tanja Schouwey, Frances Shanahan, Qiong Shen, Christelle Stamm, Christine Stephan, Volker M. Stucke, Ralph Tiedt, Malini Varadarajan, Kavitha Venkatesan, Alberto C. Vitari, Marco Wallroth, Jan Weiler, Jing Zhang, Craig Mickanin, Vic E. Myer, Jeffery A. Porter, Albert Lai, Hans Bitter, Emma Lees, Nicholas Keen, Audrey Kauffmann, Frank Stegmeier, Francesco Hofmann, Tobias Schmelzle, William R. Sellers
      Elucidation of the mutational landscape of human cancer has progressed rapidly and been accompanied by the development of therapeutics targeting mutant oncogenes. However, a comprehensive mapping of cancer dependencies has lagged behind and the discovery of therapeutic targets for counteracting tumor suppressor gene loss is needed. To identify vulnerabilities relevant to specific cancer subtypes, we conducted a large-scale RNAi screen in which viability effects of mRNA knockdown were assessed for 7,837 genes using an average of 20 shRNAs per gene in 398 cancer cell lines. We describe findings of this screen, outlining the classes of cancer dependency genes and their relationships to genetic, expression, and lineage features. In addition, we describe robust gene-interaction networks recapitulating both protein complexes and functional cooperation among complexes and pathways. This dataset along with a web portal is provided to the community to assist in the discovery and translation of new therapeutic approaches for cancer.
      Graphical abstract image Teaser A large-scale RNAi screen in 398 cancer cell lines reveals vulnerabilities of specific cancer subtypes.

      PubDate: 2017-08-04T21:20:11Z
       
  • SnapShot: Channel Gating Mechanisms
    • Abstract: Publication date: 27 July 2017
      Source:Cell, Volume 170, Issue 3
      Author(s): Marcel P. Goldschen-Ohm, Baron Chanda
      Ion channel families are broadly classified into three types according to their major mechanisms of activation. This SnapShot highlights features of these three classes and conveys general modes of channel regulation. To view this SnapShot, open or download the PDF.
      Teaser Ion channel families are broadly classified into three types according to their major mechanisms of activation. This SnapShot highlights features of these three classes and conveys general modes of channel regulation. To view this SnapShot, open or download the PDF.

      PubDate: 2017-08-04T21:20:11Z
       
  • Enhancer Reprogramming Promotes Pancreatic Cancer Metastasis
    • Abstract: Publication date: Available online 27 July 2017
      Source:Cell
      Author(s): Jae-Seok Roe, Chang-Il Hwang, Tim D.D. Somerville, Joseph P. Milazzo, Eun Jung Lee, Brandon Da Silva, Laura Maiorino, Hervé Tiriac, C. Megan Young, Koji Miyabayashi, Dea Filippini, Brianna Creighton, Richard A. Burkhart, Jonathan M. Buscaglia, Edward J. Kim, Jean L. Grem, Audrey J. Lazenby, James A. Grunkemeyer, Michael A. Hollingsworth, Paul M. Grandgenett, Mikala Egeblad, Youngkyu Park, David A. Tuveson, Christopher R. Vakoc
      Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human malignancies, owing in part to its propensity for metastasis. Here, we used an organoid culture system to investigate how transcription and the enhancer landscape become altered during discrete stages of disease progression in a PDA mouse model. This approach revealed that the metastatic transition is accompanied by massive and recurrent alterations in enhancer activity. We implicate the pioneer factor FOXA1 as a driver of enhancer activation in this system, a mechanism that renders PDA cells more invasive and less anchorage-dependent for growth in vitro, as well as more metastatic in vivo. In this context, FOXA1-dependent enhancer reprogramming activates a transcriptional program of embryonic foregut endoderm. Collectively, our study implicates enhancer reprogramming, FOXA1 upregulation, and a retrograde developmental transition in PDA metastasis.
      Graphical abstract image Teaser Large-scale enhancer reprogramming directed by transcription factors such as FOXA1 drives metastasis in the organoid model of pancreatic cancer.

      PubDate: 2017-08-04T21:20:11Z
       
  • The Molecular Architecture for RNA-Guided RNA Cleavage by Cas13a
    • Abstract: Publication date: Available online 27 July 2017
      Source:Cell
      Author(s): Liang Liu, Xueyan Li, Jun Ma, Zongqiang Li, Lilan You, Jiuyu Wang, Min Wang, Xinzheng Zhang, Yanli Wang
      Cas13a, a type VI-A CRISPR-Cas RNA-guided RNA ribonuclease, degrades invasive RNAs targeted by CRISPR RNA (crRNA) and has potential applications in RNA technology. To understand how Cas13a is activated to cleave RNA, we have determined the crystal structure of Leptotrichia buccalis (Lbu) Cas13a bound to crRNA and its target RNA, as well as the cryo-EM structure of the LbuCas13a-crRNA complex. The crRNA-target RNA duplex binds in a positively charged central channel of the nuclease (NUC) lobe, and Cas13a protein and crRNA undergo a significant conformational change upon target RNA binding. The guide-target RNA duplex formation triggers HEPN1 domain to move toward HEPN2 domain, activating the HEPN catalytic site of Cas13a protein, which subsequently cleaves both single-stranded target and collateral RNAs in a non-specific manner. These findings reveal how Cas13a of type VI CRISPR-Cas systems defend against RNA phages and set the stage for its development as a tool for RNA manipulation.
      Graphical abstract image Teaser Structural analysis of CRISPR-Cas13a (C2c2) reveals how target RNA binding induces a conformational change to activate non-specific RNA degradation.

      PubDate: 2017-08-04T21:20:11Z
       
  • Non-neutralizing Antibodies Alter the Course of HIV-1 Infection
           In Vivo
    • Abstract: Publication date: Available online 27 July 2017
      Source:Cell
      Author(s): Joshua A. Horwitz, Yotam Bar-On, Ching-Lan Lu, Daniela Fera, Ainsley A.K. Lockhart, Julio C.C. Lorenzi, Lilian Nogueira, Jovana Golijanin, Johannes F. Scheid, Michael S. Seaman, Anna Gazumyan, Susan Zolla-Pazner, Michel C. Nussenzweig
      Non-neutralizing antibodies (nnAbs) to HIV-1 show little measurable activity in prevention or therapy in animal models yet were the only correlate of protection in the RV144 vaccine trial. To investigate the role of nnAbs on HIV-1 infection in vivo, we devised a replication-competent HIV-1 reporter virus that expresses a heterologous HA-tag on the surface of infected cells and virions. Anti-HA antibodies bind to, but do not neutralize, the reporter virus in vitro. However, anti-HA protects against infection in humanized mice and strongly selects for nnAb-resistant viruses in an entirely Fc-dependent manner. Similar results were also obtained with tier 2 HIV-1 viruses using a human anti-gp41 nnAb, 246D. While nnAbs are demonstrably less effective than broadly neutralizing antibodies (bNAbs) against HIV-1 in vitro and in vivo, the data show that nnAbs can protect against and alter the course of HIV-1 infection in vivo.
      Graphical abstract image Teaser Could the induction of non-neutralizing antibodies represent an alternative solution to the HIV vaccine problem?

      PubDate: 2017-08-04T21:20:11Z
       
  • Structure of the Nav1.4-β1 Complex from Electric Eel
    • Abstract: Publication date: Available online 20 July 2017
      Source:Cell
      Author(s): Zhen Yan, Qiang Zhou, Lin Wang, Jianping Wu, Yanyu Zhao, Gaoxingyu Huang, Wei Peng, Huaizong Shen, Jianlin Lei, Nieng Yan
      Voltage-gated sodium (Nav) channels initiate and propagate action potentials. Here, we present the cryo-EM structure of EeNav1.4, the Nav channel from electric eel, in complex with the β1 subunit at 4.0 Å resolution. The immunoglobulin domain of β1 docks onto the extracellular L5I and L6IV loops of EeNav1.4 via extensive polar interactions, and the single transmembrane helix interacts with the third voltage-sensing domain (VSDIII). The VSDs exhibit “up” conformations, while the intracellular gate of the pore domain is kept open by a digitonin-like molecule. Structural comparison with closed NavPaS shows that the outward transfer of gating charges is coupled to the iris-like pore domain dilation through intricate force transmissions involving multiple channel segments. The IFM fast inactivation motif on the III-IV linker is plugged into the corner enclosed by the outer S4-S5 and inner S6 segments in repeats III and IV, suggesting a potential allosteric blocking mechanism for fast inactivation.
      Graphical abstract image Teaser Structural analysis of the eel Nav1.4 channel offers insights into the electromechanical coupling mechanism of voltage-gated sodium channels.

      PubDate: 2017-07-26T09:24:40Z
       
  • Conformational Changes of CFTR upon Phosphorylation and ATP Binding
    • Abstract: Publication date: Available online 20 July 2017
      Source:Cell
      Author(s): Zhe Zhang, Fangyu Liu, Jue Chen
      The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel evolved from an ATP-binding cassette transporter. CFTR channel gating is strictly coupled to phosphorylation and ATP hydrolysis. Previously, we reported essentially identical structures of zebrafish and human CFTR in the dephosphorylated, ATP-free form. Here, we present the structure of zebrafish CFTR in the phosphorylated, ATP-bound conformation, determined by cryoelectron microscopy to 3.4 Å resolution. Comparison of the two conformations shows major structural rearrangements leading to channel opening. The phosphorylated regulatory domain is disengaged from its inhibitory position; the nucleotide-binding domains (NBDs) form a “head-to-tail” dimer upon binding ATP; and the cytoplasmic pathway, found closed off in other ATP-binding cassette transporters, is cracked open, consistent with CFTR’s unique channel function. Unexpectedly, the extracellular mouth of the ion pore remains closed, indicating that local movements of the transmembrane helices can control ion access to the pore even in the NBD-dimerized conformation.
      Graphical abstract image Teaser Phosphorylation of CFTR leads to structural transitions that promote channel widening while ahead of extracellular gate opening.

      PubDate: 2017-07-26T09:24:40Z
       
  • Genome Organization Drives Chromosome Fragility
    • Abstract: Publication date: Available online 20 July 2017
      Source:Cell
      Author(s): Andres Canela, Yaakov Maman, Seolkyoung Jung, Nancy Wong, Elsa Callen, Amanda Day, Kyong-Rim Kieffer-Kwon, Aleksandra Pekowska, Hongliang Zhang, Suhas S.P. Rao, Su-Chen Huang, Peter J. Mckinnon, Peter D. Aplan, Yves Pommier, Erez Lieberman Aiden, Rafael Casellas, André Nussenzweig
      In this study, we show that evolutionarily conserved chromosome loop anchors bound by CCCTC-binding factor (CTCF) and cohesin are vulnerable to DNA double strand breaks (DSBs) mediated by topoisomerase 2B (TOP2B). Polymorphisms in the genome that redistribute CTCF/cohesin occupancy rewire DNA cleavage sites to novel loop anchors. While transcription- and replication-coupled genomic rearrangements have been well documented, we demonstrate that DSBs formed at loop anchors are largely transcription-, replication-, and cell-type-independent. DSBs are continuously formed throughout interphase, are enriched on both sides of strong topological domain borders, and frequently occur at breakpoint clusters commonly translocated in cancer. Thus, loop anchors serve as fragile sites that generate DSBs and chromosomal rearrangements.
      Graphical abstract image Teaser Chromatin assembly into higher-order structures generates torsional stress that makes chromosome loop anchor regions more vulnerable to topoisomerase 2-mediated DNA breaks.

      PubDate: 2017-07-26T09:24:40Z
       
  • Tiny Answers to Big Questions
    • Abstract: Publication date: 13 July 2017
      Source:Cell, Volume 170, Issue 2
      Author(s): April Pawluk


      PubDate: 2017-07-19T13:13:32Z
       
  • Biology Gone Wild
    • Abstract: Publication date: 13 July 2017
      Source:Cell, Volume 170, Issue 2
      Author(s): Diana Crow
      To study how genes, cells, or organisms operate in natural environments, researchers often need to leave the bench and venture into the field. Here are a few approaches that field biologists use in designing and conducting semi-wild experiments and the many challenges they face.
      Teaser To study how genes, cells, or organisms operate in natural environments, researchers often need to leave the bench and venture into the field. Here are a few of the approaches that field biologists use in designing and conducting semi-wild experiments and the many challenges they face.

      PubDate: 2017-07-19T13:13:32Z
       
  • IL-4Rα Inhibitor for Atopic Disease
    • Abstract: Publication date: 13 July 2017
      Source:Cell, Volume 170, Issue 2
      Author(s): Howard Y. Chang, Kari C. Nadeau
      Dupilumab is a fully human IgG4 monoclonal antibody directed against the IL-4Rα subunit of IL-4 and IL-13 receptors. It blocks the signaling pathways of IL-4 and IL-13, key cytokines that drive type 2 inflammatory response. In March 2017, dupilumab was approved for use in the treatment of atopic dermatitis (eczema). To view this Bench to Bedside, open or download the PDF.
      Teaser Dupilumab is a fully human IgG4 monoclonal antibody directed against the IL-4Rα subunit of IL-4 and IL-13 receptors. It blocks the signaling pathways of IL-4 and IL-13, key cytokines that drive type 2 inflammatory response. In March 2017, dupilumab was approved for use in the treatment of atopic dermatitis (eczema). To view this Bench to Bedside, open or download the PDF.

      PubDate: 2017-07-19T13:13:32Z
       
  • Unshielding Exosomal RNA Unleashes Tumor Growth And Metastasis
    • Abstract: Publication date: 13 July 2017
      Source:Cell, Volume 170, Issue 2
      Author(s): Irina Matei, Han Sang Kim, David Lyden
      Reciprocal interactions between tumor cells and their microenvironment drive cancer progression and therapy resistance. In this issue, Nabet et al. demonstrate that dynamic feedback between tumor and stroma subverts normal inflammatory responses by triggering the release of exosomes containing unshielded RNAs that activate pattern recognition receptors, thereby promoting tumor growth and metastasis.
      Teaser Reciprocal interactions between tumor cells and their microenvironment drive cancer progression and therapy resistance. In this issue, Nabet et al. demonstrate that dynamic feedback between tumor and stroma subverts normal inflammatory responses by triggering the release of exosomes containing unshielded RNAs that activate pattern recognition receptors, thereby promoting tumor growth and metastasis.

      PubDate: 2017-07-19T13:13:32Z
       
  • Evolution of the Human Nervous System Function, Structure, and Development
    • Abstract: Publication date: 13 July 2017
      Source:Cell, Volume 170, Issue 2
      Author(s): André M.M. Sousa, Kyle A. Meyer, Gabriel Santpere, Forrest O. Gulden, Nenad Sestan
      The nervous system—in particular, the brain and its cognitive abilities—is among humans’ most distinctive and impressive attributes. How the nervous system has changed in the human lineage and how it differs from that of closely related primates is not well understood. Here, we consider recent comparative analyses of extant species that are uncovering new evidence for evolutionary changes in the size and the number of neurons in the human nervous system, as well as the cellular and molecular reorganization of its neural circuits. We also discuss the developmental mechanisms and underlying genetic and molecular changes that generate these structural and functional differences. As relevant new information and tools materialize at an unprecedented pace, the field is now ripe for systematic and functionally relevant studies of the development and evolution of human nervous system specializations.
      Teaser How does the human nervous system differ from those of closely related primates in terms of function, organization, and development'

      PubDate: 2017-07-19T13:13:32Z
       
  • Functional Profiling of a Plasmodium Genome Reveals an Abundance of
           Essential Genes
    • Abstract: Publication date: 13 July 2017
      Source:Cell, Volume 170, Issue 2
      Author(s): Ellen Bushell, Ana Rita Gomes, Theo Sanderson, Burcu Anar, Gareth Girling, Colin Herd, Tom Metcalf, Katarzyna Modrzynska, Frank Schwach, Rowena E. Martin, Michael W. Mather, Geoffrey I. McFadden, Leopold Parts, Gavin G. Rutledge, Akhil B. Vaidya, Kai Wengelnik, Julian C. Rayner, Oliver Billker
      The genomes of malaria parasites contain many genes of unknown function. To assist drug development through the identification of essential genes and pathways, we have measured competitive growth rates in mice of 2,578 barcoded Plasmodium berghei knockout mutants, representing >50% of the genome, and created a phenotype database. At a single stage of its complex life cycle, P. berghei requires two-thirds of genes for optimal growth, the highest proportion reported from any organism and a probable consequence of functional optimization necessitated by genomic reductions during the evolution of parasitism. In contrast, extreme functional redundancy has evolved among expanded gene families operating at the parasite-host interface. The level of genetic redundancy in a single-celled organism may thus reflect the degree of environmental variation it experiences. In the case of Plasmodium parasites, this helps rationalize both the relative successes of drugs and the greater difficulty of making an effective vaccine.
      Graphical abstract image Teaser An in vivo genetic screen in a mouse model of malaria reveals the essential genes and pathways required by Plasmodium parasite, with a surprising two-thirds of the genome being required for normal parasite growth in the blood.

      PubDate: 2017-07-19T13:13:32Z
       
  • Development of a Novel Lead that Targets M. tuberculosis Polyketide
           Synthase 13
    • Abstract: Publication date: Available online 29 June 2017
      Source:Cell
      Author(s): Anup Aggarwal, Maloy K. Parai, Nishant Shetty, Deeann Wallis, Lisa Woolhiser, Courtney Hastings, Noton K. Dutta, Stacy Galaviz, Ramesh C. Dhakal, Rupesh Shrestha, Shoko Wakabayashi, Chris Walpole, David Matthews, David Floyd, Paul Scullion, Jennifer Riley, Ola Epemolu, Suzanne Norval, Thomas Snavely, Gregory T. Robertson, Eric J. Rubin, Thomas R. Ioerger, Frik A. Sirgel, Ruben van der Merwe, Paul D. van Helden, Peter Keller, Erik C. Böttger, Petros C. Karakousis, Anne J. Lenaerts, James C. Sacchettini
      Widespread resistance to first-line TB drugs is a major problem that will likely only be resolved through the development of new drugs with novel mechanisms of action. We have used structure-guided methods to develop a lead molecule that targets the thioesterase activity of polyketide synthase Pks13, an essential enzyme that forms mycolic acids, required for the cell wall of Mycobacterium tuberculosis. Our lead, TAM16, is a benzofuran class inhibitor of Pks13 with highly potent in vitro bactericidal activity against drug-susceptible and drug-resistant clinical isolates of M. tuberculosis. In multiple mouse models of TB infection, TAM16 showed in vivo efficacy equal to the first-line TB drug isoniazid, both as a monotherapy and in combination therapy with rifampicin. TAM16 has excellent pharmacological and safety profiles, and the frequency of resistance for TAM16 is ∼100-fold lower than INH, suggesting that it can be developed as a new antitubercular aimed at the acute infection.
      Graphical abstract image Teaser A small molecule inhibitor of M. tuberculosis polyketide synthase shows strong efficacy in murine models of infection.

      PubDate: 2017-07-09T17:13:01Z
       
 
 
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