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Journal Cover Cell
  [SJR: 28.188]   [H-I: 616]   [831 followers]  Follow
    
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   ISSN (Print) 0092-8674 - ISSN (Online) 1097-4172
   Published by Elsevier Homepage  [3043 journals]
  • 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
       
  • Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia
           Progression
    • Abstract: Publication date: 7 September 2017
      Source:Cell, Volume 170, Issue 6
      Author(s): Luisa Cimmino, Igor Dolgalev, Yubao Wang, Akihide Yoshimi, Gaëlle H. Martin, Jingjing Wang, Victor Ng, Bo Xia, Matthew T. Witkowski, Marisa Mitchell-Flack, Isabella Grillo, Sofia Bakogianni, Delphine Ndiaye-Lobry, Miguel Torres Martín, Maria Guillamot, Robert S. Banh, Mingjiang Xu, Maria E. Figueroa, Ross A. Dickins, Omar Abdel-Wahab, Christopher Y. Park, Aristotelis Tsirigos, Benjamin G. Neel, Iannis Aifantis
      Loss-of-function mutations in TET2 occur frequently in patients with clonal hematopoiesis, myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML) and are associated with a DNA hypermethylation phenotype. To determine the role of TET2 deficiency in leukemia stem cell maintenance, we generated a reversible transgenic RNAi mouse to model restoration of endogenous Tet2 expression. Tet2 restoration reverses aberrant hematopoietic stem and progenitor cell (HSPC) self-renewal in vitro and in vivo. Treatment with vitamin C, a co-factor of Fe2+ and α-KG-dependent dioxygenases, mimics TET2 restoration by enhancing 5-hydroxymethylcytosine formation in Tet2-deficient mouse HSPCs and suppresses human leukemic colony formation and leukemia progression of primary human leukemia PDXs. Vitamin C also drives DNA hypomethylation and expression of a TET2-dependent gene signature in human leukemia cell lines. Furthermore, TET-mediated DNA oxidation induced by vitamin C treatment in leukemia cells enhances their sensitivity to PARP inhibition and could provide a safe and effective combination strategy to selectively target TET deficiency in cancer. PaperClip
      Graphical abstract image Teaser Vitamin C treatment mimics the effect of TET2 restoration on leukemic stem cells and enhances the efficacy of PARP inhibition in suppressing leukemia progression.

      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
       
  • Non-coding Transcription Instructs Chromatin Folding and
           Compartmentalization to Dictate Enhancer-Promoter Communication and T Cell
           Fate
    • Abstract: Publication date: 21 September 2017
      Source:Cell, Volume 171, Issue 1
      Author(s): Takeshi Isoda, Amanda J. Moore, Zhaoren He, Vivek Chandra, Masatoshi Aida, Matthew Denholtz, Jan Piet van Hamburg, Kathleen M. Fisch, Aaron N. Chang, Shawn P. Fahl, David L. Wiest, Cornelis Murre
      It is now established that Bcl11b specifies T cell fate. Here, we show that in developing T cells, the Bcl11b enhancer repositioned from the lamina to the nuclear interior. Our search for factors that relocalized the Bcl11b enhancer identified a non-coding RNA named ThymoD (thymocyte differentiation factor). ThymoD-deficient mice displayed a block at the onset of T cell development and developed lymphoid malignancies. We found that ThymoD transcription promoted demethylation at CTCF bound sites and activated cohesin-dependent looping to reposition the Bcl11b enhancer from the lamina to the nuclear interior and to juxtapose the Bcl11b enhancer and promoter into a single-loop domain. These large-scale changes in nuclear architecture were associated with the deposition of activating epigenetic marks across the loop domain, plausibly facilitating phase separation. These data indicate how, during developmental progression and tumor suppression, non-coding transcription orchestrates chromatin folding and compartmentalization to direct with high precision enhancer-promoter communication.
      Graphical abstract image Teaser Transcription of a non-coding locus facilitates chromatin folding and compartmentalization to reposition T-lineage-specific enhancer and promoter elements into a single-loop domain.

      PubDate: 2017-09-21T17:36:03Z
       
  • A Spatial Interactome Reveals the Protein Organization of the Algal
           CO2-Concentrating Mechanism
    • Abstract: Publication date: 21 September 2017
      Source:Cell, Volume 171, Issue 1
      Author(s): Luke C.M. Mackinder, Chris Chen, Ryan D. Leib, Weronika Patena, Sean R. Blum, Matthew Rodman, Silvia Ramundo, Christopher M. Adams, Martin C. Jonikas
      Approximately one-third of global CO2 fixation is performed by eukaryotic algae. Nearly all algae enhance their carbon assimilation by operating a CO2-concentrating mechanism (CCM) built around an organelle called the pyrenoid, whose protein composition is largely unknown. Here, we developed tools in the model alga Chlamydomonas reinhardtii to determine the localizations of 135 candidate CCM proteins and physical interactors of 38 of these proteins. Our data reveal the identity of 89 pyrenoid proteins, including Rubisco-interacting proteins, photosystem I assembly factor candidates, and inorganic carbon flux components. We identify three previously undescribed protein layers of the pyrenoid: a plate-like layer, a mesh layer, and a punctate layer. We find that the carbonic anhydrase CAH6 is in the flagella, not in the stroma that surrounds the pyrenoid as in current models. These results provide an overview of proteins operating in the eukaryotic algal CCM, a key process that drives global carbon fixation.
      Graphical abstract image Teaser Microscopy and proteomic analyses reveal three previously unknown layers of the pyrenoid, the cellular organelle in algae responsible for one-third of global CO2 fixation

      PubDate: 2017-09-21T17:36:03Z
       
  • The Eukaryotic CO2-Concentrating Organelle Is Liquid-like and Exhibits
           Dynamic Reorganization
    • Abstract: Publication date: 21 September 2017
      Source:Cell, Volume 171, Issue 1
      Author(s): Elizabeth S. Freeman Rosenzweig, Bin Xu, Luis Kuhn Cuellar, Antonio Martinez-Sanchez, Miroslava Schaffer, Mike Strauss, Heather N. Cartwright, Pierre Ronceray, Jürgen M. Plitzko, Friedrich Förster, Ned S. Wingreen, Benjamin D. Engel, Luke C.M. Mackinder, Martin C. Jonikas
      Approximately 30%–40% of global CO2 fixation occurs inside a non-membrane-bound organelle called the pyrenoid, which is found within the chloroplasts of most eukaryotic algae. The pyrenoid matrix is densely packed with the CO2-fixing enzyme Rubisco and is thought to be a crystalline or amorphous solid. Here, we show that the pyrenoid matrix of the unicellular alga Chlamydomonas reinhardtii is not crystalline but behaves as a liquid that dissolves and condenses during cell division. Furthermore, we show that new pyrenoids are formed both by fission and de novo assembly. Our modeling predicts the existence of a “magic number” effect associated with special, highly stable heterocomplexes that influences phase separation in liquid-like organelles. This view of the pyrenoid matrix as a phase-separated compartment provides a paradigm for understanding its structure, biogenesis, and regulation. More broadly, our findings expand our understanding of the principles that govern the architecture and inheritance of liquid-like organelles.
      Graphical abstract image Teaser The pyrenoid, a Rubisco-containing organelle that enhances carbon fixation, mixes internally and undergoes phase transitions.

      PubDate: 2017-09-21T17:36:03Z
       
  • Cancer-Specific Retargeting of BAF Complexes by a Prion-like Domain
    • Abstract: Publication date: 21 September 2017
      Source:Cell, Volume 171, Issue 1
      Author(s): Gaylor Boulay, Gabriel J. Sandoval, Nicolo Riggi, Sowmya Iyer, Rémi Buisson, Beverly Naigles, Mary E. Awad, Shruthi Rengarajan, Angela Volorio, Matthew J. McBride, Liliane C. Broye, Lee Zou, Ivan Stamenkovic, Cigall Kadoch, Miguel N. Rivera
      Alterations in transcriptional regulators can orchestrate oncogenic gene expression programs in cancer. Here, we show that the BRG1/BRM-associated factor (BAF) chromatin remodeling complex, which is mutated in over 20% of human tumors, interacts with EWSR1, a member of a family of proteins with prion-like domains (PrLD) that are frequent partners in oncogenic fusions with transcription factors. In Ewing sarcoma, we find that the BAF complex is recruited by the EWS-FLI1 fusion protein to tumor-specific enhancers and contributes to target gene activation. This process is a neomorphic property of EWS-FLI1 compared to wild-type FLI1 and depends on tyrosine residues that are necessary for phase transitions of the EWSR1 prion-like domain. Furthermore, fusion of short fragments of EWSR1 to FLI1 is sufficient to recapitulate BAF complex retargeting and EWS-FLI1 activities. Our studies thus demonstrate that the physical properties of prion-like domains can retarget critical chromatin regulatory complexes to establish and maintain oncogenic gene expression programs.
      Graphical abstract image Teaser Phase transition properties of a prion-like domain in an oncogenic fusion protein are critical for retargeting BAF chromatin remodeling complexes and activating enhancers, thereby driving the transcriptional program that promotes Ewing sarcoma.

      PubDate: 2017-09-21T17:36:03Z
       
  • Regulatory Innate Lymphoid Cells Control Innate Intestinal Inflammation
    • Abstract: Publication date: 21 September 2017
      Source:Cell, Volume 171, Issue 1
      Author(s): Shuo Wang, Pengyan Xia, Yi Chen, Yuan Qu, Zhen Xiong, Buqing Ye, Ying Du, Yong Tian, Zhinan Yin, Zhiheng Xu, Zusen Fan
      An emerging family of innate lymphoid cells (termed ILCs) has an essential role in the initiation and regulation of inflammation. However, it is still unclear how ILCs are regulated in the duration of intestinal inflammation. Here, we identify a regulatory subpopulation of ILCs (called ILCregs) that exists in the gut and harbors a unique gene identity that is distinct from that of ILCs or regulatory T cells (Tregs). During inflammatory stimulation, ILCregs can be induced in the intestine and suppress the activation of ILC1s and ILC3s via secretion of IL-10, leading to protection against innate intestinal inflammation. Moreover, TGF-β1 is induced by ILCregs during the innate intestinal inflammation, and autocrine TGF-β1 sustains the maintenance and expansion of ILCregs. Therefore, ILCregs play an inhibitory role in the innate immune response, favoring the resolution of intestinal inflammation.
      Graphical abstract image Teaser A subpopulation of innate lymphoid cells, called ILCregs, are found to have a regulatory role in intestinal homeostasis and innate immune defenses akin to Treg cells.

      PubDate: 2017-09-21T17:36:03Z
       
  • A Human Bi-specific Antibody against Zika Virus with High Therapeutic
           Potential
    • Abstract: Publication date: 21 September 2017
      Source:Cell, Volume 171, Issue 1
      Author(s): Jiaqi Wang, Marco Bardelli, Diego A. Espinosa, Mattia Pedotti, Thiam-Seng Ng, Siro Bianchi, Luca Simonelli, Elisa X.Y. Lim, Mathilde Foglierini, Fabrizia Zatta, Stefano Jaconi, Martina Beltramello, Elisabetta Cameroni, Guntur Fibriansah, Jian Shi, Taylor Barca, Isabel Pagani, Alicia Rubio, Vania Broccoli, Elisa Vicenzi, Victoria Graham, Steven Pullan, Stuart Dowall, Roger Hewson, Simon Jurt, Oliver Zerbe, Karin Stettler, Antonio Lanzavecchia, Federica Sallusto, Andrea Cavalli, Eva Harris, Shee-Mei Lok, Luca Varani, Davide Corti
      Zika virus (ZIKV), a mosquito-borne flavivirus, causes devastating congenital birth defects. We isolated a human monoclonal antibody (mAb), ZKA190, that potently cross-neutralizes multi-lineage ZIKV strains. ZKA190 is highly effective in vivo in preventing morbidity and mortality of ZIKV-infected mice. NMR and cryo-electron microscopy show its binding to an exposed epitope on DIII of the E protein. ZKA190 Fab binds all 180 E protein copies, altering the virus quaternary arrangement and surface curvature. However, ZIKV escape mutants emerged in vitro and in vivo in the presence of ZKA190, as well as of other neutralizing mAbs. To counter this problem, we developed a bispecific antibody (FIT-1) comprising ZKA190 and a second mAb specific for DII of E protein. In addition to retaining high in vitro and in vivo potencies, FIT-1 robustly prevented viral escape, warranting its development as a ZIKV immunotherapy.
      Graphical abstract image Teaser A bispecific antibody comprising human monoclonal antibodies to distinct sites on the E protein of Zika virus efficiently neutralizes multiple strains, prevents viral escape and demonstrates in vivo efficacy.

      PubDate: 2017-09-21T17:36:03Z
       
  • A Unifying Theory of Branching Morphogenesis
    • Abstract: Publication date: 21 September 2017
      Source:Cell, Volume 171, Issue 1
      Author(s): Edouard Hannezo, Colinda L.G.J. Scheele, Mohammad Moad, Nicholas Drogo, Rakesh Heer, Rosemary V. Sampogna, Jacco van Rheenen, Benjamin D. Simons
      The morphogenesis of branched organs remains a subject of abiding interest. Although much is known about the underlying signaling pathways, it remains unclear how macroscopic features of branched organs, including their size, network topology, and spatial patterning, are encoded. Here, we show that, in mouse mammary gland, kidney, and human prostate, these features can be explained quantitatively within a single unifying framework of branching and annihilating random walks. Based on quantitative analyses of large-scale organ reconstructions and proliferation kinetics measurements, we propose that morphogenesis follows from the proliferative activity of equipotent tips that stochastically branch and randomly explore their environment but compete neutrally for space, becoming proliferatively inactive when in proximity with neighboring ducts. These results show that complex branched epithelial structures develop as a self-organized process, reliant upon a strikingly simple but generic rule, without recourse to a rigid and deterministic sequence of genetically programmed events.
      Graphical abstract image Teaser Complex branched epithelial structures in mammalian tissues develop as a self-organized process, reliant upon a simple set of local rules.

      PubDate: 2017-09-21T17:36:03Z
       
  • Retraction Notice to: Calcium and SOL Protease Mediate Temperature
           Resetting of Circadian Clocks
    • Abstract: Publication date: 21 September 2017
      Source:Cell, Volume 171, Issue 1
      Author(s): Ozgur Tataroglu, Xiaohu Zhao, Ania Busza, Jinli Ling, John S. O’Neill, Patrick Emery


      PubDate: 2017-09-21T17:36:03Z
       
  • SnapShot: N-Glycosylation Processing Pathways across Kingdoms
    • Abstract: Publication date: 21 September 2017
      Source:Cell, Volume 171, Issue 1
      Author(s): Cheng-Yu Chung, Natalia I. Majewska, Qiong Wang, Jackson T. Paul, Michael J. Betenbaugh
      Post-translational modification of proteins with carbohydrates shapes their localization and function. This SnapShot presents the core pathways from different organisms that install these complex and highly variable structures.
      Teaser Post-translational modification of proteins with carbohydrates shapes their localization and function. This SnapShot presents the core pathways from different organisms that install these complex and highly variable structures.

      PubDate: 2017-09-21T17:36:03Z
       
  • Intestinal Epithelial and Intraepithelial T Cell Crosstalk Mediates a
           Dynamic Response to Infection
    • Abstract: Publication date: Available online 21 September 2017
      Source:Cell
      Author(s): David P. Hoytema van Konijnenburg, Bernardo S. Reis, Virginia A. Pedicord, Julia Farache, Gabriel D. Victora, Daniel Mucida
      Intestinal intraepithelial lymphocytes (IELs) are located at the critical interface between the intestinal lumen, which is chronically exposed to food and microbes, and the core of the body. Using high-resolution microscopy techniques and intersectional genetic tools, we investigated the nature of IEL responses to luminal microbes. We observed that TCRγδ IELs exhibit unique microbiota-dependent location and movement patterns in the epithelial compartment. This behavioral pattern quickly changes upon exposure to different enteric pathogens, resulting in increased interepithelial cell (EC) scanning, expression of antimicrobial genes, and glycolysis. Both dynamic and metabolic changes to γδ IEL depend on pathogen sensing by ECs. Direct modulation of glycolysis is sufficient to change γδ IEL behavior and susceptibility to early pathogen invasion. Our results uncover a coordinated EC-IEL response to enteric infections that modulates lymphocyte energy utilization and dynamics and supports maintenance of the intestinal epithelial barrier.
      Graphical abstract image Teaser Communication between epithelial cells and intraepithelial lymphocytes guides lymphocyte energy utilization and dynamic behavior, helping to support maintenance of the intestinal epithelial barrier during infections.

      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
       
  • Structure of an Intron Lariat Spliceosome from Saccharomyces cerevisiae
    • Abstract: Publication date: Available online 14 September 2017
      Source:Cell
      Author(s): Ruixue Wan, Chuangye Yan, Rui Bai, Jianlin Lei, Yigong Shi
      The disassembly of the intron lariat spliceosome (ILS) marks the end of a splicing cycle. Here we report a cryoelectron microscopy structure of the ILS complex from Saccharomyces cerevisiae at an average resolution of 3.5 Å. The intron lariat remains bound in the spliceosome whereas the ligated exon is already dissociated. The step II splicing factors Prp17 and Prp18, along with Cwc21 and Cwc22 that stabilize the 5′ exon binding to loop I of U5 small nuclear RNA (snRNA), have been released from the active site assembly. The DEAH family ATPase/helicase Prp43 binds Syf1 at the periphery of the spliceosome, with its RNA-binding site close to the 3′ end of U6 snRNA. The C-terminal domain of Ntr1/Spp382 associates with the GTPase Snu114, and Ntr2 is anchored to Prp8 while interacting with the superhelical domain of Ntr1. These structural features suggest a plausible mechanism for the disassembly of the ILS complex.
      Graphical abstract image Teaser Visualization of the Ntr complex through structural analysis of the intron lariat spliceosome from Saccharomyces cerevisiae provides insights into the mechanism of spliceosome disassembly.

      PubDate: 2017-09-16T06:49:50Z
       
  • Seeing DNA Where It Lives
    • Abstract: Publication date: 7 September 2017
      Source:Cell, Volume 170, Issue 6
      Author(s): Lara Szewczak
      Teaser It’s the stuff of life, and we’re fascinated by DNA and how it’s packaged into chromatin and compacted into chromosomes. Advances in looking at chromatin organization in cells are letting us see this polymer, its packing, and its function with fresh eyes.

      PubDate: 2017-09-10T01:10:30Z
       
  • Barbara McClintock’s Final Years as Nobelist and Mentor: A Memoir
    • Abstract: Publication date: 7 September 2017
      Source:Cell, Volume 170, Issue 6
      Author(s): Paul Chomet, Rob Martienssen
      September 2, 2017, marks the 25th year after the passing of Dr. Barbara McClintock, geneticist and recipient of the 1983 Nobel Prize in Physiology or Medicine for her discovery of transposable elements in maize. This memoir focuses on the last years of her life—after the prize—and includes personal recollections of how she mentored young scientists and inspired the age of genetics, epigenetics, and genomics.
      Teaser September 2, 2017, marks the 25th year after the passing of Dr. Barbara McClintock, geneticist and recipient of the 1983 Nobel Prize in Physiology or Medicine for her discovery of transposable elements in maize. This memoir focuses on the last years of her life—after the prize—and includes personal recollections of how she mentored young scientists and inspired the age of genetics, epigenetics, and genomics.

      PubDate: 2017-09-10T01:10:30Z
       
  • Converting Cold into Hot Tumors by Combining Immunotherapies
    • Abstract: Publication date: 7 September 2017
      Source:Cell, Volume 170, Issue 6
      Author(s): John B.A.G. Haanen
      In a small phase Ib study in this issue of Cell, Ribas et al. report that the combination of intralesional injection of a modified human herpes simplex virus and systemic anti-PD-1 treatment resulted in a 62% response rate in patients with metastatic melanoma, accompanied by enhanced T cell infiltration in virus-injected lesions.
      Teaser In a small phase Ib study in this issue of Cell, Ribas et al. report that the combination of intralesional injection of a modified human herpes simplex virus and systemic anti-PD-1 treatment resulted in a 62% response rate in patients with metastatic melanoma, accompanied by enhanced T cell infiltration in virus-injected lesions.

      PubDate: 2017-09-10T01:10:30Z
       
  • Crowd Control: E7 Conservation Is the Key to Cancer
    • Abstract: Publication date: 7 September 2017
      Source:Cell, Volume 170, Issue 6
      Author(s): Elizabeth A. White, Karl Munger
      Several human papillomavirus type 16 (HPV16) oncoproteins contribute to cellular transformation in vitro. In this issue of Cell, Mirabello and colleagues use high-throughput sequencing data to assess the diversity of HPV16 isolates from human patients. These data suggest that the E7 oncoprotein is the fundamental contributor to in vivo carcinogenesis.
      Teaser Several human papillomavirus type 16 (HPV16) oncoproteins contribute to cellular transformation in vitro. In this issue of Cell, Mirabello and colleagues use high-throughput sequencing data to assess the diversity of HPV16 isolates from human patients. These data suggest that the E7 oncoprotein is the fundamental contributor to in vivo carcinogenesis.

      PubDate: 2017-09-10T01:10:30Z
       
  • Eukaryotic Sexual Reproduction Evoked “with a Little Help from My
           Friends”
    • Abstract: Publication date: 7 September 2017
      Source:Cell, Volume 170, Issue 6
      Author(s): James Umen, Ursula Goodenough, Joseph Heitman
      Bacteria and eukaryotes interact in many ways—from the microbiome that educates the mammalian immune system and enhances nutrition to relationships that are commensal, symbiotic, or parasitic. Now in an unexpected twist, King and colleagues have expanded the repertoire of prokaryotic influence over eukaryotic physiology to include mating.
      Teaser Bacteria and eukaryotes interact in many ways—from the microbiome that educates the mammalian immune system and enhances nutrition to relationships that are commensal, symbiotic, or parasitic. Now in an unexpected twist, King and colleagues have expanded the repertoire of prokaryotic influence over eukaryotic physiology to include mating.

      PubDate: 2017-09-10T01:10:30Z
       
  • Putting p53 in Context
    • Abstract: Publication date: 7 September 2017
      Source:Cell, Volume 170, Issue 6
      Author(s): Edward R. Kastenhuber, Scott W. Lowe
      TP53 is the most frequently mutated gene in human cancer. Functionally, p53 is activated by a host of stress stimuli and, in turn, governs an exquisitely complex anti-proliferative transcriptional program that touches upon a bewildering array of biological responses. Despite the many unveiled facets of the p53 network, a clear appreciation of how and in what contexts p53 exerts its diverse effects remains unclear. How can we interpret p53’s disparate activities and the consequences of its dysfunction to understand how cell type, mutation profile, and epigenetic cell state dictate outcomes, and how might we restore its tumor-suppressive activities in cancer'
      Teaser The most frequently mutated gene in human cancer, p53, governs a complex anti-proliferative program that in turn impacts an array of biological responses in a context-specific manner.

      PubDate: 2017-09-10T01:10:30Z
       
  • In Situ Architecture and Cellular Interactions of PolyQ Inclusions
    • Abstract: Publication date: Available online 7 September 2017
      Source:Cell
      Author(s): Felix J.B. Bäuerlein, Itika Saha, Archana Mishra, Maria Kalemanov, Antonio Martínez-Sánchez, Rüdiger Klein, Irina Dudanova, Mark S. Hipp, F. Ulrich Hartl, Wolfgang Baumeister, Rubén Fernández-Busnadiego
      Expression of many disease-related aggregation-prone proteins results in cytotoxicity and the formation of large intracellular inclusion bodies. To gain insight into the role of inclusions in pathology and the in situ structure of protein aggregates inside cells, we employ advanced cryo-electron tomography methods to analyze the structure of inclusions formed by polyglutamine (polyQ)-expanded huntingtin exon 1 within their intact cellular context. In primary mouse neurons and immortalized human cells, polyQ inclusions consist of amyloid-like fibrils that interact with cellular endomembranes, particularly of the endoplasmic reticulum (ER). Interactions with these fibrils lead to membrane deformation, the local impairment of ER organization, and profound alterations in ER membrane dynamics at the inclusion periphery. These results suggest that aberrant interactions between fibrils and endomembranes contribute to the deleterious cellular effects of protein aggregation.
      Graphical abstract image Teaser Cryo-electron tomography shows that fibrils from polyglutamine inclusions distort organellar membranes and perturb membrane dynamics.

      PubDate: 2017-09-10T01:10:30Z
       
  • Sensory Neurons Co-opt Classical Immune Signaling Pathways to Mediate
           Chronic Itch
    • Abstract: Publication date: Available online 7 September 2017
      Source:Cell
      Author(s): Landon K. Oetjen, Madison R. Mack, Jing Feng, Timothy M. Whelan, Haixia Niu, Changxiong J. Guo, Sisi Chen, Anna M. Trier, Amy Z. Xu, Shivani V. Tripathi, Jialie Luo, Xiaofei Gao, Lihua Yang, Samantha L. Hamilton, Peter L. Wang, Jonathan R. Brestoff, M. Laurin Council, Richard Brasington, András Schaffer, Frank Brombacher, Chyi-Song Hsieh, Robert W. Gereau, Mark J. Miller, Zhou-Feng Chen, Hongzhen Hu, Steve Davidson, Qin Liu, Brian S. Kim
      Mammals have evolved neurophysiologic reflexes, such as coughing and scratching, to expel invading pathogens and noxious environmental stimuli. It is well established that these responses are also associated with chronic inflammatory diseases, including asthma and atopic dermatitis. However, the mechanisms by which inflammatory pathways promote sensations such as itch remain poorly understood. Here, we show that type 2 cytokines directly activate sensory neurons in both mice and humans. Further, we demonstrate that chronic itch is dependent on neuronal IL-4Rα and JAK1 signaling. We also observe that patients with recalcitrant chronic itch that failed other immunosuppressive therapies markedly improve when treated with JAK inhibitors. Thus, signaling mechanisms previously ascribed to the immune system may represent novel therapeutic targets within the nervous system. Collectively, this study reveals an evolutionarily conserved paradigm in which the sensory nervous system employs classical immune signaling pathways to influence mammalian behavior.
      Graphical abstract image Teaser Type 2 cytokines directly stimulate itch-sensory neurons, and blocking this pathway is effective in a proof-of-concept study in patients with recalcitrant chronic itch.

      PubDate: 2017-09-10T01:10:30Z
       
  • 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
       
  • Dynamic Control of X Chromosome Conformation and Repression by a Histone
           H4K20 Demethylase
    • Abstract: Publication date: Available online 31 August 2017
      Source:Cell
      Author(s): Katjuša Brejc, Qian Bian, Satoru Uzawa, Bayly S. Wheeler, Erika C. Anderson, David S. King, Philip J. Kranzusch, Christine G. Preston, Barbara J. Meyer
      Chromatin modification and higher-order chromosome structure play key roles in gene regulation, but their functional interplay in controlling gene expression is elusive. We have discovered the machinery and mechanism underlying the dynamic enrichment of histone modification H4K20me1 on hermaphrodite X chromosomes during C. elegans dosage compensation and demonstrated H4K20me1’s pivotal role in regulating higher-order chromosome structure and X-chromosome-wide gene expression. The structure and the activity of the dosage compensation complex (DCC) subunit DPY-21 define a Jumonji demethylase subfamily that converts H4K20me2 to H4K20me1 in worms and mammals. Selective inactivation of demethylase activity eliminates H4K20me1 enrichment in somatic cells, elevates X-linked gene expression, reduces X chromosome compaction, and disrupts X chromosome conformation by diminishing the formation of topologically associating domains (TADs). Unexpectedly, DPY-21 also associates with autosomes of germ cells in a DCC-independent manner to enrich H4K20me1 and trigger chromosome compaction. Our findings demonstrate the direct link between chromatin modification and higher-order chromosome structure in long-range regulation of gene expression.
      Graphical abstract image Teaser A histone demethylase regulates 3D chromosome structure and gene expression by modulating the dynamic enrichment of H4K20me1.

      PubDate: 2017-09-05T15:15:36Z
       
  • Load Adaptation of Lamellipodial Actin Networks
    • Abstract: Publication date: Available online 31 August 2017
      Source:Cell
      Author(s): Jan Mueller, Gregory Szep, Maria Nemethova, Ingrid de Vries, Arnon D. Lieber, Christoph Winkler, Karsten Kruse, J. Victor Small, Christian Schmeiser, Kinneret Keren, Robert Hauschild, Michael Sixt
      Actin filaments polymerizing against membranes power endocytosis, vesicular traffic, and cell motility. In vitro reconstitution studies suggest that the structure and the dynamics of actin networks respond to mechanical forces. We demonstrate that lamellipodial actin of migrating cells responds to mechanical load when membrane tension is modulated. In a steady state, migrating cell filaments assume the canonical dendritic geometry, defined by Arp2/3-generated 70° branch points. Increased tension triggers a dense network with a broadened range of angles, whereas decreased tension causes a shift to a sparse configuration dominated by filaments growing perpendicularly to the plasma membrane. We show that these responses emerge from the geometry of branched actin: when load per filament decreases, elongation speed increases and perpendicular filaments gradually outcompete others because they polymerize the shortest distance to the membrane, where they are protected from capping. This network-intrinsic geometrical adaptation mechanism tunes protrusive force in response to mechanical load.
      Graphical abstract image Teaser How do mechanical perturbations influence the density and the geometry of actin networks at the leading edge of migrating cells?

      PubDate: 2017-09-05T15:15:36Z
       
 
 
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