Somatostatin Interneurons Promote Neuronal Synchrony in the Neonatal Hippocampus
Publication date: 19 March 2019Source: Cell Reports, Volume 26, Issue 12Author(s): Tom Flossmann, Thomas Kaas, Vahid Rahmati, Stefan J. Kiebel, Otto W. Witte, Knut Holthoff, Knut KirmseSummarySynchronized activity is a universal characteristic of immature neural circuits that is essential for their developmental refinement and strongly depends on GABAergic neurotransmission. A major subpopulation of GABA-releasing interneurons (INs) expresses somatostatin (SOM) and proved critical for rhythm generation in adulthood. Here, we report a mechanism whereby SOM INs promote neuronal synchrony in the neonatal CA1 region. Combining...
Source: Cell Reports - March 20, 2019 Category: Cytology Source Type: research

A Protein Disulfide Isomerase Controls Neuronal Migration through Regulation of Wnt Secretion
Publication date: 19 March 2019Source: Cell Reports, Volume 26, Issue 12Author(s): Nanna Torpe, Sandeep Gopal, Oguzhan Baltaci, Lorenzo Rella, Ava Handley, Hendrik C. Korswagen, Roger PocockSummaryAppropriate Wnt morphogen secretion is required to control animal development and homeostasis. Although correct Wnt globular structure is essential for secretion, proteins that directly mediate Wnt folding and maturation remain uncharacterized. Here, we report that protein disulfide isomerase-1 (PDI-1), a protein-folding catalyst and chaperone, controls secretion of the Caenorhabditis elegans Wnt ortholog EGL-20. We find tha...
Source: Cell Reports - March 20, 2019 Category: Cytology Source Type: research

SOX2-Dependent Transcription in Clock Neurons Promotes the Robustness of the Central Circadian Pacemaker
Publication date: 19 March 2019Source: Cell Reports, Volume 26, Issue 12Author(s): Arthur H. Cheng, Pascale Bouchard-Cannon, Sara Hegazi, Christopher Lowden, Samuel W. Fung, Cheng-Kang Chiang, Rob W. Ness, Hai-Ying Mary ChengSummaryClock neurons within the mammalian suprachiasmatic nuclei (SCN) encode circadian time using interlocked transcription-translation feedback loops (TTFLs) that drive rhythmic gene expression. However, the contributions of other transcription factors outside of the circadian TTFLs to the functionality of the SCN remain obscure. Here, we report that the stem and progenitor cell transcription factor,...
Source: Cell Reports - March 20, 2019 Category: Cytology Source Type: research

Modeling Patient-Derived Glioblastoma with Cerebral Organoids
Publication date: 19 March 2019Source: Cell Reports, Volume 26, Issue 12Author(s): Amanda Linkous, Demosthenes Balamatsias, Matija Snuderl, Lincoln Edwards, Ken Miyaguchi, Teresa Milner, Batsheva Reich, Leona Cohen-Gould, Andrew Storaska, Yasumi Nakayama, Emily Schenkein, Richa Singhania, Stefano Cirigliano, Tarig Magdeldin, Ying Lin, Gouri Nanjangud, Kalyani Chadalavada, David Pisapia, Conor Liston, Howard A. FineSummaryThe prognosis of patients with glioblastoma (GBM) remains dismal, with a median survival of approximately 15 months. Current preclinical GBM models are limited by the lack of a “normal” hu...
Source: Cell Reports - March 20, 2019 Category: Cytology Source Type: research

Entosis Controls a Developmental Cell Clearance in C. elegans
Publication date: 19 March 2019Source: Cell Reports, Volume 26, Issue 12Author(s): Yongchan Lee, Jens C. Hamann, Mark Pellegrino, Joanne Durgan, Marie-Charlotte Domart, Lucy M. Collinson, Cole M. Haynes, Oliver Florey, Michael OverholtzerSummaryMetazoan cell death mechanisms are diverse and include numerous non-apoptotic programs. One program called entosis involves the invasion of live cells into their neighbors and is known to occur in cancers. Here, we identify a developmental function for entosis: to clear the male-specific linker cell in C. elegans. The linker cell leads migration to shape the gonad and is remove...
Source: Cell Reports - March 20, 2019 Category: Cytology Source Type: research

Prolyl Isomerase Pin1 Suppresses Thermogenic Programs in Adipocytes by Promoting Degradation of Transcriptional Co-activator PRDM16
Publication date: 19 March 2019Source: Cell Reports, Volume 26, Issue 12Author(s): Yusuke Nakatsu, Yasuka Matsunaga, Takeshi Yamamotoya, Koji Ueda, Masa-ki Inoue, Yu Mizuno, Mikako Nakanishi, Tomomi Sano, Yosuke Yamawaki, Akifumi Kushiyama, Hideyuki Sakoda, Midori Fujishiro, Akihide Ryo, Hiraku Ono, Tohru Minamino, Shin-Ichiro Takahashi, Haruya Ohno, Masayasu Yoneda, Kei Takahashi, Hisamitsu IshiharaSummaryNon-shivering thermogenesis in adipocytes provides defense against low temperatures and obesity development, but the underlying regulatory mechanism remains to be fully clarified. Based on both markedly increased Pin1 ex...
Source: Cell Reports - March 20, 2019 Category: Cytology Source Type: research

In Vivo Generation of Post-infarct Human Cardiac Muscle by Laminin-Promoted Cardiovascular Progenitors
Publication date: 19 March 2019Source: Cell Reports, Volume 26, Issue 12Author(s): Lynn Yap, Jiong-Wei Wang, Aida Moreno-Moral, Li Yen Chong, Yi Sun, Nathan Harmston, Xiaoyuan Wang, Suet Yen Chong, Miina K. Öhman, Heming Wei, Ralph Bunte, Sujoy Gosh, Stuart Cook, Outi Hovatta, Dominique P.V. de Kleijn, Enrico Petretto, Karl TryggvasonSummaryRegeneration of injured human heart muscle is limited and an unmet clinical need. There are no methods for the reproducible generation of clinical-quality stem cell-derived cardiovascular progenitors (CVPs). We identified laminin-221 (LN-221) as the most likely expressed cardiac la...
Source: Cell Reports - March 20, 2019 Category: Cytology Source Type: research

Enhanced Renewal of Erythroid Progenitors in Myelodysplastic Anemia by Peripheral Serotonin
Publication date: 19 March 2019Source: Cell Reports, Volume 26, Issue 12Author(s): David Sibon, Tereza Coman, Julien Rossignol, Mathilde Lamarque, Olivier Kosmider, Elisa Bayard, Guillemette Fouquet, Rachel Rignault, Selin Topçu, Pierre Bonneau, Florence Bernex, Michael Dussiot, Kathy Deroy, Laetitia Laurent, Jacques Callebert, Jean-Marie Launay, Sophie Georgin-Lavialle, Geneviève Courtois, Luc Maroteaux, Cathy VaillancourtSummaryTryptophan as the precursor of several active compounds, including kynurenine and serotonin, is critical for numerous important metabolic functions. Enhanced tryptophan metabolism to...
Source: Cell Reports - March 20, 2019 Category: Cytology Source Type: research

Nidogen-1 Contributes to the Interaction Network Involved in Pro-B Cell Retention in the Peri-sinusoidal Hematopoietic Stem Cell Niche
Publication date: 19 March 2019Source: Cell Reports, Volume 26, Issue 12Author(s): Marielle Balzano, Maria De Grandis, Thien-Phong Vu Manh, Lionel Chasson, Florence Bardin, Anne Farina, Arnauld Sergé, Ghislain Bidaut, Pierre Charbord, Léonard Hérault, Anne-Laure Bailly, Amandine Cartier-Michaud, Annie Boned, Marc Dalod, Estelle Duprez, Paul Genever, Mark Coles, Marc Bajenoff, Luc Xerri, Michel Aurrand-LionsSummaryIn the bone marrow, CXCL12 and IL-7 are essential for B cell differentiation, whereas hematopoietic stem cell (HSC) maintenance requires SCF and CXCL12. Peri-sinusoidal stromal (PSS) cells are...
Source: Cell Reports - March 20, 2019 Category: Cytology Source Type: research

Dissecting Cell Lineage Specification and Sex Fate Determination in Gonadal Somatic Cells Using Single-Cell Transcriptomics
Publication date: 19 March 2019Source: Cell Reports, Volume 26, Issue 12Author(s): Isabelle Stévant, Françoise Kühne, Andy Greenfield, Marie-Christine Chaboissier, Emmanouil T. Dermitzakis, Serge NefSummarySex determination is a unique process that allows the study of multipotent progenitors and their acquisition of sex-specific fates during differentiation of the gonad into a testis or an ovary. Using time series single-cell RNA sequencing (scRNA-seq) on ovarian Nr5a1-GFP+ somatic cells during sex determination, we identified a single population of early progenitors giving rise to both pre-granulos...
Source: Cell Reports - March 20, 2019 Category: Cytology Source Type: research

Nanoscale Subsynaptic Domains Underlie the Organization of the Inhibitory Synapse
Publication date: 19 March 2019Source: Cell Reports, Volume 26, Issue 12Author(s): Kevin C. Crosby, Sara E. Gookin, Joshua D. Garcia, Katlin M. Hahm, Mark L. Dell’Acqua, Katharine R. SmithSummaryInhibitory synapses mediate the majority of synaptic inhibition in the brain, thereby controlling neuronal excitability, firing, and plasticity. Although essential for neuronal function, the central question of how these synapses are organized at the subsynaptic level remains unanswered. Here, we use three-dimensional (3D) super-resolution microscopy to image key components of the inhibitory postsynaptic domain and presynapti...
Source: Cell Reports - March 20, 2019 Category: Cytology Source Type: research

Ndfip Proteins Target Robo Receptors for Degradation and Allow Commissural Axons to Cross the Midline in the Developing Spinal Cord
Publication date: 19 March 2019Source: Cell Reports, Volume 26, Issue 12Author(s): Madhavi Gorla, Celine Santiago, Karina Chaudhari, Awo Akosua Kesewa Layman, Paula M. Oliver, Greg J. BashawSummaryCommissural axons initially respond to attractive signals at the midline, but once they cross, they become sensitive to repulsive cues. This switch prevents axons from re-entering the midline. In insects and mammals, negative regulation of Roundabout (Robo) receptors prevents premature response to the midline repellant Slit. In Drosophila, the endosomal protein Commissureless (Comm) prevents Robo1 surface expression before midlin...
Source: Cell Reports - March 20, 2019 Category: Cytology Source Type: research

Widespread Alterations in Translation Elongation in the Brain of Juvenile Fmr1 Knockout Mice
Publication date: 19 March 2019Source: Cell Reports, Volume 26, Issue 12Author(s): Sohani Das Sharma, Jordan B. Metz, Hongyu Li, Benjamin D. Hobson, Nicholas Hornstein, David Sulzer, Guomei Tang, Peter A. SimsSummaryFMRP (fragile X mental retardation protein) is a polysome-associated RNA-binding protein encoded by Fmr1 that is lost in fragile X syndrome. Increasing evidence suggests that FMRP regulates both translation initiation and elongation, but the gene specificity of these effects is unclear. To elucidate the impact of Fmr1 loss on translation, we utilize ribosome profiling for genome-wide measurements of riboso...
Source: Cell Reports - March 20, 2019 Category: Cytology Source Type: research

DBC1 Regulates p53 Stability via Inhibition of CBP-Dependent p53 Polyubiquitination
Publication date: 19 March 2019Source: Cell Reports, Volume 26, Issue 12Author(s): Oluwatoyin E. Akande, Priyadarshan K. Damle, Marius Pop, Nicholas E. Sherman, Barbara B. Szomju, Larisa V. Litovchick, Steven R. GrossmanSummaryThe control of p53 protein stability is critical to its tumor suppressor functions. The CREB binding protein (CBP) transcriptional co-activator co-operates with MDM2 to maintain normally low physiological p53 levels in cells via exclusively cytoplasmic E4 polyubiquitination activity. Using mass spectrometry to identify nuclear and cytoplasmic CBP-interacting proteins that regulate compartmentalized C...
Source: Cell Reports - March 20, 2019 Category: Cytology Source Type: research

Structural Insight into DNA-Dependent Activation of Human Metalloprotease Spartan
Publication date: 19 March 2019Source: Cell Reports, Volume 26, Issue 12Author(s): Faxiang Li, Joanna E. Raczynska, Zhe Chen, Hongtao YuSummaryThe DNA-dependent metalloprotease Spartan (SPRTN) cleaves DNA-protein crosslinks (DPCs) and protects cells from DPC-induced genome instability. Germline mutations of SPRTN are linked to human Ruijs-Aalfs syndrome (RJALS) characterized by progeria and early-onset hepatocellular carcinoma. The mechanism of DNA-mediated activation of SPRTN is not understood. Here, we report the crystal structure of the human SPRTN SprT domain bound to single-stranded DNA (ssDNA). Our structure reveals ...
Source: Cell Reports - March 20, 2019 Category: Cytology Source Type: research

Structural and Functional Analysis of the CAPS SNARE-Binding Domain Required for SNARE Complex Formation and Exocytosis
Publication date: 19 March 2019Source: Cell Reports, Volume 26, Issue 12Author(s): Hao Zhou, Ziqing Wei, Shen Wang, Deqiang Yao, Rongguang Zhang, Cong MaSummaryExocytosis of synaptic vesicles and dense-core vesicles requires both the Munc13 and CAPS (Ca2+-dependent activator proteins for secretion) proteins. CAPS contains a soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-binding region (called the DAMH domain), which has been found to be essential for SNARE-mediated exocytosis. Here we report a crystal structure of the CAPS-1 DAMH domain at 2.9-Å resolution and reveal a dual role of CAPS...
Source: Cell Reports - March 20, 2019 Category: Cytology Source Type: research

Structural Basis for Neutralization and Protection by a Zika Virus-Specific Human Antibody
Publication date: 19 March 2019Source: Cell Reports, Volume 26, Issue 12Author(s): Lin Wang, Ruoke Wang, Lei Wang, Haijing Ben, Lei Yu, Fei Gao, Xuanling Shi, Chibiao Yin, Fuchun Zhang, Ye Xiang, Linqi ZhangSummaryWe previously reported a human monoclonal antibody, ZK2B10, capable of protection against Zika virus (ZIKV) infection and microcephaly in developing mouse embryos. Here, we report the structural features and mechanism of action of ZK2B10. The crystal structure at a resolution of 2.32 Å revealed that the epitope is located on the lateral ridge of DIII of the envelope glycoprotein. Cryo-EM structure...
Source: Cell Reports - March 20, 2019 Category: Cytology Source Type: research

Cytoskeletal Control of Antigen-Dependent T Cell Activation
Publication date: 19 March 2019Source: Cell Reports, Volume 26, Issue 12Author(s): Huw Colin-York, Yousef Javanmardi, Mark Skamrahl, Sudha Kumari, Veronica T. Chang, Satya Khuon, Aaron Taylor, Teng-Leong Chew, Eric Betzig, Emad Moeendarbary, Vincenzo Cerundolo, Christian Eggeling, Marco FritzscheSummaryCytoskeletal actin dynamics is essential for T cell activation. Here, we show evidence that the binding kinetics of the antigen engaging the T cell receptor influences the nanoscale actin organization and mechanics of the immune synapse. Using an engineered T cell system expressing a specific T cell recep...
Source: Cell Reports - March 20, 2019 Category: Cytology Source Type: research

Chlamydia trachomatis CT229 Subverts Rab GTPase-Dependent CCV Trafficking Pathways to Promote Chlamydial Infection
This study highlights CT229 as a master regulator of multiple host vesicular trafficking pathways essential for chlamydial infection.Graphical Abstract (Source: Cell Reports)
Source: Cell Reports - March 20, 2019 Category: Cytology Source Type: research

Alterations in Phosphorylation of Hepatocyte Ribosomal Protein S6 Control Plasmodium Liver Stage Infection
Publication date: 19 March 2019Source: Cell Reports, Volume 26, Issue 12Author(s): Elizabeth K.K. Glennon, Laura S. Austin, Nadia Arang, Heather S. Kain, Fred D. Mast, Kamalakannan Vijayan, John D. Aitchison, Stefan H.I. Kappe, Alexis KaushanskySummaryPlasmodium parasites are highly selective when infecting hepatocytes and induce many changes within the host cell upon infection. While several host cell factors have been identified that are important for liver infection, our understanding of what facilitates the maintenance of infection remains incomplete. Here, we describe a role for phosphorylated ribosomal protein S6 (Se...
Source: Cell Reports - March 20, 2019 Category: Cytology Source Type: research

Sequential Ubiquitination of Ribosomal Protein uS3 Triggers the Degradation of Non-functional 18S rRNA
Publication date: 19 March 2019Source: Cell Reports, Volume 26, Issue 12Author(s): Takato Sugiyama, Sihan Li, Misaki Kato, Ken Ikeuchi, Atsushi Ichimura, Yoshitaka Matsuo, Toshifumi InadaSummary18S non-functional rRNA decay (NRD) eliminates non-functional 18S rRNA with deleterious mutations in the decoding center. Dissociation of the non-functional 80S ribosome into 40S and 60S subunits is a prerequisite step for degradation of the non-functional 18S rRNA. However, the mechanisms by which the non-functional ribosome is recognized and dissociated into subunits remain elusive. Here, we report that the sequential ubiquit...
Source: Cell Reports - March 20, 2019 Category: Cytology Source Type: research

Oxidative Stress Triggers Selective tRNA Retrograde Transport in Human Cells during the Integrated Stress Response
Publication date: 19 March 2019Source: Cell Reports, Volume 26, Issue 12Author(s): Hagen Schwenzer, Frank Jühling, Alexander Chu, Laura J. Pallett, Thomas F. Baumert, Mala Maini, Ariberto FassatiSummaryIn eukaryotes, tRNAs are transcribed in the nucleus and exported to the cytosol, where they deliver amino acids to ribosomes for protein translation. This nuclear-cytoplasmic movement was believed to be unidirectional. However, active shuttling of tRNAs, named tRNA retrograde transport, between the cytosol and nucleus has been discovered. This pathway is conserved in eukaryotes, suggesting a fundamental function; howeve...
Source: Cell Reports - March 20, 2019 Category: Cytology Source Type: research

Multi-dimensional Transcriptional Remodeling by Physiological Insulin In Vivo
Publication date: 19 March 2019Source: Cell Reports, Volume 26, Issue 12Author(s): Thiago M. Batista, Ruben Garcia-Martin, Weikang Cai, Masahiro Konishi, Brian T. O’Neill, Masaji Sakaguchi, Jong Hun Kim, Dae Young Jung, Jason K. Kim, C. Ronald KahnSummaryRegulation of gene expression is an important aspect of insulin action but in vivo is intertwined with changing levels of glucose and counter-regulatory hormones. Here we demonstrate that under euglycemic clamp conditions, physiological levels of insulin regulate interrelated networks of more than 1,000 transcripts in muscle and liver. These include expected pat...
Source: Cell Reports - March 20, 2019 Category: Cytology Source Type: research

Expanded Expression Landscape and Prioritization of Circular RNAs in Mammals
Publication date: 19 March 2019Source: Cell Reports, Volume 26, Issue 12Author(s): Peifeng Ji, Wanying Wu, Shuai Chen, Yi Zheng, Lin Zhou, Jinyang Zhang, Hao Cheng, Jin Yan, Shaogeng Zhang, Penghui Yang, Fangqing ZhaoSummaryCircular RNAs (circRNAs) are emerging as essential regulators of various biological and disease processes. To comprehensively understand the diversity of circRNAs and prioritize their importance, we present a large-scale study of circRNA repertoires from multiple tissues from human, macaque, and mouse. We discovered totals of 104,388, 96,675, and 82,321 circRNAs from the three species, respectively, wit...
Source: Cell Reports - March 20, 2019 Category: Cytology Source Type: research

Dependency of the Cancer-Specific Transcriptional Regulation Circuitry on the Promoter DNA Methylome
Publication date: 19 March 2019Source: Cell Reports, Volume 26, Issue 12Author(s): Yu Liu, Yang Liu, Rongyao Huang, Wanlu Song, Jiawei Wang, Zhengtao Xiao, Shengcheng Dong, Yang Yang, Xuerui YangSummaryDynamic dysregulation of the promoter DNA methylome is a signature of cancer. However, comprehensive understandings about how the DNA methylome is incorporated in the transcriptional regulation circuitry and involved in regulating the gene expression abnormality in cancers are still missing. We introduce an integrative analysis pipeline based on mutual information theory and tailored for the multi-omics profiling data in The...
Source: Cell Reports - March 20, 2019 Category: Cytology Source Type: research

Mitofusin 2 in Mature Adipocytes Controls Adiposity and Body Weight
Publication date: 12 March 2019Source: Cell Reports, Volume 26, Issue 11Author(s): Giacomo Mancini, Kevin Pirruccio, Xiaoyong Yang, Matthias Blücher, Matthew Rodeheffer, Tamas L. HorvathSummaryWe found that exposure of adult animals to calorie-dense foods rapidly abolished expression of mitofusin 2 (Mfn2), a gene promoting mitochondrial fusion and mitochondrion-endoplasmic reticulum interactions, in white and brown fat. Mfn2 mRN was also robustly lower in obese human subjects compared with lean controls. Adipocyte-specific knockdown of Mfn2 in adult mice led to increased food intake, adiposity, and impaired glucose me...
Source: Cell Reports - March 14, 2019 Category: Cytology Source Type: research

Interstitial Migration of CD8αβ T Cells in the Small Intestine Is Dynamic and Is Dictated by Environmental Cues
Publication date: 12 March 2019Source: Cell Reports, Volume 26, Issue 11Author(s): Emily A. Thompson, Jason S. Mitchell, Lalit K. Beura, David J. Torres, Paulus Mrass, Mark J. Pierson, Judy L. Cannon, David Masopust, Brian T. Fife, Vaiva VezysSummaryThe migratory capacity of adaptive CD8αβ T cells dictates their ability to locate target cells and exert cytotoxicity, which is the basis of immune surveillance for the containment of microbes and disease. The small intestine (SI) is the largest mucosal surface and is a primary site of pathogen entrance. Using two-photon laser scanning microscopy, we found that ...
Source: Cell Reports - March 14, 2019 Category: Cytology Source Type: research

Cortical State Fluctuations across Layers of V1 during Visual Spatial Perception
Publication date: 12 March 2019Source: Cell Reports, Volume 26, Issue 11Author(s): Anderson Speed, Joseph Del Rosario, Christopher P. Burgess, Bilal HaiderSummaryMany factors modulate the state of cortical activity, but the importance of cortical state variability for sensory perception remains debated. We trained mice to detect spatially localized visual stimuli and simultaneously measured local field potentials and excitatory and inhibitory neuron populations across layers of primary visual cortex (V1). Cortical states with low spontaneous firing and correlations in excitatory neurons, and suppression of 3- to 7-Hz oscil...
Source: Cell Reports - March 14, 2019 Category: Cytology Source Type: research

Interphase Microtubules Safeguard Mitotic Progression by Suppressing an Aurora B-Dependent Arrest Induced by DNA Replication Stress
Publication date: 12 March 2019Source: Cell Reports, Volume 26, Issue 11Author(s): Guillaume Laflamme, Shannon Sim, Allen Leary, Mirela Pascariu, Jackie Vogel, Damien D’AmoursSummaryThe segregation of chromosomes is a critical step during cell division. This process is driven by the elongation of spindle microtubules and is tightly regulated by checkpoint mechanisms. It is unknown whether microtubules affect checkpoint responses as passive contributors or active regulators of the process. We show here that interphase microtubules are essential to temporally restrict the effects of DNA replication stress to S phase in...
Source: Cell Reports - March 14, 2019 Category: Cytology Source Type: research

Condensin II Counteracts Cohesin and RNA Polymerase II in the Establishment of 3D Chromatin Organization
Publication date: 12 March 2019Source: Cell Reports, Volume 26, Issue 11Author(s): M. Jordan Rowley, Xiaowen Lyu, Vibhuti Rana, Masami Ando-Kuri, Rachael Karns, Giovanni Bosco, Victor G. CorcesSummaryInteraction domains in Drosophila chromosomes form by segregation of active and inactive chromatin in the absence of CTCF loops, but the role of transcription versus other architectural proteins in chromatin organization is unclear. Here, we find that positioning of RNAPII via transcription elongation is essential in the formation of gene loops, which in turn interact to form compartmental domains. Inhibition of transcription ...
Source: Cell Reports - March 14, 2019 Category: Cytology Source Type: research

lncRNA KHPS1 Activates a Poised Enhancer by Triplex-Dependent Recruitment of Epigenomic Regulators
Publication date: 12 March 2019Source: Cell Reports, Volume 26, Issue 11Author(s): Alena Blank-Giwojna, Anna Postepska-Igielska, Ingrid GrummtSummaryTranscription of the proto-oncogene SPHK1 is regulated by KHPS1, an antisense RNA that activates SPHK1 expression by forming a triple-helical RNA-DNA-DNA structure at the SPHK1 enhancer. Triplex-mediated tethering of KHPS1 to its target gene is required for recruitment of E2F1 and p300 and transcription of the RNA derived from the SPHK1 enhancer (eRNA-Sphk1). eRNA-Sphk1 evicts CTCF, which insulates the enhancer from the SPHK1 promoter, thus facilitating SPHK1 expression. ...
Source: Cell Reports - March 14, 2019 Category: Cytology Source Type: research

Displacement of WDR5 from Chromatin by a WIN Site Inhibitor with Picomolar Affinity
Publication date: 12 March 2019Source: Cell Reports, Volume 26, Issue 11Author(s): Erin R. Aho, Jing Wang, Rocco D. Gogliotti, Gregory C. Howard, Jason Phan, Pankaj Acharya, Jonathan D. Macdonald, Ken Cheng, Shelly L. Lorey, Bin Lu, Sabine Wenzel, Audra M. Foshage, Joseph Alvarado, Feng Wang, J. Grace Shaw, Bin Zhao, April M. Weissmiller, Lance R. Thomas, Christopher R. Vakoc, Matthew D. HallSummaryThe chromatin-associated protein WDR5 is a promising target for pharmacological inhibition in cancer. Drug discovery efforts center on the blockade of the “WIN site” of WDR5, a well-defined pocket that is a...
Source: Cell Reports - March 14, 2019 Category: Cytology Source Type: research

Functional Interaction between U1snRNP and Sam68 Insures Proper 3′ End Pre-mRNA Processing during Germ Cell Differentiation
Publication date: 12 March 2019Source: Cell Reports, Volume 26, Issue 11Author(s): Chiara Naro, Livia Pellegrini, Ariane Jolly, Donatella Farini, Eleonora Cesari, Pamela Bielli, Pierre de la Grange, Claudio SetteSummaryMale germ cells express the widest repertoire of transcript variants in mammalian tissues. Nevertheless, factors and mechanisms underlying such pronounced diversity are largely unknown. The splicing regulator Sam68 is highly expressed in meiotic cells, and its ablation results in defective spermatogenesis. Herein, we uncover an extensive splicing program operated by Sam68 across meiosis, primarily characteri...
Source: Cell Reports - March 14, 2019 Category: Cytology Source Type: research

Dlk1-Mediated Temporal Regulation of Notch Signaling Is Required for Differentiation of Alveolar Type II to Type I Cells during Repair
Publication date: 12 March 2019Source: Cell Reports, Volume 26, Issue 11Author(s): Johanna Finn, Kilian Sottoriva, Kostandin V. Pajcini, Jan K. Kitajewski, Chang Chen, Wei Zhang, Asrar B. Malik, Yuru LiuSummaryLung alveolar type I cells (AT1) and alveolar type II cells (AT2) regulate the structural integrity and function of alveoli. AT1, covering ∼95% of the surface area, are responsible for gas exchange, whereas AT2 serve multiple functions, including alveolar repair through proliferation and differentiation into AT1. However, the signaling mechanisms for alveolar repair remain unclear. Here, we demonstrate, in Pseudo...
Source: Cell Reports - March 14, 2019 Category: Cytology Source Type: research

PDGF-B Is Required for Development of the Glymphatic System
Publication date: 12 March 2019Source: Cell Reports, Volume 26, Issue 11Author(s): Anne Sofie Munk, Wei Wang, Nicholas Burdon Bèchet, Ahmed M. Eltanahy, Anne Xiaoan Cheng, Björn Sigurdsson, Abdellatif Benraiss, Maarja A. Mäe, Benjamin Travis Kress, Douglas H. Kelley, Christer Betsholtz, Kjeld Møllgård, Anja Meissner, Maiken Nedergaard, Iben LundgaardSummaryThe glymphatic system is a highly polarized cerebrospinal fluid (CSF) transport system that facilitates the clearance of neurotoxic molecules through a brain-wide network of perivascular pathways. Herein we have mapped the development of the...
Source: Cell Reports - March 14, 2019 Category: Cytology Source Type: research

Genetic Perturbation of TIA1 Reveals a Physiological Role in Fear Memory
Publication date: 12 March 2019Source: Cell Reports, Volume 26, Issue 11Author(s): Joseph B. Rayman, Joud Hijazi, Xiang Li, Nancy Kedersha, Paul J. Anderson, Eric R. KandelSummaryTIA1 is a prion-related RNA-binding protein whose capacity to form various types of intracellular aggregates has been implicated in neurodegenerative disease. However, its role in normal brain function is poorly understood. Here, we show that TIA1 bidirectionally modulates stress-dependent synaptic plasticity in the hippocampus, a brain region involved in fear memory and olfactory discrimination learning. At the behavioral level, conditioned odor ...
Source: Cell Reports - March 14, 2019 Category: Cytology Source Type: research

A GPR17-cAMP-Lactate Signaling Axis in Oligodendrocytes Regulates Whole-Body Metabolism
Publication date: 12 March 2019Source: Cell Reports, Volume 26, Issue 11Author(s): Zhimin Ou, Yanchen Ma, Yuxia Sun, Gege Zheng, Shiyun Wang, Rui Xing, Xiang Chen, Ying Han, Jiajia Wang, Q. Richard Lu, Tong-Jin Zhao, Ying ChenSummaryThe CNS plays a pivotal role in energy homeostasis, but whether oligodendrocytes are involved has been largely unexplored. Here, we show that signaling through GPR17, a G-protein-coupled receptor predominantly expressed in the oligodendrocyte lineage, regulates food intake by modulating hypothalamic neuronal activities. GPR17-null mice and mice with an oligodendrocyte-specific knockout of ...
Source: Cell Reports - March 14, 2019 Category: Cytology Source Type: research

Ets1-Mediated Acetylation of FoxO1 Is Critical for Gluconeogenesis Regulation during Feed-Fast Cycles
Publication date: 12 March 2019Source: Cell Reports, Volume 26, Issue 11Author(s): Kai Li, Chen Qiu, Peng Sun, De-chen Liu, Ti-jun Wu, Kai Wang, Yun-cai Zhou, Xiao-ai Chang, Ye Yin, Fang Chen, Yun-xia Zhu, Xiao HanSummaryThe homeostatic balance of hepatic glucose uptake and production is exquisitely controlled by hormonal signals during feed-fast cycles. FoxO1, a transcription factor that functions in the regulation of glucose homeostasis, undergoes posttranslational modifications, such as acetylation, in response to hormonal signals, yet the mechanism remains poorly elucidated. Through expression profiling of 324 co-facto...
Source: Cell Reports - March 14, 2019 Category: Cytology Source Type: research

Parabrachial Interleukin-6 Reduces Body Weight and Food Intake and Increases Thermogenesis to Regulate Energy Metabolism
Publication date: 12 March 2019Source: Cell Reports, Volume 26, Issue 11Author(s): Devesh Mishra, Jennifer E. Richard, Ivana Maric, Begona Porteiro, Martin Häring, Sander Kooijman, Saliha Musovic, Kim Eerola, Lorena López-Ferreras, Eduard Peris, Katarzyna Grycel, Olesya T. Shevchouk, Peter Micallef, Charlotta S. Olofsson, Ingrid Wernstedt Asterholm, Harvey J. Grill, Ruben Nogueiras, Karolina P. SkibickaSummaryChronic low-grade inflammation and increased serum levels of the cytokine IL-6 accompany obesity. For brain-produced IL-6, the mechanisms by which it controls energy balance and its role in obesity remain ...
Source: Cell Reports - March 14, 2019 Category: Cytology Source Type: research

Decreased Expression of Cilia Genes in Pancreatic Islets as a Risk Factor for Type 2 Diabetes in Mice and Humans
Publication date: 12 March 2019Source: Cell Reports, Volume 26, Issue 11Author(s): Oliver Kluth, Mandy Stadion, Pascal Gottmann, Heja Aga, Markus Jähnert, Stephan Scherneck, Heike Vogel, Ulrika Krus, Anett Seelig, Charlotte Ling, Jantje Gerdes, Annette SchürmannSummaryAn insufficient adaptive beta-cell compensation is a hallmark of type 2 diabetes (T2D). Primary cilia function as versatile sensory antennae regulating various cellular processes, but their role on compensatory beta-cell replication has not been examined. Here, we identify a significant enrichment of downregulated, cilia-annotated genes in pancreati...
Source: Cell Reports - March 14, 2019 Category: Cytology Source Type: research

The FBXW7-SHOC2-Raptor Axis Controls the Cross-Talks between the RAS-ERK and mTORC1 Signaling Pathways
Publication date: 12 March 2019Source: Cell Reports, Volume 26, Issue 11Author(s): Chuan-Ming Xie, Mingjia Tan, Xiao-Tong Lin, Di Wu, Yihan Jiang, Ye Tan, Haomin Li, Yuanyuan Ma, Xiufang Xiong, Yi SunSummaryFBXW7 is a tumor suppressive E3 ligase, whereas RAS-ERK and mechanistic target of rapamycin kinase (mTORC1) are two major oncogenic pathways. Whether and how FBXW7 regulates these two oncogenic pathways are unknown. Here, we showed that SHOC2, a RAS activator, is a FBXW7 substrate. Growth stimuli trigger SHOC2 phosphorylation on Thr507 by the mitogen-activated protein kinase (MAPK) signal, which facilitat...
Source: Cell Reports - March 14, 2019 Category: Cytology Source Type: research

p53 Promotes Cancer Cell Adaptation to Glutamine Deprivation by Upregulating Slc7a3 to Increase Arginine Uptake
Publication date: 12 March 2019Source: Cell Reports, Volume 26, Issue 11Author(s): Xazmin H. Lowman, Eric A. Hanse, Ying Yang, Mari B. Ishak Gabra, Thai Q. Tran, Haiqing Li, Mei KongSummaryCancer cells heavily depend on the amino acid glutamine to meet the demands associated with growth and proliferation. Due to the rapid consumption of glutamine, cancer cells frequently undergo glutamine starvation in vivo. We and others have shown that p53 is a critical regulator in metabolic stress resistance. To better understand the molecular mechanisms by which p53 activation promotes cancer cell adaptation to glutamine deprivat...
Source: Cell Reports - March 14, 2019 Category: Cytology Source Type: research

A Pan-ALDH1A Inhibitor Induces Necroptosis in Ovarian Cancer Stem-like Cells
Publication date: 12 March 2019Source: Cell Reports, Volume 26, Issue 11Author(s): Ilana Chefetz, Edward Grimley, Kun Yang, Linda Hong, Ekaterina V. Vinogradova, Radu Suciu, Ilya Kovalenko, David Karnak, Cynthia A. Morgan, Mikhail Chtcherbinine, Cameron Buchman, Brandt Huddle, Scott Barraza, Meredith Morgan, Kara A. Bernstein, Euisik Yoon, David B. Lombard, Andrea Bild, Geeta Mehta, Iris RomeroSummaryOvarian cancer is typified by the development of chemotherapy resistance. Chemotherapy resistance is associated with high aldehyde dehydrogenase (ALDH) enzymatic activity, increased cancer “stemness,” and expr...
Source: Cell Reports - March 14, 2019 Category: Cytology Source Type: research

FOXM1 Deubiquitination by USP21 Regulates Cell Cycle Progression and Paclitaxel Sensitivity in Basal-like Breast Cancer
Publication date: 12 March 2019Source: Cell Reports, Volume 26, Issue 11Author(s): Anthony Arceci, Thomas Bonacci, Xianxi Wang, Kyle Stewart, Jeffrey S. Damrauer, Katherine A. Hoadley, Michael J. EmanueleSummaryThe transcription factor FOXM1 contributes to cell cycle progression and is significantly upregulated in basal-like breast cancer (BLBC). Despite its importance in normal and cancer cell cycles, we lack a complete understanding of mechanisms that regulate FOXM1. We identified USP21 in an RNAi-based screen for deubiquitinases that control FOXM1 abundance. USP21 increases the stability of FOXM1, and USP21 binds a...
Source: Cell Reports - March 14, 2019 Category: Cytology Source Type: research

The Metastable XBP1u Transmembrane Domain Defines Determinants for Intramembrane Proteolysis by Signal Peptide Peptidase
Publication date: 12 March 2019Source: Cell Reports, Volume 26, Issue 11Author(s): Sara Suna Yücel, Walter Stelzer, Alessandra Lorenzoni, Manfred Wozny, Dieter Langosch, Marius K. LembergSummaryUnspliced XBP1 mRNA encodes XBP1u, the transcriptionally inert variant of the unfolded protein response (UPR) transcription factor XBP1s. XBP1u targets its mRNA-ribosome-nascent-chain-complex to the endoplasmic reticulum (ER) to facilitate UPR activation and prevents overactivation. Yet, its membrane association is controversial. Here, we use cell-free translocation and cellular assays to define a moderately hydrophobic stretch...
Source: Cell Reports - March 14, 2019 Category: Cytology Source Type: research

An Integrated Global Analysis of Compartmentalized HRAS Signaling
Publication date: 12 March 2019Source: Cell Reports, Volume 26, Issue 11Author(s): Tapesh Santra, Ana Herrero, Javier Rodriguez, Alex von Kriegsheim, Luis F. Iglesias-Martinez, Thomas Schwarzl, Des Higgins, Thin-Thin Aye, Albert J.R. Heck, Fernando Calvo, Lorena Agudo-Ibáñez, Piero Crespo, David Matallanas, Walter KolchSummaryModern omics technologies allow us to obtain global information on different types of biological networks. However, integrating these different types of analyses into a coherent framework for a comprehensive biological interpretation remains challenging. Here, we present a conceptual fra...
Source: Cell Reports - March 14, 2019 Category: Cytology Source Type: research

Single-Cell Analysis Reveals Heterogeneity of High Endothelial Venules and Different Regulation of Genes Controlling Lymphocyte Entry to Lymph Nodes
Publication date: 12 March 2019Source: Cell Reports, Volume 26, Issue 11Author(s): Krystle Veerman, Claire Tardiveau, Frédéric Martins, Juliette Coudert, Jean-Philippe GirardSummaryHigh-endothelial venules (HEVs) are specialized blood vessels allowing recirculation of naive lymphocytes through lymphoid organs. Here, using full-length, single-cell RNA sequencing, RNA fluorescence in situ hybridization (FISH), flow cytometry, and immunohistofluorescence, we reveal the heterogeneity of HEVs in adult mouse peripheral lymph nodes (PLNs) under conditions of homeostasis, antigenic stimulation, and after inhibition o...
Source: Cell Reports - March 14, 2019 Category: Cytology Source Type: research

Single-Cell Heterogeneity Analysis and CRISPR Screen Identify Key β-Cell-Specific Disease Genes
Publication date: 12 March 2019Source: Cell Reports, Volume 26, Issue 11Author(s): Zhou Fang, Chen Weng, Haiyan Li, Ran Tao, Weihua Mai, Xiaoxiao Liu, Leina Lu, Sisi Lai, Qing Duan, Carlos Alvarez, Peter Arvan, Anthony Wynshaw-Boris, Yun Li, Yanxin Pei, Fulai Jin, Yan LiSummaryIdentification of human disease signature genes typically requires samples from many donors to achieve statistical significance. Here, we show that single-cell heterogeneity analysis may overcome this hurdle by significantly improving the test sensitivity. We analyzed the transcriptome of 39,905 single islets cells from 9 donors and observed distinct...
Source: Cell Reports - March 14, 2019 Category: Cytology Source Type: research

Genetic Single Neuron Anatomy Reveals Fine Granularity of Cortical Axo-Axonic Cells
Publication date: 12 March 2019Source: Cell Reports, Volume 26, Issue 11Author(s): Xiaojun Wang, Jason Tucciarone, Siqi Jiang, Fangfang Yin, Bor-Shuen Wang, Dingkang Wang, Yao Jia, Xueyan Jia, Yuxin Li, Tao Yang, Zhengchao Xu, Masood A. Akram, Yusu Wang, Shaoqun Zeng, Giorgio A. Ascoli, Partha Mitra, Hui Gong, Qingming Luo, Z. Josh HuangSummaryParsing diverse nerve cells into biological types is necessary for understanding neural circuit organization. Morphology is an intuitive criterion for neuronal classification and a proxy of connectivity, but morphological diversity and variability often preclude resolving the gr...
Source: Cell Reports - March 14, 2019 Category: Cytology Source Type: research

Insights into the Biology of Hearing and Deafness Revealed by Single-Cell RNA Sequencing
Publication date: 12 March 2019Source: Cell Reports, Volume 26, Issue 11Author(s): Paul T. Ranum, Alexander T. Goodwin, Hidekane Yoshimura, Diana L. Kolbe, William D. Walls, Jin-Young Koh, David Z.Z. He, Richard J.H. SmithSummarySingle-cell RNA sequencing is a powerful tool by which to characterize the transcriptional profile of low-abundance cell types, but its application to the inner ear has been hampered by the bony labyrinth, tissue sparsity, and difficulty dissociating the ultra-rare cells of the membranous cochlea. Herein, we present a method to isolate individual inner hair cells (IHCs), outer hair cells (OHCs...
Source: Cell Reports - March 14, 2019 Category: Cytology Source Type: research