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Journal Cover Cell
  [SJR: 28.188]   [H-I: 616]   [865 followers]  Follow
    
   Full-text available via subscription Subscription journal
   ISSN (Print) 0092-8674 - ISSN (Online) 1097-4172
   Published by Elsevier Homepage  [3089 journals]
  • YY1 Is a Structural Regulator of Enhancer-Promoter Loops
    • Abstract: Publication date: Available online 7 December 2017
      Source:Cell
      Author(s): Abraham S. Weintraub, Charles H. Li, Alicia V. Zamudio, Alla A. Sigova, Nancy M. Hannett, Daniel S. Day, Brian J. Abraham, Malkiel A. Cohen, Behnam Nabet, Dennis L. Buckley, Yang Eric Guo, Denes Hnisz, Rudolf Jaenisch, James E. Bradner, Nathanael S. Gray, Richard A. Young
      There is considerable evidence that chromosome structure plays important roles in gene control, but we have limited understanding of the proteins that contribute to structural interactions between gene promoters and their enhancer elements. Large DNA loops that encompass genes and their regulatory elements depend on CTCF-CTCF interactions, but most enhancer-promoter interactions do not employ this structural protein. Here, we show that the ubiquitously expressed transcription factor Yin Yang 1 (YY1) contributes to enhancer-promoter structural interactions in a manner analogous to DNA interactions mediated by CTCF. YY1 binds to active enhancers and promoter-proximal elements and forms dimers that facilitate the interaction of these DNA elements. Deletion of YY1 binding sites or depletion of YY1 protein disrupts enhancer-promoter looping and gene expression. We propose that YY1-mediated enhancer-promoter interactions are a general feature of mammalian gene control.
      Graphical abstract image Teaser YY1 is a structural regulator of enhancer-promoter interactions and facilitates gene expression.

      PubDate: 2017-12-09T09:47:27Z
       
  • A Living Biobank of Breast Cancer Organoids Captures Disease Heterogeneity
    • Abstract: Publication date: Available online 7 December 2017
      Source:Cell
      Author(s): Norman Sachs, Joep de Ligt, Oded Kopper, Ewa Gogola, Gergana Bounova, Fleur Weeber, Anjali Vanita Balgobind, Karin Wind, Ana Gracanin, Harry Begthel, Jeroen Korving, Ruben van Boxtel, Alexandra Alves Duarte, Daphne Lelieveld, Arne van Hoeck, Robert Frans Ernst, Francis Blokzijl, Isaac Johannes Nijman, Marlous Hoogstraat, Marieke van de Ven, David Anthony Egan, Vittoria Zinzalla, Jurgen Moll, Sylvia Fernandez Boj, Emile Eugene Voest, Lodewyk Wessels, Paul Joannes van Diest, Sven Rottenberg, Robert Gerhardus Jacob Vries, Edwin Cuppen, Hans Clevers
      Breast cancer (BC) comprises multiple distinct subtypes that differ genetically, pathologically, and clinically. Here, we describe a robust protocol for long-term culturing of human mammary epithelial organoids. Using this protocol, >100 primary and metastatic BC organoid lines were generated, broadly recapitulating the diversity of the disease. BC organoid morphologies typically matched the histopathology, hormone receptor status, and HER2 status of the original tumor. DNA copy number variations as well as sequence changes were consistent within tumor-organoid pairs and largely retained even after extended passaging. BC organoids furthermore populated all major gene-expression-based classification groups and allowed in vitro drug screens that were consistent with in vivo xeno-transplantations and patient response. This study describes a representative collection of well-characterized BC organoids available for cancer research and drug development, as well as a strategy to assess in vitro drug response in a personalized fashion.
      Graphical abstract image Teaser The heterogeneity of breast cancer subtypes can be captured using organoid cultures that can facilitate drug screens that corroborate with patient responses.

      PubDate: 2017-12-09T09:47:27Z
       
  • Combined Social and Spatial Coding in a Descending Projection from the
           Prefrontal Cortex
    • Abstract: Publication date: Available online 7 December 2017
      Source:Cell
      Author(s): Malavika Murugan, Hee Jae Jang, Michelle Park, Ellia M. Miller, Julia Cox, Joshua P. Taliaferro, Nathan F. Parker, Varun Bhave, Hong Hur, Yupu Liang, Alexander R. Nectow, Jonathan W. Pillow, Ilana B. Witten
      Social behaviors are crucial to all mammals. Although the prelimbic cortex (PL, part of medial prefrontal cortex) has been implicated in social behavior, it is not clear which neurons are relevant or how they contribute. We found that PL contains anatomically and molecularly distinct subpopulations that target three downstream regions that have been implicated in social behavior: the nucleus accumbens (NAc), amygdala, and ventral tegmental area. Activation of NAc-projecting PL neurons (PL-NAc), but not the other subpopulations, decreased the preference for a social target. To determine what information PL-NAc neurons convey, we selectively recorded from them and found that individual neurons were active during social investigation, but only in specific spatial locations. Spatially specific manipulation of these neurons bidirectionally regulated the formation of a social-spatial association. Thus, the unexpected combination of social and spatial information within the PL-NAc may contribute to social behavior by supporting social-spatial learning.
      Graphical abstract image Teaser Prefrontal neurons that project to the accumbens encode a combination of social and spatial information and bidirectionally modulate social-spatial learning.

      PubDate: 2017-12-09T09:47:27Z
       
  • Mfd Dynamically Regulates Transcription via a Release and Catch-Up
           Mechanism
    • Abstract: Publication date: Available online 7 December 2017
      Source:Cell
      Author(s): Tung T. Le, Yi Yang, Chuang Tan, Margaret M. Suhanovsky, Robert M. Fulbright, James T. Inman, Ming Li, Jaeyoon Lee, Sarah Perelman, Jeffrey W. Roberts, Alexandra M. Deaconescu, Michelle D. Wang
      The bacterial Mfd ATPase is increasingly recognized as a general transcription factor that participates in the resolution of transcription conflicts with other processes/roadblocks. This function stems from Mfd’s ability to preferentially act on stalled RNA polymerases (RNAPs). However, the mechanism underlying this preference and the subsequent coordination between Mfd and RNAP have remained elusive. Here, using a novel real-time translocase assay, we unexpectedly discovered that Mfd translocates autonomously on DNA. The speed and processivity of Mfd dictate a “release and catch-up” mechanism to efficiently patrol DNA for frequently stalled RNAPs. Furthermore, we showed that Mfd prevents RNAP backtracking or rescues a severely backtracked RNAP, allowing RNAP to overcome stronger obstacles. However, if an obstacle’s resistance is excessive, Mfd dissociates the RNAP, clearing the DNA for other processes. These findings demonstrate a remarkably delicate coordination between Mfd and RNAP, allowing efficient targeting and recycling of Mfd and expedient conflict resolution.
      Graphical abstract image Teaser A “release and catch-up” mechanism allows the bacterial protein Mfd to restart or remove stalled RNA polymerases.

      PubDate: 2017-12-09T09:47:27Z
       
  • In Vivo Target Gene Activation via CRISPR/Cas9-Mediated
           Trans-epigenetic Modulation
    • Abstract: Publication date: Available online 7 December 2017
      Source:Cell
      Author(s): Hsin-Kai Liao, Fumiyuki Hatanaka, Toshikazu Araoka, Pradeep Reddy, Min-Zu Wu, Yinghui Sui, Takayoshi Yamauchi, Masahiro Sakurai, David D. O’Keefe, Estrella Núñez-Delicado, Pedro Guillen, Josep M. Campistol, Cheng-Jang Wu, Li-Fan Lu, Concepcion Rodriguez Esteban, Juan Carlos Izpisua Belmonte
      Current genome-editing systems generally rely on inducing DNA double-strand breaks (DSBs). This may limit their utility in clinical therapies, as unwanted mutations caused by DSBs can have deleterious effects. CRISPR/Cas9 system has recently been repurposed to enable target gene activation, allowing regulation of endogenous gene expression without creating DSBs. However, in vivo implementation of this gain-of-function system has proven difficult. Here, we report a robust system for in vivo activation of endogenous target genes through trans-epigenetic remodeling. The system relies on recruitment of Cas9 and transcriptional activation complexes to target loci by modified single guide RNAs. As proof-of-concept, we used this technology to treat mouse models of diabetes, muscular dystrophy, and acute kidney disease. Results demonstrate that CRISPR/Cas9-mediated target gene activation can be achieved in vivo, leading to measurable phenotypes and amelioration of disease symptoms. This establishes new avenues for developing targeted epigenetic therapies against human diseases.
      Graphical abstract image Teaser In vivo delivery of a Cas9-based epigenetic gene activation system ameliorates disease phenotypes in mouse models of type I diabetes, acute kidney injury, and muscular dystrophy

      PubDate: 2017-12-09T09:47:27Z
       
  • Structural Basis for Regulated Proteolysis by the α-Secretase ADAM10
    • Abstract: Publication date: Available online 7 December 2017
      Source:Cell
      Author(s): Tom C.M. Seegar, Lauren B. Killingsworth, Nayanendu Saha, Peter A. Meyer, Dhabaleswar Patra, Brandon Zimmerman, Peter W. Janes, Eric Rubinstein, Dimitar B. Nikolov, Georgios Skiniotis, Andrew C. Kruse, Stephen C. Blacklow
      Cleavage of membrane-anchored proteins by ADAM (a disintegrin and metalloproteinase) endopeptidases plays a key role in a wide variety of biological signal transduction and protein turnover processes. Among ADAM family members, ADAM10 stands out as particularly important because it is both responsible for regulated proteolysis of Notch receptors and catalyzes the non-amyloidogenic α-secretase cleavage of the Alzheimer’s precursor protein (APP). We present here the X-ray crystal structure of the ADAM10 ectodomain, which, together with biochemical and cellular studies, reveals how access to the enzyme active site is regulated. The enzyme adopts an unanticipated architecture in which the C-terminal cysteine-rich domain partially occludes the enzyme active site, preventing unfettered substrate access. Binding of a modulatory antibody to the cysteine-rich domain liberates the catalytic domain from autoinhibition, enhancing enzymatic activity toward a peptide substrate. Together, these studies reveal a mechanism for regulation of ADAM activity and offer a roadmap for its modulation.
      Graphical abstract image Teaser The X-ray structure of the ADAM10 ectodomain, together with biochemical and cell-based studies, reveals mechanistic insights into its enzymatic function in Notch signaling and in processing of the Alzheimer's precursor protein APP.

      PubDate: 2017-12-09T09:47:27Z
       
  • Rapid Mobilization Reveals a Highly Engraftable Hematopoietic Stem Cell
    • Abstract: Publication date: Available online 7 December 2017
      Source:Cell
      Author(s): Jonathan Hoggatt, Pratibha Singh, Tiffany A. Tate, Bin-Kuan Chou, Shruti R. Datari, Seiji Fukuda, Liqiong Liu, Peter V. Kharchenko, Amir Schajnovitz, Ninib Baryawno, Francois E. Mercier, Joseph Boyer, Jason Gardner, Dwight M. Morrow, David T. Scadden, Louis M. Pelus
      Hematopoietic stem cell transplantation is a potential curative therapy for malignant and nonmalignant diseases. Improving the efficiency of stem cell collection and the quality of the cells acquired can broaden the donor pool and improve patient outcomes. We developed a rapid stem cell mobilization regimen utilizing a unique CXCR2 agonist, GROβ, and the CXCR4 antagonist AMD3100. A single injection of both agents resulted in stem cell mobilization peaking within 15 min that was equivalent in magnitude to a standard multi-day regimen of granulocyte colony-stimulating factor (G-CSF). Mechanistic studies determined that rapid mobilization results from synergistic signaling on neutrophils, resulting in enhanced MMP-9 release, and unexpectedly revealed genetic polymorphisms in MMP-9 that alter activity. This mobilization regimen results in preferential trafficking of stem cells that demonstrate a higher engraftment efficiency than those mobilized by G-CSF. Our studies suggest a potential new strategy for the rapid collection of an improved hematopoietic graft.
      Graphical abstract image Teaser A new strategy for stem cell mobilization enables rapid collection of an improved hematopoietic graft in humans.

      PubDate: 2017-12-09T09:47:27Z
       
  • The Ferrous Awakens
    • Abstract: Publication date: 30 November 2017
      Source:Cell, Volume 171, Issue 6
      Author(s): Andrew J. Rennekamp
      Teaser Recent discoveries provide a new hope that relapses of several types of cancer can be prevented by inducing ferroptosis.

      PubDate: 2017-12-09T09:47:27Z
       
  • How Cryo-EM Became so Hot
    • Abstract: Publication date: 30 November 2017
      Source:Cell, Volume 171, Issue 6
      Author(s): Yifan Cheng, Robert M. Glaeser, Eva Nogales
      The Royal Swedish Academy of Sciences awarded the 2017 Nobel Prize for Chemistry to Jacques Dubochet, Joachim Frank, and Richard Henderson for “developing cryoelectron microscopy for the high-resolution structure determination of biomolecules in solution.” Achieving this goal, which required innovation, persistence, and uncommon physical insight, has broadened horizons for structural studies in molecular and cell biology.
      Teaser The Royal Swedish Academy of Sciences awarded the 2017 Nobel Prize for Chemistry to Jacques Dubochet, Joachim Frank, and Richard Henderson for “developing cryoelectron microscopy for the high-resolution structure determination of biomolecules in solution.” Achieving this goal, which required innovation, persistence, and uncommon physical insight, has broadened horizons for structural studies in molecular and cell biology.

      PubDate: 2017-12-09T09:47:27Z
       
  • Physiology Flies with Time
    • Abstract: Publication date: 30 November 2017
      Source:Cell, Volume 171, Issue 6
      Author(s): Amita Sehgal
      The 2017 Nobel Prize in Medicine or Physiology has been awarded to Jeffrey Hall, Michael Rosbash, and Michael Young for elucidating molecular mechanisms of the circadian clock. From studies beginning in fruit flies, we now know that circadian regulation pervades most biological processes and has strong ties to human health and disease.
      Teaser The 2017 Nobel Prize in Medicine or Physiology has been awarded to Jeffrey Hall, Michael Rosbash, and Michael Young for elucidating molecular mechanisms of the circadian clock. From studies beginning in fruit flies, we now know that circadian regulation pervades most biological processes and has strong ties to human health and disease.

      PubDate: 2017-12-09T09:47:27Z
       
  • As Time Flew By
    • Abstract: Publication date: 30 November 2017
      Source:Cell, Volume 171, Issue 6
      Author(s): Michael W. Young


      PubDate: 2017-12-09T09:47:27Z
       
  • Life Is an N of 1
    • Abstract: Publication date: 30 November 2017
      Source:Cell, Volume 171, Issue 6
      Author(s): Michael Rosbash


      PubDate: 2017-12-09T09:47:27Z
       
  • A Nobel Pursuit May Not Run like Clockwork
    • Abstract: Publication date: 30 November 2017
      Source:Cell, Volume 171, Issue 6
      Living in rural Maine, Jeffrey Hall’s own rhythm has been thrown upside down after he received a very unexpected call one morning on the award of this year’s Nobel Prize in Physiology or Medicine. Together with Michael Rosbash and Mike Young, they were recognized “for their discoveries of molecular mechanisms controlling the circadian rhythm.” Cell editor Marta Koch caught up with Jeff on a calm Sunday morning, when electricity at his house had just returned after recent storms. Annotated excerpts from their chat about behavior, misbehavior, and the challenges and joys of working with fruit flies, are presented below.
      Teaser Living in rural Maine, Jeffrey Hall’s own rhythm has been thrown upside down after he received a very unexpected call communicating he, together with Michael Rosbash and Mike Young, had been awarded this year’s Nobel Prize in Physiology or Medicine for their “for their discoveries of molecular mechanisms controlling the circadian rhythm.” Cell editor Marta Koch was fortunate to catch Jeff Hall on a calm Sunday morning, when electricity was back on despite recent storms, and chat about behavior, misbehavior, and the challenges and joys of working with fruit flies. Annotated excerpts from this conversation are presented below, and the full conversation is available with the article online.

      PubDate: 2017-12-09T09:47:27Z
       
  • Tumor Evolution: A Problem of Histocompatibility
    • Abstract: Publication date: 30 November 2017
      Source:Cell, Volume 171, Issue 6
      Author(s): Natalie I. Vokes, Eliezer M. Van Allen
      In this issue of Cell, two articles show that tumor-specific changes in HLA-mediated antigen presentation affect tumor immunogenicity and may play a role in shaping cancer cell survival.
      Teaser In this issue of Cell, two articles show that tumor-specific changes in HLA-mediated antigen presentation affect tumor immunogenicity and may play a role in shaping cancer cell survival.

      PubDate: 2017-12-09T09:47:27Z
       
  • Phytochromes: Where to Start'
    • Abstract: Publication date: 30 November 2017
      Source:Cell, Volume 171, Issue 6
      Author(s): Sookyung Oh, Beronda L. Montgomery
      Phytochrome signaling allows plants to sense and respond to light through gene regulation. Ushijima et al. (2017) demonstrate a role for phytochromes in widespread regulation of alternative promoter usage, resulting in light-dependent protein isoforms with altered subcellular localization that help the plant respond metabolically to fluctuating light conditions.
      Teaser Phytochrome signaling allows plants to sense and respond to light through gene regulation. Ushijima et al. (2017) demonstrate a role for phytochromes in widespread regulation of alternative promoter usage, resulting in light-dependent protein isoforms with altered subcellular localization that help the plant respond metabolically to fluctuating light conditions.

      PubDate: 2017-12-09T09:47:27Z
       
  • Platelets, On Your Marks, Get Set, Migrate!
    • Abstract: Publication date: 30 November 2017
      Source:Cell, Volume 171, Issue 6
      Author(s): Sarah K. Bambach, Tim Lämmermann
      The idea that anucleate platelets display autonomous migration has long been viewed with skepticism. Gaertner et al. provide in vivo evidence that platelets undergo active migration at sites of thrombus formation and in inflamed liver sinusoids. Integrin-dependent migration allows platelets to scavenge and bundle fibrin-bound material, including intravascular bacteria.
      Teaser The idea that anucleate platelets display autonomous migration has long been viewed with skepticism. Gaertner et al. provide in vivo evidence that platelets undergo active migration at sites of thrombus formation and in inflamed liver sinusoids. Integrin-dependent migration allows platelets to scavenge and bundle fibrin-bound material, including intravascular bacteria.

      PubDate: 2017-12-09T09:47:27Z
       
  • Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution
    • Abstract: Publication date: 30 November 2017
      Source:Cell, Volume 171, Issue 6
      Author(s): Nicholas McGranahan, Rachel Rosenthal, Crispin T. Hiley, Andrew J. Rowan, Thomas B.K. Watkins, Gareth A. Wilson, Nicolai J. Birkbak, Selvaraju Veeriah, Peter Van Loo, Javier Herrero, Charles Swanton
      Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. Video
      Graphical abstract image Teaser Development of the bioinformatics tool LOHHLA allows precise measurement of allele-specific HLA copy number, improves the accuracy in neoantigen prediction, and uncovers insights into how immune escape contributes to tumor evolution in non-small-cell lung cancer.

      PubDate: 2017-12-09T09:47:27Z
       
  • MHC-I Genotype Restricts the Oncogenic Mutational Landscape
    • Abstract: Publication date: 30 November 2017
      Source:Cell, Volume 171, Issue 6
      Author(s): Rachel Marty, Saghar Kaabinejadian, David Rossell, Michael J. Slifker, Joris van de Haar, Hatice Billur Engin, Nicola de Prisco, Trey Ideker, William H. Hildebrand, Joan Font-Burgada, Hannah Carter
      MHC-I molecules expose the intracellular protein content on the cell surface, allowing T cells to detect foreign or mutated peptides. The combination of six MHC-I alleles each individual carries defines the sub-peptidome that can be effectively presented. We applied this concept to human cancer, hypothesizing that oncogenic mutations could arise in gaps in personal MHC-I presentation. To validate this hypothesis, we developed and applied a residue-centric patient presentation score to 9,176 cancer patients across 1,018 recurrent oncogenic mutations. We found that patient MHC-I genotype-based scores could predict which mutations were more likely to emerge in their tumor. Accordingly, poor presentation of a mutation across patients was correlated with higher frequency among tumors. These results support that MHC-I genotype-restricted immunoediting during tumor formation shapes the landscape of oncogenic mutations observed in clinically diagnosed tumors and paves the way for predicting personal cancer susceptibilities from knowledge of MHC-I genotype.
      Graphical abstract image Teaser HLA genotype-restricted immunoediting during tumor formation shapes the landscape of oncogenic mutations observed in clinically diagnosed tumors.

      PubDate: 2017-12-09T09:47:27Z
       
  • Epigenetic Therapy Ties MYC Depletion to Reversing Immune Evasion and
           Treating Lung Cancer
    • Abstract: Publication date: 30 November 2017
      Source:Cell, Volume 171, Issue 6
      Author(s): Michael J. Topper, Michelle Vaz, Katherine B. Chiappinelli, Christina E. DeStefano Shields, Noushin Niknafs, Ray-Whay Chiu Yen, Alyssa Wenzel, Jessica Hicks, Matthew Ballew, Meredith Stone, Phuoc T. Tran, Cynthia A. Zahnow, Matthew D. Hellmann, Valsamo Anagnostou, Pamela L. Strissel, Reiner Strick, Victor E. Velculescu, Stephen B. Baylin
      Combining DNA-demethylating agents (DNA methyltransferase inhibitors [DNMTis]) with histone deacetylase inhibitors (HDACis) holds promise for enhancing cancer immune therapy. Herein, pharmacologic and isoform specificity of HDACis are investigated to guide their addition to a DNMTi, thus devising a new, low-dose, sequential regimen that imparts a robust anti-tumor effect for non-small-cell lung cancer (NSCLC). Using in-vitro-treated NSCLC cell lines, we elucidate an interferon α/β-based transcriptional program with accompanying upregulation of antigen presentation machinery, mediated in part through double-stranded RNA (dsRNA) induction. This is accompanied by suppression of MYC signaling and an increase in the T cell chemoattractant CCL5. Use of this combination treatment schema in mouse models of NSCLC reverses tumor immune evasion and modulates T cell exhaustion state towards memory and effector T cell phenotypes. Key correlative science metrics emerge for an upcoming clinical trial, testing enhancement of immune checkpoint therapy for NSCLC.
      Graphical abstract image Teaser Myc depletion through combined epigenetic therapy reverses immune evasion and enables effective treatment of lung cancer.

      PubDate: 2017-12-09T09:47:27Z
       
  • Myc Cooperates with Ras by Programming Inflammation and Immune Suppression
    • Abstract: Publication date: 30 November 2017
      Source:Cell, Volume 171, Issue 6
      Author(s): Roderik M. Kortlever, Nicole M. Sodir, Catherine H. Wilson, Deborah L. Burkhart, Luca Pellegrinet, Lamorna Brown Swigart, Trevor D. Littlewood, Gerard I. Evan
      The two oncogenes KRas and Myc cooperate to drive tumorigenesis, but the mechanism underlying this remains unclear. In a mouse lung model of KRas G12D -driven adenomas, we find that co-activation of Myc drives the immediate transition to highly proliferative and invasive adenocarcinomas marked by highly inflammatory, angiogenic, and immune-suppressed stroma. We identify epithelial-derived signaling molecules CCL9 and IL-23 as the principal instructing signals for stromal reprogramming. CCL9 mediates recruitment of macrophages, angiogenesis, and PD-L1-dependent expulsion of T and B cells. IL-23 orchestrates exclusion of adaptive T and B cells and innate immune NK cells. Co-blockade of both CCL9 and IL-23 abrogates Myc-induced tumor progression. Subsequent deactivation of Myc in established adenocarcinomas triggers immediate reversal of all stromal changes and tumor regression, which are independent of CD4+CD8+ T cells but substantially dependent on returning NK cells. We show that Myc extensively programs an immune suppressive stroma that is obligatory for tumor progression.
      Graphical abstract image Teaser Oncogenic Myc activity orchestrates an immune suppressive tumor microenvironment.

      PubDate: 2017-12-09T09:47:27Z
       
  • Composition and Regulation of the Cellular Repertoire of SCF Ubiquitin
           Ligases
    • Abstract: Publication date: 30 November 2017
      Source:Cell, Volume 171, Issue 6
      Author(s): Justin M. Reitsma, Xing Liu, Kurt M. Reichermeier, Annie Moradian, Michael J. Sweredoski, Sonja Hess, Raymond J. Deshaies
      SCF (Skp1-Cullin-F-box) ubiquitin ligases comprise several dozen modular enzymes that have diverse roles in biological regulation. SCF enzymes share a common catalytic core containing Cul1⋅Rbx1, which is directed toward different substrates by a variable substrate receptor (SR) module comprising 1 of 69 F-box proteins bound to Skp1. Despite the broad cellular impact of SCF enzymes, important questions remain about the architecture and regulation of the SCF repertoire, including whether SRs compete for Cul1 and, if so, how this competition is managed. Here, we devise methods that preserve the in vivo assemblages of SCF complexes and apply quantitative mass spectrometry to perform a census of these complexes (the “SCFome”) in various states. We show that Nedd8 conjugation and the SR exchange factor Cand1 have a profound effect on shaping the SCFome. Together, these factors enable rapid remodeling of SCF complexes to promote biased assembly of SR modules bound to substrate.
      Graphical abstract image Teaser A cell’s repertoire of SCF ubiquitin ligases, which target proteins for degradation, is directly shaped by the substrates that are present.

      PubDate: 2017-12-09T09:47:27Z
       
  • An Unexpectedly Complex Architecture for Skin Pigmentation in Africans
    • Abstract: Publication date: 30 November 2017
      Source:Cell, Volume 171, Issue 6
      Author(s): Alicia R. Martin, Meng Lin, Julie M. Granka, Justin W. Myrick, Xiaomin Liu, Alexandra Sockell, Elizabeth G. Atkinson, Cedric J. Werely, Marlo Möller, Manjinder S. Sandhu, David M. Kingsley, Eileen G. Hoal, Xiao Liu, Mark J. Daly, Marcus W. Feldman, Christopher R. Gignoux, Carlos D. Bustamante, Brenna M. Henn
      Approximately 15 genes have been directly associated with skin pigmentation variation in humans, leading to its characterization as a relatively simple trait. However, by assembling a global survey of quantitative skin pigmentation phenotypes, we demonstrate that pigmentation is more complex than previously assumed, with genetic architecture varying by latitude. We investigate polygenicity in the KhoeSan populations indigenous to southern Africa who have considerably lighter skin than equatorial Africans. We demonstrate that skin pigmentation is highly heritable, but known pigmentation loci explain only a small fraction of the variance. Rather, baseline skin pigmentation is a complex, polygenic trait in the KhoeSan. Despite this, we identify canonical and non-canonical skin pigmentation loci, including near SLC24A5, TYRP1, SMARCA2/VLDLR, and SNX13, using a genome-wide association approach complemented by targeted resequencing. By considering diverse, under-studied African populations, we show how the architecture of skin pigmentation can vary across humans subject to different local evolutionary pressures.
      Graphical abstract image Teaser The genetic architecture of skin pigmentation is highly complex, varies across human populations, and is subject to distinct geographical evolutionary pressures.

      PubDate: 2017-12-09T09:47:27Z
       
  • Membrane Microdomain Disassembly Inhibits MRSA Antibiotic Resistance
    • Abstract: Publication date: 30 November 2017
      Source:Cell, Volume 171, Issue 6
      Author(s): Esther García-Fernández, Gudrun Koch, Rabea M. Wagner, Agnes Fekete, Stephanie T. Stengel, Johannes Schneider, Benjamin Mielich-Süss, Sebastian Geibel, Sebastian M. Markert, Christian Stigloher, Daniel Lopez
      A number of bacterial cell processes are confined functional membrane microdomains (FMMs), structurally and functionally similar to lipid rafts of eukaryotic cells. How bacteria organize these intricate platforms and what their biological significance is remain important questions. Using the pathogen methicillin-resistant Staphylococcus aureus (MRSA), we show here that membrane-carotenoid interaction with the scaffold protein flotillin leads to FMM formation, which can be visualized using super-resolution array tomography. These membrane platforms accumulate multimeric protein complexes, for which flotillin facilitates efficient oligomerization. One of these proteins is PBP2a, responsible for penicillin resistance in MRSA. Flotillin mutants are defective in PBP2a oligomerization. Perturbation of FMM assembly using available drugs interferes with PBP2a oligomerization and disables MRSA penicillin resistance in vitro and in vivo, resulting in MRSA infections that are susceptible to penicillin treatment. Our study demonstrates that bacteria possess sophisticated cell organization programs and defines alternative therapies to fight multidrug-resistant pathogens using conventional antibiotics.
      Graphical abstract image Teaser Using statins to disassemble bacterial membrane microdomains can decrease antibiotic resistance and re-sensitize MRSA to antibiotic therapies in vivo.

      PubDate: 2017-12-09T09:47:27Z
       
  • Migrating Platelets Are Mechano-scavengers that Collect and Bundle
           Bacteria
    • Abstract: Publication date: 30 November 2017
      Source:Cell, Volume 171, Issue 6
      Author(s): Florian Gaertner, Zerkah Ahmad, Gerhild Rosenberger, Shuxia Fan, Leo Nicolai, Benjamin Busch, Gökce Yavuz, Manja Luckner, Hellen Ishikawa-Ankerhold, Roman Hennel, Alexandre Benechet, Michael Lorenz, Sue Chandraratne, Irene Schubert, Sebastian Helmer, Bianca Striednig, Konstantin Stark, Marek Janko, Ralph T. Böttcher, Admar Verschoor, Catherine Leon, Christian Gachet, Thomas Gudermann, Michael Mederos y Schnitzler, Zachary Pincus, Matteo Iannacone, Rainer Haas, Gerhard Wanner, Kirsten Lauber, Michael Sixt, Steffen Massberg
      Blood platelets are critical for hemostasis and thrombosis and play diverse roles during immune responses. Despite these versatile tasks in mammalian biology, their skills on a cellular level are deemed limited, mainly consisting in rolling, adhesion, and aggregate formation. Here, we identify an unappreciated asset of platelets and show that adherent platelets use adhesion receptors to mechanically probe the adhesive substrate in their local microenvironment. When actomyosin-dependent traction forces overcome substrate resistance, platelets migrate and pile up the adhesive substrate together with any bound particulate material. They use this ability to act as cellular scavengers, scanning the vascular surface for potential invaders and collecting deposited bacteria. Microbe collection by migrating platelets boosts the activity of professional phagocytes, exacerbating inflammatory tissue injury in sepsis. This assigns platelets a central role in innate immune responses and identifies them as potential targets to dampen inflammatory tissue damage in clinical scenarios of severe systemic infection.
      Graphical abstract image Teaser In addition to their role in thrombosis and hemostasis, platelets can also migrate to sites of infection to help trap bacteria and clear the vascular surface.

      PubDate: 2017-12-09T09:47:27Z
       
  • Epsin-Dependent Ligand Endocytosis Activates Notch by Force
    • Abstract: Publication date: 30 November 2017
      Source:Cell, Volume 171, Issue 6
      Author(s): Paul D. Langridge, Gary Struhl
      DSL ligands activate Notch by inducing proteolytic cleavage of the receptor ectodomain, an event that requires ligand to be endocytosed in signal-sending cells by the adaptor protein Epsin. Two classes of explanation for this unusual requirement are (1) recycling models, in which the ligand must be endocytosed to be modified or repositioned before it binds Notch and (2) pulling models, in which the ligand must be endocytosed after it binds Notch to exert force that exposes an otherwise buried site for cleavage. We demonstrate in vivo that ligands that cannot enter the Epsin pathway nevertheless bind Notch but fail to activate the receptor because they cannot exert sufficient force. This argues against recycling models and in favor of pulling models. Our results also suggest that once ligand binds receptor, activation depends on a competition between Epsin-mediated ligand endocytosis, which induces cleavage, and transendocytosis of the ligand by the receptor, which aborts the incipient signal.
      Graphical abstract image Teaser Force exerted by Epsin-mediated ligand endocytosis induces ectodomain cleavage of Notch to initiate signaling.

      PubDate: 2017-12-09T09:47:27Z
       
  • Force Triggers YAP Nuclear Entry by Regulating Transport across Nuclear
           Pores
    • Abstract: Publication date: 30 November 2017
      Source:Cell, Volume 171, Issue 6
      Author(s): Alberto Elosegui-Artola, Ion Andreu, Amy E.M. Beedle, Ainhoa Lezamiz, Marina Uroz, Anita J. Kosmalska, Roger Oria, Jenny Z. Kechagia, Palma Rico-Lastres, Anabel-Lise Le Roux, Catherine M. Shanahan, Xavier Trepat, Daniel Navajas, Sergi Garcia-Manyes, Pere Roca-Cusachs
      YAP is a mechanosensitive transcriptional activator with a critical role in cancer, regeneration, and organ size control. Here, we show that force applied to the nucleus directly drives YAP nuclear translocation by decreasing the mechanical restriction of nuclear pores to molecular transport. Exposure to a stiff environment leads cells to establish a mechanical connection between the nucleus and the cytoskeleton, allowing forces exerted through focal adhesions to reach the nucleus. Force transmission then leads to nuclear flattening, which stretches nuclear pores, reduces their mechanical resistance to molecular transport, and increases YAP nuclear import. The restriction to transport is further regulated by the mechanical stability of the transported protein, which determines both active nuclear transport of YAP and passive transport of small proteins. Our results unveil a mechanosensing mechanism mediated directly by nuclear pores, demonstrated for YAP but with potential general applicability in transcriptional regulation.
      Graphical abstract image Teaser Force-dependent changes in nuclear pores control protein access to the nucleus.

      PubDate: 2017-12-09T09:47:27Z
       
  • Ancestral Circuits for the Coordinated Modulation of Brain State
    • Abstract: Publication date: 30 November 2017
      Source:Cell, Volume 171, Issue 6
      Author(s): Matthew Lovett-Barron, Aaron S. Andalman, William E. Allen, Sam Vesuna, Isaac Kauvar, Vanessa M. Burns, Karl Deisseroth
      Internal states of the brain profoundly influence behavior. Fluctuating states such as alertness can be governed by neuromodulation, but the underlying mechanisms and cell types involved are not fully understood. We developed a method to globally screen for cell types involved in behavior by integrating brain-wide activity imaging with high-content molecular phenotyping and volume registration at cellular resolution. We used this method (MultiMAP) to record from 22 neuromodulatory cell types in behaving zebrafish during a reaction-time task that reports alertness. We identified multiple monoaminergic, cholinergic, and peptidergic cell types linked to alertness and found that activity in these cell types was mutually correlated during heightened alertness. We next recorded from and controlled homologous neuromodulatory cells in mice; alertness-related cell-type dynamics exhibited striking evolutionary conservation and modulated behavior similarly. These experiments establish a method for unbiased discovery of cellular elements underlying behavior and reveal an evolutionarily conserved set of diverse neuromodulatory systems that collectively govern internal state.
      Graphical abstract image Teaser Registration of brain-wide activity measurements with multiple molecular markers at cellular resolution uncovers multiple diverse neuromodulatory pathways linked to brain state.

      PubDate: 2017-12-09T09:47:27Z
       
  • A Next Generation Connectivity Map: L1000 Platform and the First 1,000,000
           Profiles
    • Abstract: Publication date: 30 November 2017
      Source:Cell, Volume 171, Issue 6
      Author(s): Aravind Subramanian, Rajiv Narayan, Steven M. Corsello, David D. Peck, Ted E. Natoli, Xiaodong Lu, Joshua Gould, John F. Davis, Andrew A. Tubelli, Jacob K. Asiedu, David L. Lahr, Jodi E. Hirschman, Zihan Liu, Melanie Donahue, Bina Julian, Mariya Khan, David Wadden, Ian C. Smith, Daniel Lam, Arthur Liberzon, Courtney Toder, Mukta Bagul, Marek Orzechowski, Oana M. Enache, Federica Piccioni, Sarah A. Johnson, Nicholas J. Lyons, Alice H. Berger, Alykhan F. Shamji, Angela N. Brooks, Anita Vrcic, Corey Flynn, Jacqueline Rosains, David Y. Takeda, Roger Hu, Desiree Davison, Justin Lamb, Kristin Ardlie, Larson Hogstrom, Peyton Greenside, Nathanael S. Gray, Paul A. Clemons, Serena Silver, Xiaoyun Wu, Wen-Ning Zhao, Willis Read-Button, Xiaohua Wu, Stephen J. Haggarty, Lucienne V. Ronco, Jesse S. Boehm, Stuart L. Schreiber, John G. Doench, Joshua A. Bittker, David E. Root, Bang Wong, Todd R. Golub
      We previously piloted the concept of a Connectivity Map (CMap), whereby genes, drugs, and disease states are connected by virtue of common gene-expression signatures. Here, we report more than a 1,000-fold scale-up of the CMap as part of the NIH LINCS Consortium, made possible by a new, low-cost, high-throughput reduced representation expression profiling method that we term L1000. We show that L1000 is highly reproducible, comparable to RNA sequencing, and suitable for computational inference of the expression levels of 81% of non-measured transcripts. We further show that the expanded CMap can be used to discover mechanism of action of small molecules, functionally annotate genetic variants of disease genes, and inform clinical trials. The 1.3 million L1000 profiles described here, as well as tools for their analysis, are available at https://clue.io.
      Graphical abstract image Teaser The next generation Connectivity Map, a large-scale compendium of functional perturbations in cultured human cells coupled to a gene-expression readout, facilitates the discovery of connections between genes, drugs, and diseases.

      PubDate: 2017-12-09T09:47:27Z
       
  • SnapShot: Circadian Clock
    • Abstract: Publication date: 30 November 2017
      Source:Cell, Volume 171, Issue 6
      Author(s): Bryan J. Song, Dragana Rogulja
      Most creatures on this planet possess an ability to anticipate upcoming events in the environment, courtesy of their circadian clocks. This allows them to prepare for those changes instead of being caught by surprise, which could mean the difference between life and death. In this SnapShot, we describe the basics of how the clock ticks.
      Teaser Most creatures on this planet possess an ability to anticipate upcoming events in the environment, courtesy of their circadian clocks. This allows them to prepare for those changes instead of being caught by surprise, which could mean the difference between life and death. In this SnapShot, we describe the basics of how the clock ticks.

      PubDate: 2017-12-09T09:47:27Z
       
  • A J-Protein Co-chaperone Recruits BiP to Monomerize IRE1 and Repress the
           Unfolded Protein Response
    • Abstract: Publication date: Available online 30 November 2017
      Source:Cell
      Author(s): Niko Amin-Wetzel, Reuben A. Saunders, Maarten J. Kamphuis, Claudia Rato, Steffen Preissler, Heather P. Harding, David Ron
      When unfolded proteins accumulate in the endoplasmic reticulum (ER), the unfolded protein response (UPR) increases ER-protein-folding capacity to restore protein-folding homeostasis. Unfolded proteins activate UPR signaling across the ER membrane to the nucleus by promoting oligomerization of IRE1, a conserved transmembrane ER stress receptor. However, the coupling of ER stress to IRE1 oligomerization and activation has remained obscure. Here, we report that the ER luminal co-chaperone ERdj4/DNAJB9 is a selective IRE1 repressor that promotes a complex between the luminal Hsp70 BiP and the luminal stress-sensing domain of IRE1α (IRE1LD). In vitro, ERdj4 is required for complex formation between BiP and IRE1LD. ERdj4 associates with IRE1LD and recruits BiP through the stimulation of ATP hydrolysis, forcibly disrupting IRE1 dimers. Unfolded proteins compete for BiP and restore IRE1LD to its default, dimeric, and active state. These observations establish BiP and its J domain co-chaperones as key regulators of the UPR.
      Graphical abstract image Teaser Molecular basis for the regulation of the unfolded protein response by chaperones and misfolded proteins.

      PubDate: 2017-12-09T09:47:27Z
       
  • Neuromodulatory Control of Long-Term Behavioral Patterns and Individuality
           across Development
    • Abstract: Publication date: Available online 30 November 2017
      Source:Cell
      Author(s): Shay Stern, Christoph Kirst, Cornelia I. Bargmann
      Animals generate complex patterns of behavior across development that may be shared or unique to individuals. Here, we examine the contributions of developmental programs and individual variation to behavior by monitoring single Caenorhabditis elegans nematodes over their complete developmental trajectories and quantifying their behavior at high spatiotemporal resolution. These measurements reveal reproducible trajectories of spontaneous foraging behaviors that are stereotyped within and between developmental stages. Dopamine, serotonin, the neuropeptide receptor NPR-1, and the TGF-β peptide DAF-7 each have stage-specific effects on behavioral trajectories, implying the existence of a modular temporal program controlled by neuromodulators. In addition, a fraction of individuals within isogenic populations raised in controlled environments have consistent, non-genetic behavioral biases that persist across development. Several neuromodulatory systems increase or decrease the degree of non-genetic individuality to shape sustained patterns of behavior across the population.
      Graphical abstract image Teaser Individual nematodes exhibit consistent, non-genetic behavioral biases that are impacted by several neuromodulatory systems.

      PubDate: 2017-12-09T09:47:27Z
       
  • Single-Cell Transcriptomic Analysis of Primary and Metastatic Tumor
           Ecosystems in Head and Neck Cancer
    • Abstract: Publication date: Available online 30 November 2017
      Source:Cell
      Author(s): Sidharth V. Puram, Itay Tirosh, Anuraag S. Parikh, Anoop P. Patel, Keren Yizhak, Shawn Gillespie, Christopher Rodman, Christina L. Luo, Edmund A. Mroz, Kevin S. Emerick, Daniel G. Deschler, Mark A. Varvares, Ravi Mylvaganam, Orit Rozenblatt-Rosen, James W. Rocco, William C. Faquin, Derrick T. Lin, Aviv Regev, Bradley E. Bernstein
      The diverse malignant, stromal, and immune cells in tumors affect growth, metastasis, and response to therapy. We profiled transcriptomes of ∼6,000 single cells from 18 head and neck squamous cell carcinoma (HNSCC) patients, including five matched pairs of primary tumors and lymph node metastases. Stromal and immune cells had consistent expression programs across patients. Conversely, malignant cells varied within and between tumors in their expression of signatures related to cell cycle, stress, hypoxia, epithelial differentiation, and partial epithelial-to-mesenchymal transition (p-EMT). Cells expressing the p-EMT program spatially localized to the leading edge of primary tumors. By integrating single-cell transcriptomes with bulk expression profiles for hundreds of tumors, we refined HNSCC subtypes by their malignant and stromal composition and established p-EMT as an independent predictor of nodal metastasis, grade, and adverse pathologic features. Our results provide insight into the HNSCC ecosystem and define stromal interactions and a p-EMT program associated with metastasis.
      Graphical abstract image Teaser Single-cell transcriptomic analysis in patients with head and neck squamous cell carcinoma highlights the heterogeneous composition of malignant and non-malignant cells in the tumor microenvironment and associates a partial EMT program with metastasis.

      PubDate: 2017-12-09T09:47:27Z
       
  • Resetting the Yeast Epigenome with Human Nucleosomes
    • Abstract: Publication date: Available online 30 November 2017
      Source:Cell
      Author(s): David M. Truong, Jef D. Boeke
      Humans and yeast are separated by a billion years of evolution, yet their conserved histones retain central roles in gene regulation. Here, we “reset” yeast to use core human nucleosomes in lieu of their own (a rare event taking 20 days), which initially only worked with variant H3.1. The cells adapt by acquiring suppressor mutations in cell-division genes or by acquiring certain aneuploid states. Converting five histone residues to their yeast counterparts restored robust growth. We reveal that humanized nucleosomes are positioned according to endogenous yeast DNA sequence and chromatin-remodeling network, as judged by a yeast-like nucleosome repeat length. However, human nucleosomes have higher DNA occupancy, globally reduce RNA content, and slow adaptation to new conditions by delaying chromatin remodeling. These humanized yeasts (including H3.3) pose fundamental new questions about how chromatin is linked to many cell processes and provide a platform to study histone variants via yeast epigenome reprogramming.
      Graphical abstract image Teaser Yeast can survive with human histones, providing insight into the regulation of nucleosome positioning and remodeling.

      PubDate: 2017-12-09T09:47:27Z
       
  • First Approved Kinase Inhibitor for AML
    • Abstract: Publication date: 16 November 2017
      Source:Cell, Volume 171, Issue 5
      Author(s): John E.J. Rasko, Timothy P. Hughes
      Activating mutations of FLT3 occur in about 30% of acute myeloid leukemia (AML) cases and are associated with relapse and poor prognosis. Midostaurin is the first drug approved for AML since 2000, and the first multi-kinase inhibitor approved for the FLT3-mutant subtype. To view this Bench to Bedside, open or download the PDF.
      Teaser Activating mutations of FLT3 occur in about 30% of acute myeloid leukemia (AML) cases and are associated with relapse and poor prognosis. Midostaurin is the first drug approved for AML since 2000, and the first multi-kinase inhibitor approved for the FLT3-mutant subtype. To view this Bench to Bedside, open or download the PDF.

      PubDate: 2017-11-28T06:04:06Z
       
  • Core Clinical Data Elements for Cancer Genomic Repositories: A
           Multi-stakeholder Consensus
    • Abstract: Publication date: 16 November 2017
      Source:Cell, Volume 171, Issue 5
      Author(s): Robert B. Conley, Dane Dickson, Jean Claude Zenklusen, Jennifer Al Naber, Donna A. Messner, Ajlan Atasoy, Lena Chaihorsky, Deborah Collyar, Carolyn Compton, Martin Ferguson, Sean Khozin, Roger D. Klein, Sri Kotte, Razelle Kurzrock, C. Jimmy Lin, Frank Liu, Ingrid Marino, Robert McDonough, Amy McNeal, Vincent Miller, Richard L. Schilsky, Lisa I. Wang
      The Center for Medical Technology Policy and the Molecular Evidence Development Consortium gathered a diverse group of more than 50 stakeholders to develop consensus on a core set of data elements and values essential to understanding the clinical utility of molecularly targeted therapies in oncology.
      Teaser The Center for Medical Technology Policy and the Molecular Evidence Development Consortium gathered a diverse group of more than 50 stakeholders to develop consensus on a core set of data elements and values essential to understanding the clinical utility of molecularly targeted therapies in oncology.

      PubDate: 2017-11-28T06:04:06Z
       
  • Cancer Evolution: No Room for Negative Selection
    • Abstract: Publication date: 16 November 2017
      Source:Cell, Volume 171, Issue 5
      Author(s): Samuel F. Bakhoum, Dan A. Landau
      In this issue of Cell, Martincorena et al. and Campbell et al. interrogated the selection dynamics during tumor evolution using large-scale genomics datasets. They found that somatic mutations in cancer are largely neutral, highlighting a near-complete absence of negative selection. Neutral evolution enables tolerance of hypermutation, which defines a surprisingly large fraction of adult cancer.
      Teaser In this issue of Cell, Martincorena et al. and Campbell et al. interrogated the selection dynamics during tumor evolution using large-scale genomics datasets. They found that somatic mutations in cancer are largely neutral, highlighting a near-complete absence of negative selection. Neutral evolution enables tolerance of hypermutation, which defines a surprisingly large fraction of adult cancer.

      PubDate: 2017-11-28T06:04:06Z
       
  • Tuning Biased GPCR Signaling for Physiological Gain
    • Abstract: Publication date: 16 November 2017
      Source:Cell, Volume 171, Issue 5
      Author(s): Skylar Spangler, Michael R. Bruchas
      Effective and safe doses of opiate painkillers, like morphine, can be limited by respiratory depression. Schmid et al. (2017) now present a quantitative method to design ligands and correlate GPCR signaling bias to the dose separation between therapeutic and adverse effects in animals.
      Teaser Effective and safe doses of opiate painkillers, like morphine, can be limited by respiratory depression. Schmid et al. (2017) now present a quantitative method to design ligands and correlate GPCR signaling bias to the dose separation between therapeutic and adverse effects in animals.

      PubDate: 2017-11-28T06:04:06Z
       
  • Risky Business: The Circuits that Impact Stress-Induced Decision-Making
    • Abstract: Publication date: 16 November 2017
      Source:Cell, Volume 171, Issue 5
      Author(s): Amy F.T. Arnsten, Daeyeol Lee, Christopher Pittenger
      How does stress promote risky decision-making' Friedman et al. find that stress disrupts inhibition of striatal circuits by prefrontal cortex, rendering animals insensitive to potential losses. This may help explain how stress contributes to substance abuse and how it can disinhibit automatic behaviors, such as tics in Tourette syndrome.
      Teaser How does stress promote risky decision-making' Friedman et al. find that stress disrupts inhibition of striatal circuits by prefrontal cortex, rendering animals insensitive to potential losses. This may help explain how stress contributes to substance abuse and how it can disinhibit automatic behaviors, such as tics in Tourette syndrome.

      PubDate: 2017-11-28T06:04:06Z
       
  • Rethinking Unconventional Translation in Neurodegeneration
    • Abstract: Publication date: 16 November 2017
      Source:Cell, Volume 171, Issue 5
      Author(s): Fen-Biao Gao, Joel D. Richter, Don W. Cleveland
      Eukaryotic translation is tightly regulated to ensure that protein production occurs at the right time and place. Recent studies on abnormal repeat proteins, especially in age-dependent neurodegenerative diseases caused by nucleotide repeat expansion, have highlighted or identified two forms of unconventional translation initiation: usage of AUG-like sites (near cognates) or repeat-associated non-AUG (RAN) translation. We discuss how repeat proteins may differ due to not just unconventional initiation, but also ribosomal frameshifting and/or imperfect repeat DNA replication, expansion, and repair, and we highlight how research on translation of repeats may uncover insights into the biology of translation and its contribution to disease.
      Teaser Recent studies on abnormal repeat proteins associated with neurodegeneration have revealed forms of unconventional translation that may shed new light into the basic biology of protein translation, as well as its contribution to disease.

      PubDate: 2017-11-28T06:04:06Z
       
  • Specification of Physiologic and Disease States by Distinct Proteins and
           Protein Conformations
    • Abstract: Publication date: 16 November 2017
      Source:Cell, Volume 171, Issue 5
      Author(s): Daniel F. Jarosz, Vikram Khurana
      Protein conformational states—from intrinsically disordered ensembles to amyloids that underlie the self-templating, infectious properties of prion-like proteins—have attracted much attention. Here, we highlight the diversity, including differences in biophysical properties, that drive distinct biological functions and pathologies among self-templating proteins. Advances in chemical genomics, gene editing, and model systems now permit deconstruction of the complex interplay between these protein states and the host factors that react to them. These methods reveal that conformational switches modulate normal and abnormal information transfer and that intimate relationships exist between the intrinsic function of proteins and the deleterious consequences of their misfolding.
      Teaser Diversity in the biophysical properties and higher-order conformations of proteins substantially impacts normal biology and disease as revealed by a number of emerging technologies”

      PubDate: 2017-11-28T06:04:06Z
       
  • Wild Mouse Gut Microbiota Promotes Host Fitness and Improves Disease
           Resistance
    • Abstract: Publication date: 16 November 2017
      Source:Cell, Volume 171, Issue 5
      Author(s): Stephan P. Rosshart, Brian G. Vassallo, Davide Angeletti, Diane S. Hutchinson, Andrew P. Morgan, Kazuyo Takeda, Heather D. Hickman, John A. McCulloch, Jonathan H. Badger, Nadim J. Ajami, Giorgio Trinchieri, Fernando Pardo-Manuel de Villena, Jonathan W. Yewdell, Barbara Rehermann
      Laboratory mice, while paramount for understanding basic biological phenomena, are limited in modeling complex diseases of humans and other free-living mammals. Because the microbiome is a major factor in mammalian physiology, we aimed to identify a naturally evolved reference microbiome to better recapitulate physiological phenomena relevant in the natural world outside the laboratory. Among 21 distinct mouse populations worldwide, we identified a closely related wild relative to standard laboratory mouse strains. Its bacterial gut microbiome differed significantly from its laboratory mouse counterpart and was transferred to and maintained in laboratory mice over several generations. Laboratory mice reconstituted with natural microbiota exhibited reduced inflammation and increased survival following influenza virus infection and improved resistance against mutagen/inflammation-induced colorectal tumorigenesis. By demonstrating the host fitness-promoting traits of natural microbiota, our findings should enable the discovery of protective mechanisms relevant in the natural world and improve the modeling of complex diseases of free-living mammals. Video
      Graphical abstract image Teaser Characterization of a wild mice reference microbiome opens a window of opportunity to understand how the gut microbiota affects aspects of host physiology that are important in the natural world outside the laboratory.

      PubDate: 2017-11-28T06:04:06Z
       
  • Universal Patterns of Selection in Cancer and Somatic Tissues
    • Abstract: Publication date: 16 November 2017
      Source:Cell, Volume 171, Issue 5
      Author(s): Iñigo Martincorena, Keiran M. Raine, Moritz Gerstung, Kevin J. Dawson, Kerstin Haase, Peter Van Loo, Helen Davies, Michael R. Stratton, Peter J. Campbell
      Cancer develops as a result of somatic mutation and clonal selection, but quantitative measures of selection in cancer evolution are lacking. We adapted methods from molecular evolution and applied them to 7,664 tumors across 29 cancer types. Unlike species evolution, positive selection outweighs negative selection during cancer development. On average, <1 coding base substitution/tumor is lost through negative selection, with purifying selection almost absent outside homozygous loss of essential genes. This allows exome-wide enumeration of all driver coding mutations, including outside known cancer genes. On average, tumors carry ∼4 coding substitutions under positive selection, ranging from <1/tumor in thyroid and testicular cancers to >10/tumor in endometrial and colorectal cancers. Half of driver substitutions occur in yet-to-be-discovered cancer genes. With increasing mutation burden, numbers of driver mutations increase, but not linearly. We systematically catalog cancer genes and show that genes vary extensively in what proportion of mutations are drivers versus passengers.
      Graphical abstract image Teaser Adapting an evolutionary genomics approach to cancer highlights a limited impact of negative selection on cancer genomes and significant variations in the proportion of coding driver mutations per tumor among different tumor types.

      PubDate: 2017-11-28T06:04:06Z
       
  • Comprehensive Analysis of Hypermutation in Human Cancer
    • Abstract: Publication date: 16 November 2017
      Source:Cell, Volume 171, Issue 5
      Author(s): Brittany B. Campbell, Nicholas Light, David Fabrizio, Matthew Zatzman, Fabio Fuligni, Richard de Borja, Scott Davidson, Melissa Edwards, Julia A. Elvin, Karl P. Hodel, Walter J. Zahurancik, Zucai Suo, Tatiana Lipman, Katharina Wimmer, Christian P. Kratz, Daniel C. Bowers, Theodore W. Laetsch, Gavin P. Dunn, Tanner M. Johanns, Matthew R. Grimmer, Ivan V. Smirnov, Valérie Larouche, David Samuel, Annika Bronsema, Michael Osborn, Duncan Stearns, Pichai Raman, Kristina A. Cole, Phillip B. Storm, Michal Yalon, Enrico Opocher, Gary Mason, Gregory A. Thomas, Magnus Sabel, Ben George, David S. Ziegler, Scott Lindhorst, Vanan Magimairajan Issai, Shlomi Constantini, Helen Toledano, Ronit Elhasid, Roula Farah, Rina Dvir, Peter Dirks, Annie Huang, Melissa A. Galati, Jiil Chung, Vijay Ramaswamy, Meredith S. Irwin, Melyssa Aronson, Carol Durno, Michael D. Taylor, Gideon Rechavi, John M. Maris, Eric Bouffet, Cynthia Hawkins, Joseph F. Costello, M. Stephen Meyn, Zachary F. Pursell, David Malkin, Uri Tabori, Adam Shlien
      We present an extensive assessment of mutation burden through sequencing analysis of >81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations. Hypermutation was detected in tumor types not previously associated with high mutation burden. Replication repair deficiency was a major contributing factor. We uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load. Unbiased clustering, based on mutational context, revealed clinically relevant subgroups regardless of the tumors’ tissue of origin, highlighting similarities in evolutionary dynamics leading to hypermutation. Mutagens, such as UV light, were implicated in unexpected cancers, including sarcomas and lung tumors. The order of mutational signatures identified previous treatment and germline replication repair deficiency, which improved management of patients and families. These data will inform tumor classification, genetic testing, and clinical trial design.
      Graphical abstract image Teaser A large-scale analysis of hypermutation in human cancers provides insights into tumor evolution dynamics and identifies clinically actionable mutation signatures.

      PubDate: 2017-11-28T06:04:06Z
       
  • Oxysterol Restraint of Cholesterol Synthesis Prevents AIM2 Inflammasome
           Activation
    • Abstract: Publication date: 16 November 2017
      Source:Cell, Volume 171, Issue 5
      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: 2017-11-28T06:04:06Z
       
  • Structural Basis of Mitochondrial Transcription Initiation
    • Abstract: Publication date: 16 November 2017
      Source:Cell, Volume 171, Issue 5
      Author(s): Hauke S. Hillen, Yaroslav I. Morozov, Azadeh Sarfallah, Dmitry Temiakov, Patrick Cramer
      Transcription in human mitochondria is driven by a single-subunit, factor-dependent RNA polymerase (mtRNAP). Despite its critical role in both expression and replication of the mitochondrial genome, transcription initiation by mtRNAP remains poorly understood. Here, we report crystal structures of human mitochondrial transcription initiation complexes assembled on both light and heavy strand promoters. The structures reveal how transcription factors TFAM and TFB2M assist mtRNAP to achieve promoter-dependent initiation. TFAM tethers the N-terminal region of mtRNAP to recruit the polymerase to the promoter whereas TFB2M induces structural changes in mtRNAP to enable promoter opening and trapping of the DNA non-template strand. Structural comparisons demonstrate that the initiation mechanism in mitochondria is distinct from that in the well-studied nuclear, bacterial, or bacteriophage transcription systems but that similarities are found on the topological and conceptual level. These results provide a framework for studying the regulation of gene expression and DNA replication in mitochondria.
      Graphical abstract image Teaser A structural view of human mitochondrial transcription initiation gives new insights into its unique mechanism and regulation.

      PubDate: 2017-11-28T06:04:06Z
       
  • Mechanism of Transcription Anti-termination in Human Mitochondria
    • Abstract: Publication date: 16 November 2017
      Source:Cell, Volume 171, Issue 5
      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: 2017-11-28T06:04:06Z
       
  • NRF1 Is an ER Membrane Sensor that Is Central to Cholesterol Homeostasis
    • Abstract: Publication date: 16 November 2017
      Source:Cell, Volume 171, Issue 5
      Author(s): Scott B. Widenmaier, Nicole A. Snyder, Truc B. Nguyen, Alessandro Arduini, Grace Y. Lee, Ana Paula Arruda, Jani Saksi, Alexander Bartelt, Gökhan S. Hotamisligil
      Cholesterol is a critical nutrient requiring tight constraint in the endoplasmic reticulum (ER) due to its uniquely challenging biophysical properties. While the mechanisms by which the ER defends against cholesterol insufficiency are well described, it remains unclear how the ER senses and effectively defends against cholesterol excess. Here, we identify the ER-bound transcription factor nuclear factor erythroid 2 related factor-1, Nrf1/Nfe2L1, as a critical mediator of this process. We show that Nrf1 directly binds to and specifically senses cholesterol in the ER through a defined domain and that cholesterol regulates Nrf1 turnover, processing, localization, and activity. In Nrf1 deficiency, in vivo cholesterol challenges induce massive hepatic cholesterol accumulation and damage, which is rescued by replacing Nrf1 exogenously. This Nrf1-mediated mechanism involves the suppression of CD36-driven inflammatory signaling and derepression of liver X receptor activity. These findings reveal Nrf1 as a guardian of cholesterol homeostasis and a core component of adaptive responses to excess cellular cholesterol.
      Graphical abstract image Teaser An ER-bound factor, Nrf1, senses and responds to excess cellular cholesterol levels by modulating hepatic inflammatory signaling and adaptive metabolic responses.

      PubDate: 2017-11-28T06:04:06Z
       
  • Precise Editing at DNA Replication Forks Enables Multiplex Genome
           Engineering in Eukaryotes
    • Abstract: Publication date: Available online 16 November 2017
      Source:Cell
      Author(s): Edward M. Barbieri, Paul Muir, Benjamin O. Akhuetie-Oni, Christopher M. Yellman, Farren J. Isaacs
      We describe a multiplex genome engineering technology in Saccharomyces cerevisiae based on annealing synthetic oligonucleotides at the lagging strand of DNA replication. The mechanism is independent of Rad51-directed homologous recombination and avoids the creation of double-strand DNA breaks, enabling precise chromosome modifications at single base-pair resolution with an efficiency of >40%, without unintended mutagenic changes at the targeted genetic loci. We observed the simultaneous incorporation of up to 12 oligonucleotides with as many as 60 targeted mutations in one transformation. Iterative transformations of a complex pool of oligonucleotides rapidly produced large combinatorial genomic diversity >105. This method was used to diversify a heterologous β-carotene biosynthetic pathway that produced genetic variants with precise mutations in promoters, genes, and terminators, leading to altered carotenoid levels. Our approach of engineering the conserved processes of DNA replication, repair, and recombination could be automated and establishes a general strategy for multiplex combinatorial genome engineering in eukaryotes.
      Graphical abstract image Teaser Replication forks can be co-opted to introduce multisite mutations in eukaryotic genomes without the need for DNA double-strand break.

      PubDate: 2017-11-28T06:04:06Z
       
  • Efficient Generation of Transcriptomic Profiles by Random Composite
           Measurements
    • Abstract: Publication date: Available online 16 November 2017
      Source:Cell
      Author(s): Brian Cleary, Le Cong, Anthea Cheung, Eric S. Lander, Aviv Regev
      RNA profiles are an informative phenotype of cellular and tissue states but can be costly to generate at massive scale. Here, we describe how gene expression levels can be efficiently acquired with random composite measurements—in which abundances are combined in a random weighted sum. We show (1) that the similarity between pairs of expression profiles can be approximated with very few composite measurements; (2) that by leveraging sparse, modular representations of gene expression, we can use random composite measurements to recover high-dimensional gene expression levels (with 100 times fewer measurements than genes); and (3) that it is possible to blindly recover gene expression from composite measurements, even without access to training data. Our results suggest new compressive modalities as a foundation for massive scaling in high-throughput measurements and new insights into the interpretation of high-dimensional data.
      Graphical abstract image Teaser A roadmap to generate a high-dimensional transcriptomic profile from sequencing a small, random selection of genes.

      PubDate: 2017-11-28T06:04:06Z
       
  • Light Controls Protein Localization through Phytochrome-Mediated
           Alternative Promoter Selection
    • Abstract: Publication date: Available online 9 November 2017
      Source:Cell
      Author(s): Tomokazu Ushijima, Kousuke Hanada, Eiji Gotoh, Wataru Yamori, Yutaka Kodama, Hiroyuki Tanaka, Miyako Kusano, Atsushi Fukushima, Mutsutomo Tokizawa, Yoshiharu Y. Yamamoto, Yasuomi Tada, Yutaka Suzuki, Tomonao Matsushita
      Alternative promoter usage is a proteome-expanding mechanism that allows multiple pre-mRNAs to be transcribed from a single gene. The impact of this mechanism on the proteome and whether it is positively exploited in normal organismal responses remain unclear. We found that the plant photoreceptor phytochrome induces genome-wide changes in alternative promoter selection in Arabidopsis thaliana. Through this mechanism, protein isoforms with different N termini are produced that display light-dependent differences in localization. For instance, shade-grown plants accumulate a cytoplasmic isoform of glycerate kinase (GLYK), an essential photorespiration enzyme that was previously thought to localize exclusively to the chloroplast. Cytoplasmic GLYK constitutes a photorespiratory bypass that alleviates fluctuating light-induced photoinhibition. Therefore, phytochrome controls alternative promoter selection to modulate protein localization in response to changing light conditions. This study suggests that alternative promoter usage represents another ubiquitous layer of gene expression regulation in eukaryotes that contributes to diversification of the proteome.
      Graphical abstract image Teaser Light signaling through phytochrome receptors changes protein localization through alternative promoter selection, allowing plants to metabolically respond to changing light conditions.

      PubDate: 2017-11-10T07:34:24Z
       
 
 
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