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Cell Reports

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https://www.readbyqxmd.com/read/29045849/a-synthetic-oligo-library-and-sequencing-approach-reveals-an-insulation-mechanism-encoded-within-bacterial-%C3%AF-54-promoters
#1
Lior Levy, Leon Anavy, Oz Solomon, Roni Cohen, Michal Brunwasser-Meirom, Shilo Ohayon, Orna Atar, Sarah Goldberg, Zohar Yakhini, Roee Amit
We use an oligonucleotide library of >10,000 variants to identify an insulation mechanism encoded within a subset of σ(54) promoters. Insulation manifests itself as reduced protein expression for a downstream gene that is expressed by transcriptional readthrough. It is strongly associated with the presence of short CT-rich motifs (3-5 bp), positioned within 25 bp upstream of the Shine-Dalgarno (SD) motif of the silenced gene. We provide evidence that insulation is triggered by binding of the ribosome binding site (RBS) to the upstream CT-rich motif...
October 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/29045848/single-molecule-sequencing-reveals-the-chromosome-scale-genomic-architecture-of-the-nematode-model-organism-pristionchus-pacificus
#2
Christian Rödelsperger, Jan M Meyer, Neel Prabh, Christa Lanz, Felix Bemm, Ralf J Sommer
The nematode Pristionchus pacificus is an established model for integrative evolutionary biology and comparative studies with Caenorhabditis elegans. While an existing genome draft facilitated the identification of several genes controlling various developmental processes, its high degree of fragmentation complicated virtually all genomic analyses. Here, we present a de novo genome assembly from single-molecule, long-read sequencing data consisting of 135 P. pacificus contigs. When combined with a genetic linkage map, 99% of the assembly could be ordered and oriented into six chromosomes...
October 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/29045847/cross-tissue-transcriptomic-analysis-of-human-secondary-lymphoid-organ-residing-ilc3s-reveals-a-quiescent-state-in-the-absence-of-inflammation
#3
Yotam E Bar-Ephraim, Ferry Cornelissen, Natalie Papazian, Tanja Konijn, Remco M Hoogenboezem, Mathijs A Sanders, Bart A Westerman, Mehmet Gönültas, Jaap Kwekkeboom, Joke M M Den Haan, Rogier M Reijmers, Reina E Mebius, Tom Cupedo
A substantial number of human and mouse group 3 innate lymphoid cells (ILC3s) reside in secondary lymphoid organs, yet the phenotype and function of these ILC3s is incompletely understood. Here, we employed an unbiased cross-tissue transcriptomic approach to compare human ILC3s from non-inflamed lymph nodes and spleen to their phenotypic counterparts in inflamed tonsils and from circulation. These analyses revealed that, in the absence of inflammation, lymphoid organ-residing ILC3s lack transcription of cytokines associated with classical ILC3 functions...
October 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/29045846/identification-of-genetically-intact-hiv-1-proviruses-in-specific-cd4-t-cells-from-effectively-treated-participants
#4
Bonnie Hiener, Bethany A Horsburgh, John-Sebastian Eden, Kirston Barton, Timothy E Schlub, Eunok Lee, Susanne von Stockenstrom, Lina Odevall, Jeffrey M Milush, Teri Liegler, Elizabeth Sinclair, Rebecca Hoh, Eli A Boritz, Daniel Douek, Rémi Fromentin, Nicolas Chomont, Steven G Deeks, Frederick M Hecht, Sarah Palmer
Latent replication-competent HIV-1 persists in individuals on long-term antiretroviral therapy (ART). We developed the Full-Length Individual Proviral Sequencing (FLIPS) assay to determine the distribution of latent replication-competent HIV-1 within memory CD4(+) T cell subsets in six individuals on long-term ART. FLIPS is an efficient, high-throughput assay that amplifies and sequences near full-length (∼9 kb) HIV-1 proviral genomes and determines potential replication competency through genetic characterization...
October 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/29045845/revealing-the-determinants-of-widespread-alternative-splicing-perturbation-in-cancer
#5
Yongsheng Li, Nidhi Sahni, Rita Pancsa, Daniel J McGrail, Juan Xu, Xu Hua, Jasmin Coulombe-Huntington, Michael Ryan, Boranai Tychhon, Dhanistha Sudhakar, Limei Hu, Michael Tyers, Xiaoqian Jiang, Shiaw-Yih Lin, M Madan Babu, Song Yi
It is increasingly appreciated that alternative splicing plays a key role in generating functional specificity and diversity in cancer. However, the mechanisms by which cancer mutations perturb splicing remain unknown. Here, we developed a network-based strategy, DrAS-Net, to investigate more than 2.5 million variants across cancer types and link somatic mutations with cancer-specific splicing events. We identified more than 40,000 driver variant candidates and their 80,000 putative splicing targets deregulated in 33 cancer types and inferred their functional impact...
October 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/29045844/a-b-cell-regulome-links-notch-to-downstream-oncogenic-pathways-in-small-b-cell-lymphomas
#6
Russell J H Ryan, Jelena Petrovic, Dylan M Rausch, Yeqiao Zhou, Caleb A Lareau, Michael J Kluk, Amanda L Christie, Winston Y Lee, Daniel R Tarjan, Bingqian Guo, Laura K H Donohue, Shawn M Gillespie, Valentina Nardi, Ephraim P Hochberg, Stephen C Blacklow, David M Weinstock, Robert B Faryabi, Bradley E Bernstein, Jon C Aster, Warren S Pear
Gain-of-function Notch mutations are recurrent in mature small B cell lymphomas such as mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL), but the Notch target genes that contribute to B cell oncogenesis are largely unknown. We performed integrative analysis of Notch-regulated transcripts, genomic binding of Notch transcription complexes, and genome conformation data to identify direct Notch target genes in MCL cell lines. This B cell Notch regulome is largely controlled through Notch-bound distal enhancers and includes genes involved in B cell receptor and cytokine signaling and the oncogene MYC, which sustains proliferation of Notch-dependent MCL cell lines via a Notch-regulated lineage-restricted enhancer complex...
October 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/29045843/high-throughput-functional-genetic-and-compound-screens-identify-targets-for-senescence-induction-in-cancer
#7
Liqin Wang, Rodrigo Leite de Oliveira, Cun Wang, João M Fernandes Neto, Sara Mainardi, Bastiaan Evers, Cor Lieftink, Ben Morris, Fleur Jochems, Lisa Willemsen, Roderick L Beijersbergen, René Bernards
Senescence is a proliferation arrest that can result from a variety of stresses. Cancer cells can also undergo senescence, but the stresses that provoke cancer cells to undergo senescence are unclear. Here, we use both functional genetic and compound screens in cancer cells harboring a reporter that is activated during senescence to find targets that induce senescence. We show that suppression of the SWI/SNF component SMARCB1 induces senescence in melanoma through strong activation of the MAP kinase pathway...
October 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/29045842/the-conserved-rna-exonuclease-rexo5-is-required-for-3-end-maturation-of-28s-rrna-5s-rrna-and-snornas
#8
Stefanie Gerstberger, Cindy Meyer, Sigi Benjamin-Hong, Joe Rodriguez, Daniel Briskin, Claudia Bognanni, Kimberly Bogardus, Hermann Steller, Thomas Tuschl
Non-coding RNA biogenesis in higher eukaryotes has not been fully characterized. Here, we studied the Drosophila melanogaster Rexo5 (CG8368) protein, a metazoan-specific member of the DEDDh 3'-5' single-stranded RNA exonucleases, by genetic, biochemical, and RNA-sequencing approaches. Rexo5 is required for small nucleolar RNA (snoRNA) and rRNA biogenesis and is essential in D. melanogaster. Loss-of-function mutants accumulate improperly 3' end-trimmed 28S rRNA, 5S rRNA, and snoRNA precursors in vivo. Rexo5 is ubiquitously expressed at low levels in somatic metazoan cells but extremely elevated in male and female germ cells...
October 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/29045841/phosphorylation-of-irhom2-controls-stimulated-proteolytic-shedding-by-the-metalloprotease-adam17-tace
#9
Miguel Cavadas, Ioanna Oikonomidi, Catarina J Gaspar, Emma Burbridge, Marina Badenes, Inês Félix, Alfonso Bolado, Tianyi Hu, Andrea Bileck, Christopher Gerner, Pedro M Domingos, Alex von Kriegsheim, Colin Adrain
Cell surface metalloproteases coordinate signaling during development, tissue homeostasis, and disease. TACE (TNF-α-converting enzyme), is responsible for cleavage ("shedding") of membrane-tethered signaling molecules, including the cytokine TNF, and activating ligands of the EGFR. The trafficking of TACE within the secretory pathway requires its binding to iRhom2, which mediates the exit of TACE from the endoplasmic reticulum. An important, but mechanistically unclear, feature of TACE biology is its ability to be stimulated rapidly on the cell surface by numerous inflammatory and growth-promoting agents...
October 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/29045840/clonal-heterogeneity-influences-the-fate-of-new-adaptive-mutations
#10
Ignacio Vázquez-García, Francisco Salinas, Jing Li, Andrej Fischer, Benjamin Barré, Johan Hallin, Anders Bergström, Elisa Alonso-Perez, Jonas Warringer, Ville Mustonen, Gianni Liti
The joint contribution of pre-existing and de novo genetic variation to clonal adaptation is poorly understood but essential to designing successful antimicrobial or cancer therapies. To address this, we evolve genetically diverse populations of budding yeast, S. cerevisiae, consisting of diploid cells with unique haplotype combinations. We study the asexual evolution of these populations under selective inhibition with chemotherapeutic drugs by time-resolved whole-genome sequencing and phenotyping. All populations undergo clonal expansions driven by de novo mutations but remain genetically and phenotypically diverse...
October 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/29045839/heterotopic-transplantations-reveal-environmental-influences-on-interneuron-diversity-and-maturation
#11
Giulia Quattrocolo, Gord Fishell, Timothy J Petros
During embryogenesis, neural progenitors in the ganglionic eminences give rise to diverse GABAergic interneuron subtypes that populate all forebrain regions. The extent to which these cells are genetically predefined or determined by postmigratory environmental cues remains unknown. To address this question, we performed homo- and heterotopic transplantation of early postnatal MGE-derived cortical and hippocampal interneurons. Grafted cells migrated, and displayed neurochemical, electrophysiological, morphological, and neurochemical profiles similar to endogenous interneurons...
October 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/29045838/p75-is-required-for-the-establishment-of-postnatal-sensory-neuron-diversity-by-potentiating-ret-signaling
#12
Zhijiang Chen, Christopher R Donnelly, Bertha Dominguez, Yoshinobu Harada, Weichun Lin, Alan S Halim, Tasha G Bengoechea, Brian A Pierchala, Kuo-Fen Lee
Producing the neuronal diversity required to adequately discriminate all elements of somatosensation is a complex task during organogenesis. The mechanisms guiding this process during dorsal root ganglion (DRG) sensory neuron specification remain poorly understood. Here, we show that the p75 neurotrophin receptor interacts with Ret and its GFRα co-receptor upon stimulation with glial cell line-derived neurotrophic factor (GDNF). Furthermore, we demonstrate that p75 is required for GDNF-mediated Ret activation, survival, and cell surface localization of Ret in DRG neurons...
October 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/29045837/the-circadian-clock-gene-bmal1-controls-thyroid-hormone-mediated-spectral-identity-and-cone-photoreceptor-function
#13
Onkar B Sawant, Amanda M Horton, Olivia F Zucaro, Ricky Chan, Vera L Bonilha, Ivy S Samuels, Sujata Rao
Circadian clocks regulate various aspects of photoreceptor physiology, but their contribution to photoreceptor development and function is unclear. Cone photoreceptors are critical for color vision. Here, we define the molecular function of circadian activity within cone photoreceptors and reveal a role for the clock genes Bmal1 and Per2 in regulating cone spectral identity. ChIP analysis revealed that BMAL1 binds to the promoter region of the thyroid hormone (TH)-activating enzyme type 2 iodothyronine deiodinase (Dio2) and thus regulates the expression of Dio2...
October 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/29045836/arc-requires-psd95-for-assembly-into-postsynaptic-complexes-involved-with-neural-dysfunction-and-intelligence
#14
Esperanza Fernández, Mark O Collins, René A W Frank, Fei Zhu, Maksym V Kopanitsa, Jess Nithianantharajah, Sarah A Lemprière, David Fricker, Kathryn A Elsegood, Catherine L McLaughlin, Mike D R Croning, Colin Mclean, J Douglas Armstrong, W David Hill, Ian J Deary, Giulia Cencelli, Claudia Bagni, Menachem Fromer, Shaun M Purcell, Andrew J Pocklington, Jyoti S Choudhary, Noboru H Komiyama, Seth G N Grant
Arc is an activity-regulated neuronal protein, but little is known about its interactions, assembly into multiprotein complexes, and role in human disease and cognition. We applied an integrated proteomic and genetic strategy by targeting a tandem affinity purification (TAP) tag and Venus fluorescent protein into the endogenous Arc gene in mice. This allowed biochemical and proteomic characterization of native complexes in wild-type and knockout mice. We identified many Arc-interacting proteins, of which PSD95 was the most abundant...
October 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/29045835/a-role-for-dystonia-associated-genes-in-spinal-gabaergic-interneuron-circuitry
#15
Juliet Zhang, Jarret A P Weinrich, Jeffrey B Russ, John D Comer, Praveen K Bommareddy, Richard J DiCasoli, Christopher V E Wright, Yuqing Li, Peter J van Roessel, Julia A Kaltschmidt
Spinal interneurons are critical modulators of motor circuit function. In the dorsal spinal cord, a set of interneurons called GABApre presynaptically inhibits proprioceptive sensory afferent terminals, thus negatively regulating sensory-motor signaling. Although deficits in presynaptic inhibition have been inferred in human motor diseases, including dystonia, it remains unclear whether GABApre circuit components are altered in these conditions. Here, we use developmental timing to show that GABApre neurons are a late Ptf1a-expressing subclass and localize to the intermediate spinal cord...
October 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/29045834/a-latent-propriospinal-network-can-restore-diaphragm-function-after-high-cervical-spinal-cord-injury
#16
Jared M Cregg, Kevin A Chu, Lydia E Hager, Rachel S J Maggard, Daimen R Stoltz, Michaela Edmond, Warren J Alilain, Polyxeni Philippidou, Lynn T Landmesser, Jerry Silver
Spinal cord injury (SCI) above cervical level 4 disrupts descending axons from the medulla that innervate phrenic motor neurons, causing permanent paralysis of the diaphragm. Using an ex vivo preparation in neonatal mice, we have identified an excitatory spinal network that can direct phrenic motor bursting in the absence of medullary input. After complete cervical SCI, blockade of fast inhibitory synaptic transmission caused spontaneous, bilaterally coordinated phrenic bursting. Here, spinal cord glutamatergic neurons were both sufficient and necessary for the induction of phrenic bursts...
October 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/29045833/intestinal-fork-head-regulates-nutrient-absorption-and-promotes-longevity
#17
Ekin Bolukbasi, Mobina Khericha, Jennifer C Regan, Dobril K Ivanov, Jennifer Adcott, Miranda C Dyson, Tobias Nespital, Janet M Thornton, Nazif Alic, Linda Partridge
Reduced activity of nutrient-sensing signaling networks can extend organismal lifespan, yet the underlying biology remains unclear. We show that the anti-aging effects of rapamycin and reduced intestinal insulin/insulin growth factor (IGF) signaling (IIS) require the Drosophila FoxA transcription factor homolog Fork Head (FKH). Intestinal FKH induction extends lifespan, highlighting a role for the gut. FKH binds to and is phosphorylated by AKT and Target of Rapamycin. Gut-specific FKH upregulation improves gut barrier function in aged flies...
October 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/29045832/utx-kdm6a-loss-enhances-the-malignant-phenotype-of-multiple-myeloma-and-sensitizes-cells-to-ezh2-inhibition
#18
Teresa Ezponda, Daphné Dupéré-Richer, Christine M Will, Eliza C Small, Nobish Varghese, Tej Patel, Behnam Nabet, Relja Popovic, Jon Oyer, Marinka Bulic, Yupeng Zheng, Xiaoxiao Huang, Mrinal Y Shah, Sayantan Maji, Alberto Riva, Manuela Occhionorelli, Giovanni Tonon, Neil Kelleher, Jonathan Keats, Jonathan D Licht
Loss or inactivation of the histone H3K27 demethylase UTX occurs in several malignancies, including multiple myeloma (MM). Using an isogenic cell system, we found that loss of UTX leads to deactivation of gene expression ultimately promoting the proliferation, clonogenicity, adhesion, and tumorigenicity of MM cells. Moreover, UTX mutant cells showed increased in vitro and in vivo sensitivity to inhibition of EZH2, a histone methyltransferase that generates H3K27me3. Such sensitivity was related to a decrease in the levels of IRF4 and c-MYC and an activation of repressors of IRF4 characteristic of germinal center B cells such as BCL6 and IRF1...
October 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/29045831/usp7-is-a-tumor-specific-wnt-activator-for-apc-mutated-colorectal-cancer-by-mediating-%C3%AE-catenin-deubiquitination
#19
Laura Novellasdemunt, Valentina Foglizzo, Laura Cuadrado, Pedro Antas, Anna Kucharska, Vesela Encheva, Ambrosius P Snijders, Vivian S W Li
The tumor suppressor gene adenomatous polyposis coli (APC) is mutated in most colorectal cancers (CRCs), resulting in constitutive Wnt activation. To understand the Wnt-activating mechanism of the APC mutation, we applied CRISPR/Cas9 technology to engineer various APC-truncated isogenic lines. We find that the β-catenin inhibitory domain (CID) in APC represents the threshold for pathological levels of Wnt activation and tumor transformation. Mechanistically, CID-deleted APC truncation promotes β-catenin deubiquitination through reverse binding of β-TrCP and USP7 to the destruction complex...
October 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/29045830/in%C3%A2-vivo-suppression-of-hiv-rebound-by-didehydro-cortistatin-a-a-block-and-lock-strategy-for-hiv-1-treatment
#20
Cari F Kessing, Christopher C Nixon, Chuan Li, Perry Tsai, Hiroshi Takata, Guillaume Mousseau, Phong T Ho, Jenna B Honeycutt, Mohammad Fallahi, Lydie Trautmann, J Victor Garcia, Susana T Valente
HIV-1 Tat activates viral transcription and limited Tat transactivation correlates with latency establishment. We postulated a "block-and-lock" functional cure approach based on properties of the Tat inhibitor didehydro-Cortistatin A (dCA). HIV-1 transcriptional inhibitors could block ongoing viremia during antiretroviral therapy (ART), locking the HIV promoter in persistent latency. We investigated this hypothesis in human CD4(+) T cells isolated from aviremic individuals. Combining dCA with ART accelerates HIV-1 suppression and prevents viral rebound after treatment interruption, even during strong cellular activation...
October 17, 2017: Cell Reports
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