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Journal Cover Cell
  [SJR: 28.188]   [H-I: 616]   [710 followers]  Follow
    
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   ISSN (Print) 0092-8674 - ISSN (Online) 1097-4172
   Published by Elsevier Homepage  [3041 journals]
  • Gel or Die: Phase Separation as a Survival Strategy
    • Abstract: Publication date: 9 March 2017
      Source:Cell, Volume 168, Issue 6
      Author(s): Sonja Kroschwald, Simon Alberti
      Stress conditions trigger protein assembly by demixing from the cytoplasm, but the biological significance is still unclear. In this issue of Cell, Riback et al. report that the yeast poly(A)-binding protein 1 (Pab1) is a phase-separating stress sensor that boosts organismal fitness under physiological stress conditions.
      Teaser Stress conditions trigger protein assembly by demixing from the cytoplasm, but the biological significance is still unclear. In this issue of Cell, Riback et al. report that the yeast poly(A)-binding protein 1 (Pab1) is a phase-separating stress sensor that boosts organismal fitness under physiological stress conditions.

      PubDate: 2017-03-14T08:20:11Z
       
  • Inside the Chamber of Secrets of the Type III Secretion System
    • Abstract: Publication date: 9 March 2017
      Source:Cell, Volume 168, Issue 6
      Author(s): Eric Cascales
      The bacterial type III secretion system is a specialized machine that injects effectors into eukaryotic cells to manipulate the host cell physiology. In this issue of Cell, Hu et al. use cryo-electron tomography to reveal an unprecedented level of details regarding the architecture of this machine and the conformational changes that occur during its assembly.
      Teaser The bacterial type III secretion system is a specialized machine that injects effectors into eukaryotic cells to manipulate the host cell physiology. In this issue of Cell, Hu et al. use cryo-electron tomography to reveal an unprecedented level of details regarding the architecture of this machine and the conformational changes that occur during its assembly.

      PubDate: 2017-03-14T08:20:11Z
       
  • Transporters Revealed
    • Abstract: Publication date: 9 March 2017
      Source:Cell, Volume 168, Issue 6
      Author(s): Jyh-Yeuan Lee, Daniel M. Rosenbaum
      The subfamily C ATP-binding cassette (ABCC) transporters mediate multidrug resistance and ion conductance regulation. Recent atomic or near-atomic resolution structures of three physiologically significant ABCC transporters (MRP1, SUR1, and CFTR), determined by using single-particle cryo-electron microscopy (cryo-EM), reveal structural details that help explain the wide functional diversity of this ABC transporter subfamily.
      Teaser The subfamily C ATP-binding cassette (ABCC) transporters mediate multidrug resistance and ion conductance regulation. Recent atomic or near-atomic resolution structures of three physiologically significant ABCC transporters (MRP1, SUR1, and CFTR), determined by using single-particle cryo-electron microscopy (cryo-EM), reveal structural details that help explain the wide functional diversity of this ABC transporter subfamily.

      PubDate: 2017-03-14T08:20:11Z
       
  • Energy in Ancient Metabolism
    • Abstract: Publication date: 9 March 2017
      Source:Cell, Volume 168, Issue 6
      Author(s): William F. Martin, Rudolf K. Thauer
      Modern metabolism would not work without ATP and phosphate, but in primordial biochemical networks, energy currencies might have been simpler. Goldford et al. report a novel systems approach to reconstructing energetics in ancient metabolism, with very interesting results.
      Teaser Modern metabolism would not work without ATP and phosphate, but in primordial biochemical networks, energy currencies might have been simpler. Goldford et al. report a novel systems approach to reconstructing energetics in ancient metabolism, with very interesting results.

      PubDate: 2017-03-14T08:20:11Z
       
  • mTOR Signaling in Growth, Metabolism, and Disease
    • Abstract: Publication date: 9 March 2017
      Source:Cell, Volume 168, Issue 6
      Author(s): Robert A. Saxton, David M. Sabatini
      The mechanistic target of rapamycin (mTOR) coordinates eukaryotic cell growth and metabolism with environmental inputs, including nutrients and growth factors. Extensive research over the past two decades has established a central role for mTOR in regulating many fundamental cell processes, from protein synthesis to autophagy, and deregulated mTOR signaling is implicated in the progression of cancer and diabetes, as well as the aging process. Here, we review recent advances in our understanding of mTOR function, regulation, and importance in mammalian physiology. We also highlight how the mTOR signaling network contributes to human disease and discuss the current and future prospects for therapeutically targeting mTOR in the clinic.
      Teaser Recent advances in our understanding of mTOR regulation and functional importance highlight the contribution of mTOR-signaling network to pathogenesis in humans, raising the prospect for targeting mTOR for therapeutic development.

      PubDate: 2017-03-14T08:20:11Z
       
  • Circular Concatemers of Ultra-Short DNA Segments Produce Regulatory RNAs
    • Abstract: Publication date: 9 March 2017
      Source:Cell, Volume 168, Issue 6
      Author(s): Sarah E. Allen, Iris Hug, Sylwia Pabian, Iwona Rzeszutek, Cristina Hoehener, Mariusz Nowacki
      In the ciliated protozoan Paramecium tetraurelia, Piwi-associated small RNAs are generated upon the elimination of tens of thousands of short transposon-derived DNA segments as part of development. These RNAs then target complementary DNA for elimination in a positive feedback process, contributing to germline defense and genome stability. In this work, we investigate the formation of these RNAs, which we show to be transcribed directly from the short (length mode 27 bp) excised DNA segments. Our data support a mechanism whereby the concatenation and circularization of excised DNA segments provides a template for RNA production. This process allows the generation of a double-stranded RNA for Dicer-like protein cleavage to give rise to a population of small regulatory RNAs that precisely match the excised DNA sequences. Video
      Graphical abstract image Teaser “Junk” DNA can be ligated into circles and transcribed to generate regulatory RNAs.

      PubDate: 2017-03-14T08:20:11Z
       
  • Super-Enhancer-Mediated RNA Processing Revealed by Integrative MicroRNA
           Network Analysis
    • Abstract: Publication date: 9 March 2017
      Source:Cell, Volume 168, Issue 6
      Author(s): Hiroshi I. Suzuki, Richard A. Young, Phillip A. Sharp
      Super-enhancers are an emerging subclass of regulatory regions controlling cell identity and disease genes. However, their biological function and impact on miRNA networks are unclear. Here, we report that super-enhancers drive the biogenesis of master miRNAs crucial for cell identity by enhancing both transcription and Drosha/DGCR8-mediated primary miRNA (pri-miRNA) processing. Super-enhancers, together with broad H3K4me3 domains, shape a tissue-specific and evolutionarily conserved atlas of miRNA expression and function. CRISPR/Cas9 genomics revealed that super-enhancer constituents act cooperatively and facilitate Drosha/DGCR8 recruitment and pri-miRNA processing to boost cell-specific miRNA production. The BET-bromodomain inhibitor JQ1 preferentially inhibits super-enhancer-directed cotranscriptional pri-miRNA processing. Furthermore, super-enhancers are characterized by pervasive interaction with DGCR8/Drosha and DGCR8/Drosha-regulated mRNA stability control, suggesting unique RNA regulation at super-enhancers. Finally, super-enhancers mark multiple miRNAs associated with cancer hallmarks. This study presents principles underlying miRNA biology in health and disease and an unrecognized higher-order property of super-enhancers in RNA processing beyond transcription.
      Graphical abstract image Teaser Super-enhancers recruit components of the miRNA-processing machinery to influence its processing.

      PubDate: 2017-03-14T08:20:11Z
       
  • 5′ End Nicotinamide Adenine Dinucleotide Cap in Human Cells Promotes RNA
           Decay through DXO-Mediated deNADding
    • Abstract: Publication date: 9 March 2017
      Source:Cell, Volume 168, Issue 6
      Author(s): Xinfu Jiao, Selom K. Doamekpor, Jeremy G. Bird, Bryce E. Nickels, Liang Tong, Ronald P. Hart, Megerditch Kiledjian
      Eukaryotic mRNAs generally possess a 5′ end N7 methyl guanosine (m7G) cap that promotes their translation and stability. However, mammalian mRNAs can also carry a 5′ end nicotinamide adenine dinucleotide (NAD+) cap that, in contrast to the m7G cap, does not support translation but instead promotes mRNA decay. The mammalian and fungal noncanonical DXO/Rai1 decapping enzymes efficiently remove NAD+ caps, and cocrystal structures of DXO/Rai1 with 3′-NADP+ illuminate the molecular mechanism for how the “deNADding” reaction produces NAD+ and 5′ phosphate RNA. Removal of DXO from cells increases NAD+-capped mRNA levels and enables detection of NAD+-capped intronic small nucleolar RNAs (snoRNAs), suggesting NAD+ caps can be added to 5′-processed termini. Our findings establish NAD+ as an alternative mammalian RNA cap and DXO as a deNADding enzyme modulating cellular levels of NAD+-capped RNAs. Collectively, these data reveal that mammalian RNAs can harbor a 5′ end modification distinct from the classical m7G cap that promotes rather than inhibits RNA decay.
      Graphical abstract image Teaser NAD+ caps destabilize eukaryotic mRNAs and snoRNAs.

      PubDate: 2017-03-14T08:20:11Z
       
  • Stress-Triggered Phase Separation Is an Adaptive, Evolutionarily Tuned
           Response
    • Abstract: Publication date: 9 March 2017
      Source:Cell, Volume 168, Issue 6
      Author(s): Joshua A. Riback, Christopher D. Katanski, Jamie L. Kear-Scott, Evgeny V. Pilipenko, Alexandra E. Rojek, Tobin R. Sosnick, D. Allan Drummond
      In eukaryotic cells, diverse stresses trigger coalescence of RNA-binding proteins into stress granules. In vitro, stress-granule-associated proteins can demix to form liquids, hydrogels, and other assemblies lacking fixed stoichiometry. Observing these phenomena has generally required conditions far removed from physiological stresses. We show that poly(A)-binding protein (Pab1 in yeast), a defining marker of stress granules, phase separates and forms hydrogels in vitro upon exposure to physiological stress conditions. Other RNA-binding proteins depend upon low-complexity regions (LCRs) or RNA for phase separation, whereas Pab1’s LCR is not required for demixing, and RNA inhibits it. Based on unique evolutionary patterns, we create LCR mutations, which systematically tune its biophysical properties and Pab1 phase separation in vitro and in vivo. Mutations that impede phase separation reduce organism fitness during prolonged stress. Poly(A)-binding protein thus acts as a physiological stress sensor, exploiting phase separation to precisely mark stress onset, a broadly generalizable mechanism.
      Graphical abstract image Teaser Demixing of an abundant RNA-binding protein into hydrogel droplets, triggered by stress-associated physiological conditions, promotes cell fitness during stress.

      PubDate: 2017-03-14T08:20:11Z
       
  • Decoupling the Functional Pleiotropy of Stem Cell Factor by Tuning c-Kit
           Signaling
    • Abstract: Publication date: 9 March 2017
      Source:Cell, Volume 168, Issue 6
      Author(s): Chia Chi M. Ho, Akanksha Chhabra, Philipp Starkl, Peter-John Schnorr, Stephan Wilmes, Ignacio Moraga, Hye-Sook Kwon, Nicolas Gaudenzio, Riccardo Sibilano, Tom S. Wehrman, Milica Gakovic, Jonathan T. Sockolosky, Matthew R. Tiffany, Aaron M. Ring, Jacob Piehler, Irving L. Weissman, Stephen J. Galli, Judith A. Shizuru, K. Christopher Garcia
      Most secreted growth factors and cytokines are functionally pleiotropic because their receptors are expressed on diverse cell types. While important for normal mammalian physiology, pleiotropy limits the efficacy of cytokines and growth factors as therapeutics. Stem cell factor (SCF) is a growth factor that acts through the c-Kit receptor tyrosine kinase to elicit hematopoietic progenitor expansion but can be toxic when administered in vivo because it concurrently activates mast cells. We engineered a mechanism-based SCF partial agonist that impaired c-Kit dimerization, truncating downstream signaling amplitude. This SCF variant elicited biased activation of hematopoietic progenitors over mast cells in vitro and in vivo. Mouse models of SCF-mediated anaphylaxis, radioprotection, and hematopoietic expansion revealed that this SCF partial agonist retained therapeutic efficacy while exhibiting virtually no anaphylactic off-target effects. The approach of biasing cell activation by tuning signaling thresholds and outputs has applications to many dimeric receptor-ligand systems.
      Graphical abstract image Teaser A ligand engineering strategy is used to amplify hematopoietic stem cells but avoid unwanted off-target effects mediated by mast cells.

      PubDate: 2017-03-14T08:20:11Z
       
  • Functional Selectivity in Cytokine Signaling Revealed Through a Pathogenic
           EPO Mutation
    • Abstract: Publication date: 9 March 2017
      Source:Cell, Volume 168, Issue 6
      Author(s): Ah Ram Kim, Jacob C. Ulirsch, Stephan Wilmes, Ekrem Unal, Ignacio Moraga, Musa Karakukcu, Daniel Yuan, Shideh Kazerounian, Nour J. Abdulhay, David S. King, Namrata Gupta, Stacey B. Gabriel, Eric S. Lander, Turkan Patiroglu, Alper Ozcan, Mehmet Akif Ozdemir, K. Christopher Garcia, Jacob Piehler, Hanna T. Gazda, Daryl E. Klein, Vijay G. Sankaran
      Cytokines are classically thought to stimulate downstream signaling pathways through monotonic activation of receptors. We describe a severe anemia resulting from a homozygous mutation (R150Q) in the cytokine erythropoietin (EPO). Surprisingly, the EPO R150Q mutant shows only a mild reduction in affinity for its receptor but has altered binding kinetics. The EPO mutant is less effective at stimulating erythroid cell proliferation and differentiation, even at maximally potent concentrations. While the EPO mutant can stimulate effectors such as STAT5 to a similar extent as the wild-type ligand, there is reduced JAK2-mediated phosphorylation of select downstream targets. This impairment in downstream signaling mechanistically arises from altered receptor dimerization dynamics due to extracellular binding changes. These results demonstrate how variation in a single cytokine can lead to biased downstream signaling and can thereby cause human disease. Moreover, we have defined a distinct treatable form of anemia through mutation identification and functional studies.
      Graphical abstract image Teaser A disease-causing mutation in erythropoietin surprisingly causes only a mild change in the affinity for its receptor, but alters extracellular binding kinetics, thereby affecting downstream signaling.

      PubDate: 2017-03-14T08:20:11Z
       
  • In Situ Molecular Architecture of the Salmonella Type III Secretion
           Machine
    • Abstract: Publication date: 9 March 2017
      Source:Cell, Volume 168, Issue 6
      Author(s): Bo Hu, Maria Lara-Tejero, Qingke Kong, Jorge E. Galán, Jun Liu
      Type III protein secretion systems have specifically evolved to deliver bacterially encoded proteins into target eukaryotic cells. The core elements of this multi-protein machine are the envelope-associated needle complex, the inner membrane export apparatus, and a large cytoplasmic sorting platform. Here, we report a high-resolution in situ structure of the Salmonella Typhimurium type III secretion machine obtained by high-throughput cryo-electron tomography and sub-tomogram averaging. Through molecular modeling and comparative analysis of machines assembled with protein-tagged components or from different deletion mutants, we determined the molecular architecture of the secretion machine in situ and localized its structural components. We also show that docking of the sorting platform results in significant conformational changes in the needle complex to provide the symmetry adaptation required for the assembly of the entire secretion machine. These studies provide major insight into the structure and assembly of a broadly distributed protein secretion machine.
      Graphical abstract image Teaser The complete structure of the Salmonella type III secretion machinery explains how bacteria deliver proteins into eukaryotic cells

      PubDate: 2017-03-14T08:20:11Z
       
  • Systemic Human ILC Precursors Provide a Substrate for Tissue ILC
           Differentiation
    • Abstract: Publication date: 9 March 2017
      Source:Cell, Volume 168, Issue 6
      Author(s): Ai Ing Lim, Yan Li, Silvia Lopez-Lastra, Ralph Stadhouders, Franziska Paul, Armanda Casrouge, Nicolas Serafini, Anne Puel, Jacinta Bustamante, Laura Surace, Guillemette Masse-Ranson, Eyal David, Helene Strick-Marchand, Lionel Le Bourhis, Roberto Cocchi, Davide Topazio, Paolo Graziano, Lucia Anna Muscarella, Lars Rogge, Xavier Norel, Jean-Michel Sallenave, Matthieu Allez, Thomas Graf, Rudi W. Hendriks, Jean-Laurent Casanova, Ido Amit, Hans Yssel, James P. Di Santo
      Innate lymphoid cells (ILCs) represent innate versions of T helper and cytotoxic T cells that differentiate from committed ILC precursors (ILCPs). How ILCPs give rise to mature tissue-resident ILCs remains unclear. Here, we identify circulating and tissue ILCPs in humans that fail to express the transcription factors and cytokine outputs of mature ILCs but have these signature loci in an epigenetically poised configuration. Human ILCPs robustly generate all ILC subsets in vitro and in vivo. While human ILCPs express low levels of retinoic acid receptor (RAR)-related orphan receptor C (RORC) transcripts, these cells are found in RORC-deficient patients and retain potential for EOMES+ natural killer (NK) cells, interferon gamma-positive (IFN-γ+) ILC1s, interleukin (IL)-13+ ILC2s, and for IL-22+, but not for IL-17A+ ILC3s. Our results support a model of tissue ILC differentiation (“ILC-poiesis”), whereby diverse ILC subsets are generated in situ from systemically distributed ILCPs in response to local environmental signals.
      Graphical abstract image Teaser Human innate lymphoid cell progenitors circulate systemically, differentiating into diverse subtypes in specific tissues in response to localized cues.

      PubDate: 2017-03-14T08:20:11Z
       
  • Complement Component 3 Adapts the Cerebrospinal Fluid for Leptomeningeal
           Metastasis
    • Abstract: Publication date: 9 March 2017
      Source:Cell, Volume 168, Issue 6
      Author(s): Adrienne Boire, Yilong Zou, Jason Shieh, Danilo G. Macalinao, Elena Pentsova, Joan Massagué
      We molecularly dissected leptomeningeal metastasis, or spread of cancer to the cerebrospinal fluid (CSF), which is a frequent and fatal condition mediated by unknown mechanisms. We selected lung and breast cancer cell lines for the ability to infiltrate and grow in CSF, a remarkably acellular, mitogen-poor metastasis microenvironment. Complement component 3 (C3) was upregulated in four leptomeningeal metastatic models and proved necessary for cancer growth within the leptomeningeal space. In human disease, cancer cells within the CSF produced C3 in correlation with clinical course. C3 expression in primary tumors was predictive of leptomeningeal relapse. Mechanistically, we found that cancer-cell-derived C3 activates the C3a receptor in the choroid plexus epithelium to disrupt the blood-CSF barrier. This effect allows plasma components, including amphiregulin, and other mitogens to enter the CSF and promote cancer cell growth. Pharmacologic interference with C3 signaling proved therapeutically beneficial in suppressing leptomeningeal metastasis in these preclinical models.
      Graphical abstract image Teaser Upregulation of complement component 3 in cancer cells promotes leptomeningeal metastasis by disrupting the integrity of the blood-cerebrospinal fluid barrier, allowing cancer cells to access nutrients.

      PubDate: 2017-03-14T08:20:11Z
       
  • Remnants of an Ancient Metabolism without Phosphate
    • Abstract: Publication date: Available online 2 March 2017
      Source:Cell
      Author(s): Joshua E. Goldford, Hyman Hartman, Temple F. Smith, Daniel Segrè
      Phosphate is essential for all living systems, serving as a building block of genetic and metabolic machinery. However, it is unclear how phosphate could have assumed these central roles on primordial Earth, given its poor geochemical accessibility. We used systems biology approaches to explore the alternative hypothesis that a protometabolism could have emerged prior to the incorporation of phosphate. Surprisingly, we identified a cryptic phosphate-independent core metabolism producible from simple prebiotic compounds. This network is predicted to support the biosynthesis of a broad category of key biomolecules. Its enrichment for enzymes utilizing iron-sulfur clusters, and the fact that thermodynamic bottlenecks are more readily overcome by thioester rather than phosphate couplings, suggest that this network may constitute a “metabolic fossil” of an early phosphate-free nonenzymatic biochemistry. Our results corroborate and expand previous proposals that a putative thioester-based metabolism could have predated the incorporation of phosphate and an RNA-based genetic system. PaperClip
      Graphical abstract image Teaser Could ancient metabolic networks, prior to the incorporation of phosphate, have led to the emergence of living systems?

      PubDate: 2017-03-06T15:37:33Z
       
  • Inefficient Crossover Maturation Underlies Elevated Aneuploidy in Human
           Female Meiosis
    • Abstract: Publication date: Available online 2 March 2017
      Source:Cell
      Author(s): Shunxin Wang, Terry Hassold, Patricia Hunt, Martin A. White, Denise Zickler, Nancy Kleckner, Liangran Zhang
      Meiosis is the cellular program that underlies gamete formation. For this program, crossovers between homologous chromosomes play an essential mechanical role to ensure regular segregation. We present a detailed study of crossover formation in human male and female meiosis, enabled by modeling analysis. Results suggest that recombination in the two sexes proceeds analogously and efficiently through most stages. However, specifically in female (but not male), ∼25% of the intermediates that should mature into crossover products actually fail to do so. Further, this “female-specific crossover maturation inefficiency” is inferred to make major contributions to the high level of chromosome mis-segregation and resultant aneuploidy that uniquely afflicts human female oocytes (e.g., giving Down syndrome). Additionally, crossover levels on different chromosomes in the same nucleus tend to co-vary, an effect attributable to global per-nucleus modulation of chromatin loop size. Maturation inefficiency could potentially reflect an evolutionary advantage of increased aneuploidy for human females.
      Graphical abstract image Teaser Human female meiosis exhibits inefficient maturation of crossovers. This effect, alone and in synergy with other features, promotes high frequencies of aneuploid eggs.

      PubDate: 2017-03-06T15:37:33Z
       
  • An Intestinal Organ Culture System Uncovers a Role for the Nervous System
           in Microbe-Immune Crosstalk
    • Abstract: Publication date: Available online 2 March 2017
      Source:Cell
      Author(s): Nissan Yissachar, Yan Zhou, Lloyd Ung, Nicole Y. Lai, James F. Mohan, Allen Ehrlicher, David A. Weitz, Dennis L. Kasper, Isaac M. Chiu, Diane Mathis, Christophe Benoist
      Investigation of host-environment interactions in the gut would benefit from a culture system that maintained tissue architecture yet allowed tight experimental control. We devised a microfabricated organ culture system that viably preserves the normal multicellular composition of the mouse intestine, with luminal flow to control perturbations (e.g., microbes, drugs). It enables studying short-term responses of diverse gut components (immune, neuronal, etc.). We focused on the early response to bacteria that induce either Th17 or RORg+ T-regulatory (Treg) cells in vivo. Transcriptional responses partially reproduced in vivo signatures, but these microbes elicited diametrically opposite changes in expression of a neuronal-specific gene set, notably nociceptive neuropeptides. We demonstrated activation of sensory neurons by microbes, correlating with RORg+ Treg induction. Colonic RORg+ Treg frequencies increased in mice lacking TAC1 neuropeptide precursor and decreased in capsaicin-diet fed mice. Thus, differential engagement of the enteric nervous system may partake in bifurcating pro- or anti-inflammatory responses to microbes.
      Graphical abstract image Teaser A 3D organ culture system preserves the intestine architecture and allows modeling the interactions between intestinal cells, the immune system, microbes, and nutrients.

      PubDate: 2017-03-06T15:37:33Z
       
  • Toward a Global BRAIN Initiative
    • Abstract: Publication date: Available online 27 February 2017
      Source:Cell
      Author(s): Rafael Yuste, Cori Bargmann
      Neuroscience is entering a collaborative era in which powerful new technologies, generated by large scientific projects in many countries, will have a dramatic impact on science, medicine, and society. Coordinating these international initiatives and ensuring broad distribution of novel technologies and open accessibility of the generated data will multiply their value, while tapping creativity and expertise from every source.
      Teaser Neuroscience is entering a “big science” era in which powerful new technologies, generated by large scientific projects in many countries, will have a dramatic impact on science, medicine, and society. Coordinating these international initiatives and ensuring broad distribution of novel technologies and open accessibility of the generated data will multiply their value, while tapping creativity and expertise from every source.

      PubDate: 2017-03-01T00:52:43Z
       
  • Oliver Smithies (1925–2017)
    • Abstract: Publication date: 23 February 2017
      Source:Cell, Volume 168, Issue 5
      Author(s): Beverly H. Koller


      PubDate: 2017-03-01T00:52:43Z
       
  • Postdocs, What Would You Tell Your Younger Self?
    • Abstract: Publication date: 23 February 2017
      Source:Cell, Volume 168, Issue 5
      Looking back at the time spent in graduate school and postdoctoral training can be illuminating. We asked postdoctoral researchers to tell us what kind of advice they would give to their younger selves.
      Teaser Looking back at your time spent in graduate school and postdoctoral training can be illuminating. We asked postdoctoral researchers to tell us what kind of advice they would give to their younger selves.

      PubDate: 2017-03-01T00:52:43Z
       
  • Doubling Down on Mutant RAS Can MEK or Break Leukemia
    • Abstract: Publication date: 23 February 2017
      Source:Cell, Volume 168, Issue 5
      Author(s): Zuzana Tothova, Benjamin L. Ebert
      Targeting of the RAS pathway has long been a critical therapeutic challenge in oncology. Burgess et al. examine how the relative expression of mutant and wild-type KRAS modulates clonal fitness and sensitivity to MEK inhibitors in a model of Kras G12D mutant acute myeloid leukemia and propose its use as a predictive biomarker.
      Teaser Targeting of the RAS pathway has long been a critical therapeutic challenge in oncology. Burgess et al. examine how the relative expression of mutant and wild-type KRAS modulates clonal fitness and sensitivity to MEK inhibitors in a model of Kras G12D mutant acute myeloid leukemia and propose its use as a predictive biomarker.

      PubDate: 2017-03-01T00:52:43Z
       
  • Mutational Processes Shaping the Genome in Early Human Embryos
    • Abstract: Publication date: 23 February 2017
      Source:Cell, Volume 168, Issue 5
      Author(s): Thierry Voet, Joris R. Vermeesch
      In-vitro-fertilized human embryos often acquire large structural and numerical chromosomal abnormalities. Liu et al. now show that multiple smaller copy number variations may also arise in in-vivo-conceived embryos. Analysis of these variations provides insight into the DNA mutational processes occurring in early embryos and the mechanisms underlying them.
      Teaser In-vitro-fertilized human embryos often acquire large structural and numerical chromosomal abnormalities. Liu et al. now show that multiple smaller copy number variations may also arise in in-vivo-conceived embryos. Analysis of these variations provides insight into the DNA mutational processes occurring in early embryos and the mechanisms underlying them.

      PubDate: 2017-03-01T00:52:43Z
       
  • Linking Protein and RNA Function within the Same Gene
    • Abstract: Publication date: 23 February 2017
      Source:Cell, Volume 168, Issue 5
      Author(s): Anthony Szempruch, Mitchell Guttman
      Exposure to ultraviolet light leads to a cell-wide DNA damage response that includes a global reduction in transcription. Williamson et al., identify a protein involved in this process as well as a noncoding RNA produced by alternative processing of RNA transcribed from the same gene that promotes recovery from the repressed state.
      Teaser Exposure to ultraviolet light leads to a cell-wide DNA damage response that includes a global reduction in transcription. Williamson et al., identify a protein involved in this process as well as a noncoding RNA produced by alternative processing of RNA transcribed from the same gene that promotes recovery from the repressed state.

      PubDate: 2017-03-01T00:52:43Z
       
  • What Came First—the Virus or the Egg?
    • Abstract: Publication date: 23 February 2017
      Source:Cell, Volume 168, Issue 5
      Author(s): Robert W. Doms
      Three recent studies find that the single-pass transmembrane protein HAP2 mediates gamete fusion and is remarkably similar to class II fusion proteins found in viruses such as dengue and Zika.
      Teaser Three recent studies find that the single-pass transmembrane protein HAP2, which has a universal role in mediating gamete fusion is remarkably similar to class II fusion proteins found in viruses such as Dengue and Zika.

      PubDate: 2017-03-01T00:52:43Z
       
  • Gut-Brain Cross-Talk in Metabolic Control
    • Abstract: Publication date: 23 February 2017
      Source:Cell, Volume 168, Issue 5
      Author(s): Christoffer Clemmensen, Timo D. Müller, Stephen C. Woods, Hans-Rudolf Berthoud, Randy J. Seeley, Matthias H. Tschöp
      Because human energy metabolism evolved to favor adiposity over leanness, the availability of palatable, easily attainable, and calorically dense foods has led to unprecedented levels of obesity and its associated metabolic co-morbidities that appear resistant to traditional lifestyle interventions. However, recent progress identifying the molecular signaling pathways through which the brain and the gastrointestinal system communicate to govern energy homeostasis, combined with emerging insights on the molecular mechanisms underlying successful bariatric surgery, gives reason to be optimistic that novel precision medicines that mimic, enhance, and/or modulate gut-brain signaling can have unprecedented potential for stopping the obesity and type 2 diabetes pandemics.
      Teaser Signaling between the brain and the gastrointestinal system is essential for energy homeostasis, with imbalances in gut-brain signaling being linked to diseases such as type 2 diabetes and obesity.

      PubDate: 2017-03-01T00:52:43Z
       
  • Fasting-Mimicking Diet Promotes Ngn3-Driven β-Cell Regeneration to
           Reverse Diabetes
    • Abstract: Publication date: 23 February 2017
      Source:Cell, Volume 168, Issue 5
      Author(s): Chia-Wei Cheng, Valentina Villani, Roberta Buono, Min Wei, Sanjeev Kumar, Omer H. Yilmaz, Pinchas Cohen, Julie B. Sneddon, Laura Perin, Valter D. Longo
      Stem-cell-based therapies can potentially reverse organ dysfunction and diseases, but the removal of impaired tissue and activation of a program leading to organ regeneration pose major challenges. In mice, a 4-day fasting mimicking diet (FMD) induces a stepwise expression of Sox17 and Pdx-1, followed by Ngn3-driven generation of insulin-producing β cells, resembling that observed during pancreatic development. FMD cycles restore insulin secretion and glucose homeostasis in both type 2 and type 1 diabetes mouse models. In human type 1 diabetes pancreatic islets, fasting conditions reduce PKA and mTOR activity and induce Sox2 and Ngn3 expression and insulin production. The effects of the FMD are reversed by IGF-1 treatment and recapitulated by PKA and mTOR inhibition. These results indicate that a FMD promotes the reprogramming of pancreatic cells to restore insulin generation in islets from T1D patients and reverse both T1D and T2D phenotypes in mouse models. PaperClip
      Graphical abstract image Teaser A periodic short-term diet that mimics fasting modulates β-cell regeneration and promotes insulin secretion and glucose homeostasis with potential to treat both type 1 and type 2 diabetes.

      PubDate: 2017-03-01T00:52:43Z
       
  • Human Adaptive Immunity Rescues an Inborn Error of Innate Immunity
    • Abstract: Publication date: 23 February 2017
      Source:Cell, Volume 168, Issue 5
      Author(s): Laura Israel, Ying Wang, Katarzyna Bulek, Erika Della Mina, Zhao Zhang, Vincent Pedergnana, Maya Chrabieh, Nicole A. Lemmens, Vanessa Sancho-Shimizu, Marc Descatoire, Théo Lasseau, Elisabeth Israelsson, Lazaro Lorenzo, Ling Yun, Aziz Belkadi, Andrew Moran, Leonard E. Weisman, François Vandenesch, Frederic Batteux, Sandra Weller, Michael Levin, Jethro Herberg, Avinash Abhyankar, Carolina Prando, Yuval Itan, Willem J.B. van Wamel, Capucine Picard, Laurent Abel, Damien Chaussabel, Xiaoxia Li, Bruce Beutler, Peter D. Arkwright, Jean-Laurent Casanova, Anne Puel
      The molecular basis of the incomplete penetrance of monogenic disorders is unclear. We describe here eight related individuals with autosomal recessive TIRAP deficiency. Life-threatening staphylococcal disease occurred during childhood in the proband, but not in the other seven homozygotes. Responses to all Toll-like receptor 1/2 (TLR1/2), TLR2/6, and TLR4 agonists were impaired in the fibroblasts and leukocytes of all TIRAP-deficient individuals. However, the whole-blood response to the TLR2/6 agonist staphylococcal lipoteichoic acid (LTA) was abolished only in the index case individual, the only family member lacking LTA-specific antibodies (Abs). This defective response was reversed in the patient, but not in interleukin-1 receptor-associated kinase 4 (IRAK-4)-deficient individuals, by anti-LTA monoclonal antibody (mAb). Anti-LTA mAb also rescued the macrophage response in mice lacking TIRAP, but not TLR2 or MyD88. Thus, acquired anti-LTA Abs rescue TLR2-dependent immunity to staphylococcal LTA in individuals with inherited TIRAP deficiency, accounting for incomplete penetrance. Combined TIRAP and anti-LTA Ab deficiencies underlie staphylococcal disease in this patient.
      Graphical abstract image Teaser Adaptive immunity can compensate for a defect in the innate immune response, as seen with humans lacking a key TLR adaptor who can mount an antibody response to a bacterial pathogen.

      PubDate: 2017-03-01T00:52:43Z
       
  • An Organismal CNV Mutator Phenotype Restricted to Early Human Development
    • Abstract: Publication date: 23 February 2017
      Source:Cell, Volume 168, Issue 5
      Author(s): Pengfei Liu, Bo Yuan, Claudia M.B. Carvalho, Arthur Wuster, Klaudia Walter, Ling Zhang, Tomasz Gambin, Zechen Chong, Ian M. Campbell, Zeynep Coban Akdemir, Violet Gelowani, Karin Writzl, Carlos A. Bacino, Sarah J. Lindsay, Marjorie Withers, Claudia Gonzaga-Jauregui, Joanna Wiszniewska, Jennifer Scull, Paweł Stankiewicz, Shalini N. Jhangiani, Donna M. Muzny, Feng Zhang, Ken Chen, Richard A. Gibbs, Bernd Rautenstrauss, Sau Wai Cheung, Janice Smith, Amy Breman, Chad A. Shaw, Ankita Patel, Matthew E. Hurles, James R. Lupski
      De novo copy number variants (dnCNVs) arising at multiple loci in a personal genome have usually been considered to reflect cancer somatic genomic instabilities. We describe a multiple dnCNV (MdnCNV) phenomenon in which individuals with genomic disorders carry five to ten constitutional dnCNVs. These CNVs originate from independent formation incidences, are predominantly tandem duplications or complex gains, exhibit breakpoint junction features reminiscent of replicative repair, and show increased de novo point mutations flanking the rearrangement junctions. The active CNV mutation shower appears to be restricted to a transient perizygotic period. We propose that a defect in the CNV formation process is responsible for the “CNV-mutator state,” and this state is dampened after early embryogenesis. The constitutional MdnCNV phenomenon resembles chromosomal instability in various cancers. Investigations of this phenomenon may provide unique access to understanding genomic disorders, structural variant mutagenesis, human evolution, and cancer biology.
      Graphical abstract image Teaser Occurrence of multiple independent de novo copy number variants in individuals with developmental disorders points to a window in early development permissive to large-scale chromosomal rearrangements.

      PubDate: 2017-03-01T00:52:43Z
       
  • Structure of the Adenosine A1 Receptor Reveals the Basis for Subtype
           Selectivity
    • Abstract: Publication date: 23 February 2017
      Source:Cell, Volume 168, Issue 5
      Author(s): Alisa Glukhova, David M. Thal, Anh T. Nguyen, Elizabeth A. Vecchio, Manuela Jörg, Peter J. Scammells, Lauren T. May, Patrick M. Sexton, Arthur Christopoulos
      The adenosine A1 receptor (A1-AR) is a G-protein-coupled receptor that plays a vital role in cardiac, renal, and neuronal processes but remains poorly targeted by current drugs. We determined a 3.2 Å crystal structure of the A1-AR bound to the selective covalent antagonist, DU172, and identified striking differences to the previously solved adenosine A2A receptor (A2A-AR) structure. Mutational and computational analysis of A1-AR revealed a distinct conformation of the second extracellular loop and a wider extracellular cavity with a secondary binding pocket that can accommodate orthosteric and allosteric ligands. We propose that conformational differences in these regions, rather than amino-acid divergence, underlie drug selectivity between these adenosine receptor subtypes. Our findings provide a molecular basis for AR subtype selectivity with implications for understanding the mechanisms governing allosteric modulation of these receptors, allowing the design of more selective agents for the treatment of ischemia-reperfusion injury, renal pathologies, and neuropathic pain.
      Graphical abstract image Teaser The structure of the adenosine receptor A1 provides insights into the ways selectivity among adenosine receptor subtypes is achieved, opening avenues for design of subtype-specific drugs.

      PubDate: 2017-03-01T00:52:43Z
       
  • Multivalent Small-Molecule Pan-RAS Inhibitors
    • Abstract: Publication date: 23 February 2017
      Source:Cell, Volume 168, Issue 5
      Author(s): Matthew E. Welsch, Anna Kaplan, Jennifer M. Chambers, Michael E. Stokes, Pieter H. Bos, Arie Zask, Yan Zhang, Marta Sanchez-Martin, Michael A. Badgley, Christine S. Huang, Timothy H. Tran, Hemanth Akkiraju, Lewis M. Brown, Renu Nandakumar, Serge Cremers, Wan Seok Yang, Liang Tong, Kenneth P. Olive, Adolfo Ferrando, Brent R. Stockwell
      Design of small molecules that disrupt protein-protein interactions, including the interaction of RAS proteins and their effectors, may provide chemical probes and therapeutic agents. We describe here the synthesis and testing of potential small-molecule pan-RAS ligands, which were designed to interact with adjacent sites on the surface of oncogenic KRAS. One compound, termed 3144, was found to bind to RAS proteins using microscale thermophoresis, nuclear magnetic resonance spectroscopy, and isothermal titration calorimetry and to exhibit lethality in cells partially dependent on expression of RAS proteins. This compound was metabolically stable in liver microsomes and displayed anti-tumor activity in xenograft mouse cancer models. These findings suggest that pan-RAS inhibition may be an effective therapeutic strategy for some cancers and that structure-based design of small molecules targeting multiple adjacent sites to create multivalent inhibitors may be effective for some proteins.
      Graphical abstract image Teaser A computational design approach yields multivalent pan-RAS inhibitors.

      PubDate: 2017-03-01T00:52:43Z
       
  • The Ancient Gamete Fusogen HAP2 Is a Eukaryotic Class II Fusion Protein
    • Abstract: Publication date: 23 February 2017
      Source:Cell, Volume 168, Issue 5
      Author(s): Juliette Fédry, Yanjie Liu, Gérard Péhau-Arnaudet, Jimin Pei, Wenhao Li, M. Alejandra Tortorici, François Traincard, Annalisa Meola, Gérard Bricogne, Nick V. Grishin, William J. Snell, Félix A. Rey, Thomas Krey
      Sexual reproduction is almost universal in eukaryotic life and involves the fusion of male and female haploid gametes into a diploid cell. The sperm-restricted single-pass transmembrane protein HAP2-GCS1 has been postulated to function in membrane merger. Its presence in the major eukaryotic taxa—animals, plants, and protists (including important human pathogens like Plasmodium)—suggests that many eukaryotic organisms share a common gamete fusion mechanism. Here, we report combined bioinformatic, biochemical, mutational, and X-ray crystallographic studies on the unicellular alga Chlamydomonas reinhardtii HAP2 that reveal homology to class II viral membrane fusion proteins. We further show that targeting the segment corresponding to the fusion loop by mutagenesis or by antibodies blocks gamete fusion. These results demonstrate that HAP2 is the gamete fusogen and suggest a mechanism of action akin to viral fusion, indicating a way to block Plasmodium transmission and highlighting the impact of virus-cell genetic exchanges on the evolution of eukaryotic life.
      Graphical abstract image Teaser Gamete fusion across eukaryotic branches uses an ancient factor homologous to viral fusion proteins.

      PubDate: 2017-03-01T00:52:43Z
       
  • Impacts of Neanderthal-Introgressed Sequences on the Landscape of Human
           Gene Expression
    • Abstract: Publication date: 23 February 2017
      Source:Cell, Volume 168, Issue 5
      Author(s): Rajiv C. McCoy, Jon Wakefield, Joshua M. Akey
      Regulatory variation influencing gene expression is a key contributor to phenotypic diversity, both within and between species. Unfortunately, RNA degrades too rapidly to be recovered from fossil remains, limiting functional genomic insights about our extinct hominin relatives. Many Neanderthal sequences survive in modern humans due to ancient hybridization, providing an opportunity to assess their contributions to transcriptional variation and to test hypotheses about regulatory evolution. We developed a flexible Bayesian statistical approach to quantify allele-specific expression (ASE) in complex RNA-seq datasets. We identified widespread expression differences between Neanderthal and modern human alleles, indicating pervasive cis-regulatory impacts of introgression. Brain regions and testes exhibited significant downregulation of Neanderthal alleles relative to other tissues, consistent with natural selection influencing the tissue-specific regulatory landscape. Our study demonstrates that Neanderthal-inherited sequences are not silent remnants of ancient interbreeding but have measurable impacts on gene expression that contribute to variation in modern human phenotypes.
      Graphical abstract image Teaser Genome-wide interrogation of the functional differences between modern human and Neanderthal alleles reveals that Neanderthal-inherited sequences are not silent remnants of ancient interbreeding but have a measurable impact on gene expression that may contribute to phenotypic variation in modern humans.

      PubDate: 2017-03-01T00:52:43Z
       
  • Widespread Proteome Remodeling and Aggregation in Aging C. elegans
    • Abstract: Publication date: 23 February 2017
      Source:Cell, Volume 168, Issue 5
      Author(s): Dirk M. Walther, Prasad Kasturi, Min Zheng, Stefan Pinkert, Giulia Vecchi, Prajwal Ciryam, Richard I. Morimoto, Christopher M. Dobson, Michele Vendruscolo, Matthias Mann, F. Ulrich Hartl


      PubDate: 2017-03-01T00:52:43Z
       
  • Epigenetic Memory Underlies Cell-Autonomous Heterogeneous Behavior of
           Hematopoietic Stem Cells
    • Abstract: Publication date: 23 February 2017
      Source:Cell, Volume 168, Issue 5
      Author(s): Vionnie W.C. Yu, Rushdia Z. Yusuf, Toshihiko Oki, Juwell Wu, Borja Saez, Xin Wang, Colleen Cook, Ninib Baryawno, Michael J. Ziller, Eunjung Lee, Hongcang Gu, Alexander Meissner, Charles P. Lin, Peter V. Kharchenko, David T. Scadden


      PubDate: 2017-03-01T00:52:43Z
       
  • SnapShot: Class 1 CRISPR-Cas Systems
    • Abstract: Publication date: 23 February 2017
      Source:Cell, Volume 168, Issue 5
      Author(s): Kira S. Makarova, Feng Zhang, Eugene V. Koonin
      Class 1 CRISPR-Cas systems are characterized by effector modules consisting of multiple subunits. Class 1 systems comprise about 90% of all CRISPR-Cas loci identified in bacteria and archaea and can target both DNA and RNA.
      Teaser Class 1 CRISPR-Cas systems are characterized by effector modules consisting of multiple subunits. Class 1 systems comprise about 90% of all CRISPR-Cas loci identified in bacteria and archaea and can target both DNA and RNA.

      PubDate: 2017-03-01T00:52:43Z
       
  • Structural Basis of Substrate Recognition by the Multidrug Resistance
           Protein MRP1
    • Abstract: Publication date: Available online 23 February 2017
      Source:Cell
      Author(s): Zachary Lee Johnson, Jue Chen
      The multidrug resistance protein MRP1 is an ATP-binding cassette (ABC) transporter that confers resistance to many anticancer drugs and plays a role in the disposition and efficacy of several opiates, antidepressants, statins, and antibiotics. In addition, MRP1 regulates redox homeostasis, inflammation, and hormone secretion. Using electron cryomicroscopy, we determined the molecular structures of bovine MRP1 in two conformations: an apo form at 3.5 Å without any added substrate and a complex form at 3.3 Å with one of its physiological substrates, leukotriene C4. These structures show that by forming a single bipartite binding site, MRP1 can recognize a spectrum of substrates with different chemical structures. We also observed large conformational changes induced by leukotriene C4, explaining how substrate binding primes the transporter for ATP hydrolysis. Structural comparison of MRP1 and P-glycoprotein advances our understanding of the common and unique properties of these two important molecules in multidrug resistance to chemotherapy.
      Graphical abstract image Teaser Structural analysis of an ABC transporter contributing to drug efflux and resistance to cancer therapy shows how substrate binding promotes the ATP-dependent transport cycle.

      PubDate: 2017-03-01T00:52:43Z
       
  • Modified mRNA Vaccines Protect against Zika Virus Infection
    • Abstract: Publication date: Available online 17 February 2017
      Source:Cell
      Author(s): Justin M. Richner, Sunny Himansu, Kimberly A. Dowd, Scott L. Butler, Vanessa Salazar, Julie M. Fox, Justin G. Julander, William W. Tang, Sujan Shresta, Theodore C. Pierson, Giuseppe Ciaramella, Michael S. Diamond
      The emergence of ZIKV infection has prompted a global effort to develop safe and effective vaccines. We engineered a lipid nanoparticle (LNP) encapsulated modified mRNA vaccine encoding wild-type or variant ZIKV structural genes and tested immunogenicity and protection in mice. Two doses of modified mRNA LNPs encoding prM-E genes that produced virus-like particles resulted in high neutralizing antibody titers (∼1/100,000) that protected against ZIKV infection and conferred sterilizing immunity. To offset a theoretical concern of ZIKV vaccines inducing antibodies that cross-react with the related dengue virus (DENV), we designed modified prM-E RNA encoding mutations destroying the conserved fusion-loop epitope in the E protein. This variant protected against ZIKV and diminished production of antibodies enhancing DENV infection in cells or mice. A modified mRNA vaccine can prevent ZIKV disease and be adapted to reduce the risk of sensitizing individuals to subsequent exposure to DENV, should this become a clinically relevant concern.
      Graphical abstract image Teaser A modified mRNA vaccine induces sterilizing immunity against Zika virus while minimizing the generation of cross-reactive antibodies that may enhance dengue infection.

      PubDate: 2017-02-21T07:53:05Z
       
  • UV Irradiation Induces a Non-coding RNA that Functionally Opposes the
           Protein Encoded by the Same Gene
    • Abstract: Publication date: Available online 16 February 2017
      Source:Cell
      Author(s): Laura Williamson, Marco Saponaro, Stefan Boeing, Philip East, Richard Mitter, Theodoros Kantidakis, Gavin P. Kelly, Anna Lobley, Jane Walker, Bradley Spencer-Dene, Michael Howell, Aengus Stewart, Jesper Q. Svejstrup
      The transcription-related DNA damage response was analyzed on a genome-wide scale with great spatial and temporal resolution. Upon UV irradiation, a slowdown of transcript elongation and restriction of gene activity to the promoter-proximal ∼25 kb is observed. This is associated with a shift from expression of long mRNAs to shorter isoforms, incorporating alternative last exons (ALEs) that are more proximal to the transcription start site. Notably, this includes a shift from a protein-coding ASCC3 mRNA to a shorter ALE isoform of which the RNA, rather than an encoded protein, is critical for the eventual recovery of transcription. The non-coding ASCC3 isoform counteracts the function of the protein-coding isoform, indicating crosstalk between them. Thus, the ASCC3 gene expresses both coding and non-coding transcript isoforms with opposite effects on transcription recovery after UV-induced DNA damage.
      Graphical abstract image Teaser UV damage generates a functional non-coding RNA through alternative pre-mRNA processing of a damage response factor transcript, identifying a pathway for repurposing protein coding genes under selective conditions.

      PubDate: 2017-02-21T07:53:05Z
       
  • CpG Island Hypermethylation Mediated by DNMT3A Is a Consequence of AML
           Progression
    • Abstract: Publication date: Available online 16 February 2017
      Source:Cell
      Author(s): David H. Spencer, David A. Russler-Germain, Shamika Ketkar, Nichole M. Helton, Tamara L. Lamprecht, Robert S. Fulton, Catrina C. Fronick, Michelle O’Laughlin, Sharon E. Heath, Marwan Shinawi, Peter Westervelt, Jacqueline E. Payton, Lukas D. Wartman, John S. Welch, Richard K. Wilson, Matthew J. Walter, Daniel C. Link, John F. DiPersio, Timothy J. Ley
      DNMT3A mutations occur in ∼25% of acute myeloid leukemia (AML) patients. The most common mutation, DNMT3A R882H, has dominant negative activity that reduces DNA methylation activity by ∼80% in vitro. To understand the contribution of DNMT3A-dependent methylation to leukemogenesis, we performed whole-genome bisulfite sequencing of primary leukemic and non-leukemic cells in patients with or without DNMT3A R882 mutations. Non-leukemic hematopoietic cells with DNMT3A R882H displayed focal methylation loss, suggesting that hypomethylation antedates AML. Although virtually all AMLs with wild-type DNMT3A displayed CpG island hypermethylation, this change was not associated with gene silencing and was essentially absent in AMLs with DNMT3A R882 mutations. Primary hematopoietic stem cells expanded with cytokines were hypermethylated in a DNMT3A-dependent manner, suggesting that hypermethylation may be a response to, rather than a cause of, cellular proliferation. Our findings suggest that hypomethylation is an initiating phenotype in AMLs with DNMT3A R882, while DNMT3A-dependent CpG island hypermethylation is a consequence of AML progression.
      Graphical abstract image Teaser Analysis of patient-derived samples shows that CpG island hypermethylation is a consequence of AML progression rather than a driver of transcriptional gene silencing during leukemogenesis.

      PubDate: 2017-02-21T07:53:05Z
       
  • Mining the Human Gut Microbiota for Immunomodulatory Organisms
    • Abstract: Publication date: Available online 16 February 2017
      Source:Cell
      Author(s): Naama Geva-Zatorsky, Esen Sefik, Lindsay Kua, Lesley Pasman, Tze Guan Tan, Adriana Ortiz-Lopez, Tsering Bakto Yanortsang, Liang Yang, Ray Jupp, Diane Mathis, Christophe Benoist, Dennis L. Kasper
      Within the human gut reside diverse microbes coexisting with the host in a mutually advantageous relationship. Evidence has revealed the pivotal role of the gut microbiota in shaping the immune system. To date, only a few of these microbes have been shown to modulate specific immune parameters. Herein, we broadly identify the immunomodulatory effects of phylogenetically diverse human gut microbes. We monocolonized mice with each of 53 individual bacterial species and systematically analyzed host immunologic adaptation to colonization. Most microbes exerted several specialized, complementary, and redundant transcriptional and immunomodulatory effects. Surprisingly, these were independent of microbial phylogeny. Microbial diversity in the gut ensures robustness of the microbiota’s ability to generate a consistent immunomodulatory impact, serving as a highly important epigenetic system. This study provides a foundation for investigation of gut microbiota-host mutualism, highlighting key players that could identify important therapeutics.
      Graphical abstract image Teaser Each of 53 human-resident bacterial species studied in monoculture in mice modulates the host immune system, providing a baseline for investigating how consortia of gut microbes interact with their host.

      PubDate: 2017-02-21T07:53:05Z
       
  • HSP90 Shapes the Consequences of Human Genetic Variation
    • Abstract: Publication date: Available online 16 February 2017
      Source:Cell
      Author(s): Georgios I. Karras, Song Yi, Nidhi Sahni, Máté Fischer, Jenny Xie, Marc Vidal, Alan D. D’Andrea, Luke Whitesell, Susan Lindquist
      HSP90 acts as a protein-folding buffer that shapes the manifestations of genetic variation in model organisms. Whether HSP90 influences the consequences of mutations in humans, potentially modifying the clinical course of genetic diseases, remains unknown. By mining data for >1,500 disease-causing mutants, we found a strong correlation between reduced phenotypic severity and a dominant (HSP90 ≥ HSP70) increase in mutant engagement by HSP90. Examining the cancer predisposition syndrome Fanconi anemia in depth revealed that mutant FANCA proteins engaged predominantly by HSP70 had severely compromised function. In contrast, the function of less severe mutants was preserved by a dominant increase in HSP90 binding. Reducing HSP90’s buffering capacity with inhibitors or febrile temperatures destabilized HSP90-buffered mutants, exacerbating FA-related chemosensitivities. Strikingly, a compensatory FANCA somatic mutation from an “experiment of nature” in monozygotic twins both prevented anemia and reduced HSP90 binding. These findings provide one plausible mechanism for the variable expressivity and environmental sensitivity of genetic diseases.
      Graphical abstract image Teaser HSP90 buffers the effects of mutations in a set of associating proteins, resulting in reduced disease impact under normal conditions. Environmental stressors that compromise chaperone function can provoke more severe outcomes.

      PubDate: 2017-02-21T07:53:05Z
       
  • KRAS Allelic Imbalance Enhances Fitness and Modulates MAP Kinase
           Dependence in Cancer
    • Abstract: Publication date: Available online 16 February 2017
      Source:Cell
      Author(s): Michael R. Burgess, Eugene Hwang, Rana Mroue, Craig M. Bielski, Anica M. Wandler, Benjamin J. Huang, Ari J. Firestone, Amy Young, Jennifer A. Lacap, Lisa Crocker, Saurabh Asthana, Elizabeth M. Davis, Jin Xu, Keiko Akagi, Michelle M. Le Beau, Qing Li, Benjamin Haley, David Stokoe, Deepak Sampath, Barry S. Taylor, Marie Evangelista, Kevin Shannon
      Investigating therapeutic “outliers” that show exceptional responses to anti-cancer treatment can uncover biomarkers of drug sensitivity. We performed preclinical trials investigating primary murine acute myeloid leukemias (AMLs) generated by retroviral insertional mutagenesis in Kras G12D “knockin” mice with the MEK inhibitor PD0325901 (PD901). One outlier AML responded and exhibited intrinsic drug resistance at relapse. Loss of wild-type (WT) Kras enhanced the fitness of the dominant clone and rendered it sensitive to MEK inhibition. Similarly, human colorectal cancer cell lines with increased KRAS mutant allele frequency were more sensitive to MAP kinase inhibition, and CRISPR-Cas9-mediated replacement of WT KRAS with a mutant allele sensitized heterozygous mutant HCT116 cells to treatment. In a prospectively characterized cohort of patients with advanced cancer, 642 of 1,168 (55%) with KRAS mutations exhibited allelic imbalance. These studies demonstrate that serial genetic changes at the Kras/KRAS locus are frequent in cancer and modulate competitive fitness and MEK dependency.
      Graphical abstract image Teaser An imbalance in the dosage of mutant and wild-type KRAS allele shapes the trade-off between rapid cancer cell growth and resistance to MEK inhibitor therapy. This imbalance explains the challenges encountered during inhibitor trials.

      PubDate: 2017-02-21T07:53:05Z
       
  • Cancer: The Road Ahead
    • Abstract: Publication date: 9 February 2017
      Source:Cell, Volume 168, Issue 4
      Author(s): The editorial team


      PubDate: 2017-02-15T13:02:02Z
       
  • Metastasis: Slipping Control
    • Abstract: Publication date: 9 February 2017
      Source:Cell, Volume 168, Issue 4
      Author(s): Xiaohong Helena Yang


      PubDate: 2017-02-15T13:02:02Z
       
  • Getting Data Sharing Right to Help Fulfill the Promise of Cancer Genomics
    • Abstract: Publication date: 9 February 2017
      Source:Cell, Volume 168, Issue 4
      Author(s): Neil Savage
      Limited access to the profusion of sequence information derived from cancer patients worldwide stymies basic research and clinical decisions. Efforts are underway to streamline and safeguard data use.
      Teaser Limited access to the profusion of sequence information derived from cancer patients worldwide stymies basic research and clinical decisions. Efforts are underway to streamline and safeguard data use.

      PubDate: 2017-02-15T13:02:02Z
       
  • PDGFRA Antibody for Soft Tissue Sarcoma
    • Abstract: Publication date: 9 February 2017
      Source:Cell, Volume 168, Issue 4
      Author(s): Lillian R. Klug, Michael C. Heinrich
      Lartruvo (olaratumab) is a monoclonal antibody against the extracellular domain of PDGFRA. Olaratumab blocks ligand binding and thereby inhibits activation of PDGFRA kinase activity. Pre-clinically, this antibody inhibited PDGFRA-dependent tumor growth. In a randomized Phase II study, adding olaratumab to doxorubicin chemotherapy significantly improved overall survival, leading to FDA approval.
      Teaser Lartruvo (olaratumab) is a monoclonal antibody against the extracellular domain of PDGFRA. Olaratumab blocks ligand binding and thereby inhibits activation of PDGFRA kinase activity. Pre-clinically, this antibody inhibited PDGFRA-dependent tumor growth. In a randomized Phase II study, adding olaratumab to doxorubicin chemotherapy significantly improved overall survival, leading to FDA approval.

      PubDate: 2017-02-15T13:02:02Z
       
  • Poisoning the Devil
    • Abstract: Publication date: 9 February 2017
      Source:Cell, Volume 168, Issue 4
      Author(s): Zhu Chen, Sai-Juan Chen


      PubDate: 2017-02-15T13:02:02Z
       
  • A Convergence of Genetics and Epigenetics in Cancer
    • Abstract: Publication date: 9 February 2017
      Source:Cell, Volume 168, Issue 4
      What is at the forefront of the intersection of genetics and epigenetics in cancer and how do we use what we’ve learned to devise new cures' These are the questions Cell editor Jiaying Tan posed to Jan Korbel and Charles Roberts. Annotated excerpts from this conversation are presented below, and the full conversation is available with the article online.
      Teaser What is at the forefront of the intersection of genetics and epigenetics in cancer and how do we use what we’ve learned to devise new cures' These are the questions Cell editor Jiaying Tan posed to Jan Korbel and Charles Roberts. Annotated excerpts from this conversation are presented below, and the full conversation is available with the article online.

      PubDate: 2017-02-15T13:02:02Z
       
  • Where is the Future of Drug Discovery for Cancer'
    • Abstract: Publication date: 9 February 2017
      Source:Cell, Volume 168, Issue 4
      With both small molecules and biologics succeeding in trials and in the clinic, the scope of drug discovery in cancer is changing. We asked a group of researchers to share their visions for how to identify new targets and how to approach taming them.
      Teaser With both small molecules and biologics succeeding in trials and in the clinic, the scope of drug discovery in cancer is changing. We asked a group of researchers to share their visions for how to identify new targets and how to approach taming them.

      PubDate: 2017-02-15T13:02:02Z
       
  • Gene Essentiality Profiling Reveals Gene Networks and Synthetic Lethal
           Interactions with Oncogenic Ras
    • Abstract: Publication date: Available online 2 February 2017
      Source:Cell
      Author(s): Tim Wang, Haiyan Yu, Nicholas W. Hughes, Bingxu Liu, Arek Kendirli, Klara Klein, Walter W. Chen, Eric S. Lander, David M. Sabatini
      The genetic dependencies of human cancers widely vary. Here, we catalog this heterogeneity and use it to identify functional gene interactions and genotype-dependent liabilities in cancer. By using genome-wide CRISPR-based screens, we generate a gene essentiality dataset across 14 human acute myeloid leukemia (AML) cell lines. Sets of genes with correlated patterns of essentiality across the lines reveal new gene relationships, the essential substrates of enzymes, and the molecular functions of uncharacterized proteins. Comparisons of differentially essential genes between Ras-dependent and -independent lines uncover synthetic lethal partners of oncogenic Ras. Screens in both human AML and engineered mouse pro-B cells converge on a surprisingly small number of genes in the Ras processing and MAPK pathways and pinpoint PREX1 as an AML-specific activator of MAPK signaling. Our findings suggest general strategies for defining mammalian gene networks and synthetic lethal interactions by exploiting the natural genetic and epigenetic diversity of human cancer cells.
      Graphical abstract image Teaser Charting global genetic interaction networks in human cells with CRISPR-based screens uncovers key Ras interactors.

      PubDate: 2017-02-09T08:33:05Z
       
 
 
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