DOCSLIB.ORG

PDF, Also Known As Version of Record

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
PDF, Also Known As Version of Record King’s Research Portal DOI: 10.1038/s41467-018-03283-z Document Version Publisher's PDF, also known as Version of record Link to publication record in King's Research Portal Citation for published version (APA): Patel, N., Weekes, D., Drosopoulos, K., Gazinska, P., Noel, E., Rashid, M., Mirza, H., Quist, J., Brasó-Maristany, F., Mathew, S., Ferro, R., Pereira, A. M., Prince, C., Noor, F., Francesch-Domenech, E., Marlow, R., de Rinaldis, E., Grigoriadis, A., Linardopoulos, S., ... Tutt, A. N. J. (2018). Integrated genomics and functional validation identifies malignant cell specific dependencies in triple negative breast cancer. Nature Communications, 9(1), [1044]. https://doi.org/10.1038/s41467-018-03283-z Citing this paper Please note that where the full-text provided on King's Research Portal is the Author Accepted Manuscript or Post-Print version this may differ from the final Published version. If citing, it is advised that you check and use the publisher's definitive version for pagination, volume/issue, and date of publication details. And where the final published version is provided on the Research Portal, if citing you are again advised to check the publisher's website for any subsequent corrections. General rights Copyright and moral rights for the publications made accessible in the Research Portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognize and abide by the legal requirements associated with these rights. •Users may download and print one copy of any publication from the Research Portal for the purpose of private study or research. •You may not further distribute the material or use it for any profit-making activity or commercial gain •You may freely distribute the URL identifying the publication in the Research Portal Take down policy If you believe that this document breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 02. Oct. 2021 ARTICLE DOI: 10.1038/s41467-018-03283-z OPEN Integrated genomics and functional validation identifies malignant cell specific dependencies in triple negative breast cancer Nirmesh Patel1,2, Daniel Weekes1,2, Konstantinos Drosopoulos3, Patrycja Gazinska1,2, Elodie Noel1,2, Mamun Rashid1,2, Hasan Mirza1,2,4, Jelmar Quist1,2,4, Fara Brasó-Maristany1,2, Sumi Mathew1,2, Riccardo Ferro1,2, Ana Mendes Pereira1,2, Cynthia Prince1,2, Farzana Noor1,2, Erika Francesch-Domenech1,2, Rebecca Marlow1,2, Emanuele de Rinaldis1,2,5, Anita Grigoriadis 1,2,4, Spiros Linardopoulos3,6, Pierfrancesco Marra1,2 & Andrew N.J. Tutt 1,2,3 1234567890():,; Triple negative breast cancers (TNBCs) lack recurrent targetable driver mutations but demonstrate frequent copy number aberrations (CNAs). Here, we describe an integrative genomic and RNAi-based approach that identifies and validates gene addictions in TNBCs. CNAs and gene expression alterations are integrated and genes scored for pre-specified target features revealing 130 candidate genes. We test functional dependence on each of these genes using RNAi in breast cancer and non-malignant cells, validating malignant cell selective dependence upon 37 of 130 genes. Further analysis reveals a cluster of 13 TNBC addiction genes frequently co-upregulated that includes genes regulating cell cycle check- points, DNA damage response, and malignant cell selective mitotic genes. We validate the mechanism of addiction to a potential drug target: the mitotic kinesin family member C1 (KIFC1/HSET), essential for successful bipolar division of centrosome-amplified malignant cells and develop a potential selection biomarker to identify patients with tumors exhibiting centrosome amplification. 1 Breast Cancer Now Research Unit, King’s College London, London SE1 9RT, UK. 2 School of Cancer and Pharmaceutical Sciences, King’s Health Partners AHSC, Faculty of Life Sciences and Medicine, King’s College London, London WC2R 2LS, UK. 3 The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW7 3RP, UK. 4 Cancer Bioinformatics, King’s College London, London SE1 9RT, UK. 5 Precision Immunology Cluster, Sanofi, 640 Memorial Drive, Cambridge, MA 02149, USA. 6 Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London SM2 5NG, UK. These contributed equally: Pierfrancesco Marra, Andrew N. J. Tutt. Correspondence and requests for materials should be addressed to A.N.J.T. (email: [email protected]) NATURE COMMUNICATIONS | (2018) 9:1044 | DOI: 10.1038/s41467-018-03283-z | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/s41467-018-03283-z – riple negative breast cancers (TNBCs) are difficult to treat normal breast epithelium samples14 16. All clinico-pathological Tand lack expression of the validated breast cancer ther- features of the cohort are provided in Supplementary Data 1.We apeutic targets: estrogen (ER), progesterone (PR), and obtained gene-centric copy number levels, frequency and focality human epidermal growth factor 2 (HER2) receptors1. TNBCs are of gene copy number changes as well as the gene expression from heterogeneous2 with substantial numbers of patients in subgroups this cohort (Fig. 1a). The data were integrated with analyses of that have high risk of early metastatic relapse commonly resistant publicly available databases such as COSMIC17, the membra- to systemic therapy. Despite frequent resistance, chemotherapy is nome18, the druggable genome19, secretome20, CAN genes21, and the only widely accepted systemic therapy option for these kinome22 (Supplementary Data 2). All the above data were col- patients, highlighting the need to better understand the under- lated in the Target ID data platform that was used as a foundation lying biology and identify tumor cell-specific therapy targets for for the application of a pre-specified selection algorithm for drug discovery or “repositioning” of known therapies. putative addiction genes in TNBC. Identification of tumor addictions (dependence on a gene for The Target ID data platform informed two complementary proliferation and survival) has in the past led to the development approaches to gene selection for functional validation (mRNA of novel therapies, notably the discovery of ERBB2 amplification overexpression and gene amplification/ mRNA expression and overexpression, now targeted by a number of therapies in correlation) with the aim being to minimize bias and limitations breast cancer3. Despite progress in characterizing the genomic inherent to any single analytical procedure. First, a copy number- – landscape of breast cancer4,5 and TNBC specifically2,6 8, targe- dependent gene expression analysis selected 1978 candidate genes table biological dependencies remain elusive and poorly char- amplified in >10% of TNBCs with a gene copy number/gene acterized. With the exception of clonally dominant mutations in expression correlation (r2 > 0.3, p < 0.01, Spearman’s rank corre- TP53, TNBCs demonstrate a high degree of inter-tumor and lation). We then linked the candidate genes to features, included intra-tumor heterogeneity at the mutational level with each driver in the Target ID data platform, which are known to be relevant to mutation only present in a subset of tumors and clones within hallmarks of malignancy in a weighted scoring system (Fig. 1a any individual tumor9. and Supplementary Data 3). The top 85 genes were taken forward TNBCs have a high frequency of chromosomal instability for functional validation. resulting in variable copy number state and levels of gene Second, a complementary gene expression-centered analysis expression7,10. Genes that are found in amplified regions and are was used as there is evidence that variations in the expression of highly expressed, may be drivers of important “hallmarks” of tumor addiction genes may also occur in the absence of in cis malignancy11 and potentially represent essential tumor addic- CNAs through multiple mechanisms, for example through tions. A number of high-throughput loss of function screening epigenetic regulation23. For the gene expression-centered analysis, studies have identified gene addictions in cellular models of we identified 1001 genes whose average expression in our TNBC cancer including breast cancer models4,5,12 but functional vali- cohort was >2-fold higher than normal breast epithelium dation has been limited and studies have rarely been informed by controls. As anticipated by the inclusion of CNA correlated evidence of upregulation of gene copy number or mRNA in large elevated gene expression in the first approach there was a numbers of patient tumors. Therefore, the main aim of this study substantial overlap with 45 of the genes from the second is to identify and validate recurrently amplified genes as being approach which were taken forward for functional validation. important for malignant phenotypes in TNBC. We perform a An additional 45 genes identified by this second approach were pre-specified integrative computational “driver” identification selected based exclusively on gene annotation and literature and RNAi-based functional validation approach, taking into review. This manually curated filtering sought to identify genes account both the copy number landscape and whole genome already shown to drive a tumor phenotype in other cancer models expression state in individual tumors, using a large discovery or being involved in biological pathways known to be key in cohort
Load more

Recommended publications
  • RNA Sequencing Reveals a Slow to Fast Muscle Fiber Type Transition After Olanzapine Infusion in Rats
    RESEARCH ARTICLE RNA Sequencing Reveals a Slow to Fast Muscle Fiber Type Transition after Olanzapine Infusion in Rats Christopher J. Lynch1*, Yuping Xu1, Andras Hajnal2, Anna C. Salzberg3, Yuka Imamura Kawasawa4,5,6 1 Department of Cellular and Molecular Physiology, College of Medicine, Penn State University, Hershey, Pennsylvania, 17033, United States of America, 2 Department of Neural and Behavioral Sciences, College of Medicine, Penn State University, Hershey, Pennsylvania, 17033, United States of America, 3 Department a11111 of Public Health Sciences, College of Medicine, Penn State University, Hershey, Pennsylvania, 17033, United States of America, 4 Department of Pharmacology, College of Medicine, Penn State University, Hershey, Pennsylvania, 17033, United States of America, 5 Department of Biochemistry and Molecular Biology, College of Medicine, Penn State University, Hershey, Pennsylvania, 17033, United States of America, 6 The Institute for Personalized Medicine, College of Medicine, Penn State University, Hershey, Pennsylvania, 17033, United States of America * [email protected] OPEN ACCESS Citation: Lynch CJ, Xu Y, Hajnal A, Salzberg AC, Kawasawa YI (2015) RNA Sequencing Reveals a Abstract Slow to Fast Muscle Fiber Type Transition after Olanzapine Infusion in Rats. PLoS ONE 10(4): Second generation antipsychotics (SGAs), like olanzapine, exhibit acute metabolic side ef- e0123966. doi:10.1371/journal.pone.0123966 fects leading to metabolic inflexibility, hyperglycemia, adiposity and diabetes. Understand- Academic Editor: Guillermo López Lluch, ing how SGAs affect the skeletal muscle transcriptome could elucidate approaches for Universidad Pablo de Olavide, Centro Andaluz de mitigating these side effects. Male Sprague-Dawley rats were infused intravenously with ve- Biología del Desarrollo-CSIC, SPAIN hicle or olanzapine for 24h using a dose leading to a mild hyperglycemia.
    [Show full text]
  • A Yeast Phenomic Model for the Gene Interaction Network Modulating
    Louie et al. Genome Medicine 2012, 4:103 http://genomemedicine.com/content/4/12/103 RESEARCH Open Access A yeast phenomic model for the gene interaction network modulating CFTR-ΔF508 protein biogenesis Raymond J Louie3†, Jingyu Guo1,2†, John W Rodgers1, Rick White4, Najaf A Shah1, Silvere Pagant3, Peter Kim3, Michael Livstone5, Kara Dolinski5, Brett A McKinney6, Jeong Hong2, Eric J Sorscher2, Jennifer Bryan4, Elizabeth A Miller3* and John L Hartman IV1,2* Abstract Background: The overall influence of gene interaction in human disease is unknown. In cystic fibrosis (CF) a single allele of the cystic fibrosis transmembrane conductance regulator (CFTR-ΔF508) accounts for most of the disease. In cell models, CFTR-ΔF508 exhibits defective protein biogenesis and degradation rather than proper trafficking to the plasma membrane where CFTR normally functions. Numerous genes function in the biogenesis of CFTR and influence the fate of CFTR-ΔF508. However it is not known whether genetic variation in such genes contributes to disease severity in patients. Nor is there an easy way to study how numerous gene interactions involving CFTR-ΔF would manifest phenotypically. Methods: To gain insight into the function and evolutionary conservation of a gene interaction network that regulates biogenesis of a misfolded ABC transporter, we employed yeast genetics to develop a ‘phenomic’ model, in which the CFTR-ΔF508-equivalent residue of a yeast homolog is mutated (Yor1-ΔF670), and where the genome is scanned quantitatively for interaction. We first confirmed that Yor1-ΔF undergoes protein misfolding and has reduced half-life, analogous to CFTR-ΔF. Gene interaction was then assessed quantitatively by growth curves for approximately 5,000 double mutants, based on alteration in the dose response to growth inhibition by oligomycin, a toxin extruded from the cell at the plasma membrane by Yor1.
    [Show full text]
  • Co-Expression Module Analysis Reveals Biological Processes
    Shi et al. BMC Systems Biology 2010, 4:74 http://www.biomedcentral.com/1752-0509/4/74 RESEARCH ARTICLE Open Access Co-expressionResearch article module analysis reveals biological processes, genomic gain, and regulatory mechanisms associated with breast cancer progression Zhiao Shi1,2, Catherine K Derow3 and Bing Zhang*3 Abstract Background: Gene expression signatures are typically identified by correlating gene expression patterns to a disease phenotype of interest. However, individual gene-based signatures usually suffer from low reproducibility and interpretability. Results: We have developed a novel algorithm Iterative Clique Enumeration (ICE) for identifying relatively independent maximal cliques as co-expression modules and a module-based approach to the analysis of gene expression data. Applying this approach on a public breast cancer dataset identified 19 modules whose expression levels were significantly correlated with tumor grade. The correlations were reproducible for 17 modules in an independent breast cancer dataset, and the reproducibility was considerably higher than that based on individual genes or modules identified by other algorithms. Sixteen out of the 17 modules showed significant enrichment in certain Gene Ontology (GO) categories. Specifically, modules related to cell proliferation and immune response were up-regulated in high- grade tumors while those related to cell adhesion was down-regulated. Further analyses showed that transcription factors NYFB, E2F1/E2F3, NRF1, and ELK1 were responsible for the up-regulation of the cell proliferation modules. IRF family and ETS family proteins were responsible for the up-regulation of the immune response modules. Moreover, inhibition of the PPARA signaling pathway may also play an important role in tumor progression.
    [Show full text]
  • View / Download 3.3 Mb
    Identification of Mechanisms and Pathways Involved in MLL2-Mediated Tumorigenesis by Chun-Chi Chang Department of Pathology Duke University Date:_______________________ Approved: ___________________________ Yiping He, Supervisor ___________________________ Salvatore Pizzo ___________________________ Hai Yan Thesis submitted in partial fulfillment of the requirements for the degree of Master of Science in the Department of Pathology in the Graduate School of Duke University 2013 ABSTRACT Identification of Mechanisms and Pathways Involved in MLL2-Mediated Tumorigenesis by Chun-Chi Chang Department of Pathology Duke University Date:_______________________ Approved: ___________________________ Yiping He, Supervisor ___________________________ Salvatore Pizzo ___________________________ Hai Yan An abstract of a thesis submitted in partial fulfillment of the requirements for the degree of Master of Science in the Department of Pathology in the Graduate School of Duke University 2013 Copyright by Chun-Chi Chang 2013 Abstract Myeloid/lymphoid or mixed-lineage leukemia (MLL)-family genes encode histone lysine methyltransferases that play important roles in epigenetic regulation of gene transcription, and these genes are frequently mutated in human cancers. While MLL1 and MLL4 have been the most extensively studied, MLL2 and its homolog MLL3 are not well-understood. Specifically, little is known regarding the extent of global MLL2 involvement in the regulation of gene expression and the mechanism underlying its alterations in mediating tumorigenesis. To study the role of MLL2 in tumorigenesis, we somatically knocked out MLL2 in a colorectal carcinoma cell line, HCT116. We observed that the MLL2 loss of function results in significant reduction of cell growth and multinuclear morphology. We further profiled MLL2 regulated genes and pathways by analyzing gene expression in MLL2 wild-type versus MLL2-null isogenic cell lines.
    [Show full text]
  • Gene Expression Profiling to Identify Eggshell Proteins Involved In
    Jonchère et al. BMC Genomics 2010, 11:57 http://www.biomedcentral.com/1471-2164/11/57 RESEARCH ARTICLE Open Access Gene expression profiling to identify eggshell proteins involved in physical defense of the chicken egg Vincent Jonchère1, Sophie Réhault-Godbert1, Christelle Hennequet-Antier1, Cédric Cabau1, Vonick Sibut1,3, Larry A Cogburn2, Yves Nys1, Joel Gautron1* Abstract Background: As uricoletic animals, chickens produce cleidoic eggs, which are self-contained bacteria-resistant biological packages for extra-uterine development of the chick embryo. The eggshell constitutes a natural physical barrier against bacterial penetration if it forms correctly and remains intact. The eggshell’s remarkable mechanical properties are due to interactions among mineral components and the organic matrix proteins. The purpose of our study was to identify novel eggshell proteins by examining the transcriptome of the uterus during calcification of the eggshell. An extensive bioinformatic analysis on genes over-expressed in the uterus allowed us to identify novel eggshell proteins that contribute to the egg’s natural defenses. Results: Our 14 K Del-Mar Chicken Integrated Systems microarray was used for transcriptional profiling in the hen’s uterus during eggshell deposition. A total of 605 transcripts were over-expressed in the uterus compared with the magnum or white isthmus across a wide range of abundance (1.1- to 79.4-fold difference). The 605 highly- expressed uterine transcripts correspond to 469 unique genes, which encode 437 different proteins. Gene Ontology (GO) analysis was used for interpretation of protein function. The most over-represented GO terms are related to genes encoding ion transport proteins, which provide eggshell mineral precursors.
    [Show full text]
  • Mutations in the VPS45 Gene, a SEC1 Homologue, Result in Vacuolar Protein Sorting Defects and Accumulation of Membrane Vesicles
    Journal of Cell Science 107, 3449-3459 (1994) 3449 Printed in Great Britain © The Company of Biologists Limited 1994 Mutations in the VPS45 gene, a SEC1 homologue, result in vacuolar protein sorting defects and accumulation of membrane vesicles Christopher R. Cowles, Scott D. Emr* and Bruce F. Horazdovsky† Division of Cellular and Molecular Medicine & Howard Hughes Medical Institute, University of California, San Diego, School of Medicine, La Jolla, California 92093-0668, USA *Author for correspondence †Present address: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75235-9038, USA SUMMARY Genetic analyses of vacuolar protein sorting in Saccha- kDa protein in labeled yeast cell extracts. Subcellular frac- romyces cerevisiae have uncovered a large number of tionation studies demonstrate that the majority of Vps45p mutants (vps) that missort and secrete vacuolar hydrolases. is associated with a high-speed membrane pellet fraction A small subset of vps mutants exhibit a temperature-con- that includes Golgi, transport vesicles and, potentially, ditional growth phenotype and show a severe defect in the endosomal membranes. Significantly, this fraction lacks localization of soluble vacuolar proteins, yet maintain a ER, vacuole and plasma membranes. Overexpression of near-normal vacuole structure. Here, we report on the Vps45p saturates the sites with which Vps45p associates. A cloning and characterization of the gene affected in one of vps45 null mutant accumulates vesicles, many of which these mutants, VPS45, which has been found to encode a were found to be present in large clusters. This accumula- member of a protein family that includes the yeast proteins tion of potential transport vesicles indicates that Vps45p Sec1p, Sly1p and Vps33p, as well as n-Sec1, UNC18 and may facilitate the targeting and/or fusion of these vesicles Rop from other eukaryotic organisms.
    [Show full text]
  • RAB11-Mediated Trafficking and Human Cancers: an Updated Review
    biology Review RAB11-Mediated Trafficking and Human Cancers: An Updated Review Elsi Ferro 1,2, Carla Bosia 1,2 and Carlo C. Campa 1,2,* 1 Department of Applied Science and Technology, Politecnico di Torino, 24 Corso Duca degli Abruzzi, 10129 Turin, Italy; [email protected] (E.F.); [email protected] (C.B.) 2 Italian Institute for Genomic Medicine, c/o IRCCS, Str. Prov. le 142, km 3.95, 10060 Candiolo, Italy * Correspondence: [email protected] Simple Summary: The small GTPase RAB11 is a master regulator of both vesicular trafficking and membrane dynamic defining the surface proteome of cellular membranes. As a consequence, the alteration of RAB11 activity induces changes in both the sensory and the transduction apparatuses of cancer cells leading to tumor progression and invasion. Here, we show that this strictly depends on RAB110s ability to control the sorting of signaling receptors from endosomes. Therefore, RAB11 is a potential therapeutic target over which to develop future therapies aimed at dampening the acquisition of aggressive traits by cancer cells. Abstract: Many disorders block and subvert basic cellular processes in order to boost their pro- gression. One protein family that is prone to be altered in human cancers is the small GTPase RAB11 family, the master regulator of vesicular trafficking. RAB11 isoforms function as membrane organizers connecting the transport of cargoes towards the plasma membrane with the assembly of autophagic precursors and the generation of cellular protrusions. These processes dramatically impact normal cell physiology and their alteration significantly affects the survival, progression and metastatization as well as the accumulation of toxic materials of cancer cells.
    [Show full text]
  • Agricultural University of Athens
    ΓΕΩΠΟΝΙΚΟ ΠΑΝΕΠΙΣΤΗΜΙΟ ΑΘΗΝΩΝ ΣΧΟΛΗ ΕΠΙΣΤΗΜΩΝ ΤΩΝ ΖΩΩΝ ΤΜΗΜΑ ΕΠΙΣΤΗΜΗΣ ΖΩΙΚΗΣ ΠΑΡΑΓΩΓΗΣ ΕΡΓΑΣΤΗΡΙΟ ΓΕΝΙΚΗΣ ΚΑΙ ΕΙΔΙΚΗΣ ΖΩΟΤΕΧΝΙΑΣ ΔΙΔΑΚΤΟΡΙΚΗ ΔΙΑΤΡΙΒΗ Εντοπισμός γονιδιωματικών περιοχών και δικτύων γονιδίων που επηρεάζουν παραγωγικές και αναπαραγωγικές ιδιότητες σε πληθυσμούς κρεοπαραγωγικών ορνιθίων ΕΙΡΗΝΗ Κ. ΤΑΡΣΑΝΗ ΕΠΙΒΛΕΠΩΝ ΚΑΘΗΓΗΤΗΣ: ΑΝΤΩΝΙΟΣ ΚΟΜΙΝΑΚΗΣ ΑΘΗΝΑ 2020 ΔΙΔΑΚΤΟΡΙΚΗ ΔΙΑΤΡΙΒΗ Εντοπισμός γονιδιωματικών περιοχών και δικτύων γονιδίων που επηρεάζουν παραγωγικές και αναπαραγωγικές ιδιότητες σε πληθυσμούς κρεοπαραγωγικών ορνιθίων Genome-wide association analysis and gene network analysis for (re)production traits in commercial broilers ΕΙΡΗΝΗ Κ. ΤΑΡΣΑΝΗ ΕΠΙΒΛΕΠΩΝ ΚΑΘΗΓΗΤΗΣ: ΑΝΤΩΝΙΟΣ ΚΟΜΙΝΑΚΗΣ Τριμελής Επιτροπή: Aντώνιος Κομινάκης (Αν. Καθ. ΓΠΑ) Ανδρέας Κράνης (Eρευν. B, Παν. Εδιμβούργου) Αριάδνη Χάγερ (Επ. Καθ. ΓΠΑ) Επταμελής εξεταστική επιτροπή: Aντώνιος Κομινάκης (Αν. Καθ. ΓΠΑ) Ανδρέας Κράνης (Eρευν. B, Παν. Εδιμβούργου) Αριάδνη Χάγερ (Επ. Καθ. ΓΠΑ) Πηνελόπη Μπεμπέλη (Καθ. ΓΠΑ) Δημήτριος Βλαχάκης (Επ. Καθ. ΓΠΑ) Ευάγγελος Ζωίδης (Επ.Καθ. ΓΠΑ) Γεώργιος Θεοδώρου (Επ.Καθ. ΓΠΑ) 2 Εντοπισμός γονιδιωματικών περιοχών και δικτύων γονιδίων που επηρεάζουν παραγωγικές και αναπαραγωγικές ιδιότητες σε πληθυσμούς κρεοπαραγωγικών ορνιθίων Περίληψη Σκοπός της παρούσας διδακτορικής διατριβής ήταν ο εντοπισμός γενετικών δεικτών και υποψηφίων γονιδίων που εμπλέκονται στο γενετικό έλεγχο δύο τυπικών πολυγονιδιακών ιδιοτήτων σε κρεοπαραγωγικά ορνίθια. Μία ιδιότητα σχετίζεται με την ανάπτυξη (σωματικό βάρος στις 35 ημέρες, ΣΒ) και η άλλη με την αναπαραγωγική
    [Show full text]
  • A SARS-Cov-2 Bioid-Based Virus-Host Membrane Protein Interactome and Virus Peptide Compendium: New Proteomics Resources for COVID-19 Research
    bioRxiv preprint doi: https://doi.org/10.1101/2020.08.28.269175; this version posted August 28, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. A SARS-CoV-2 BioID-based virus-host membrane protein interactome and virus peptide compendium: new proteomics resources for COVID-19 research Jonathan R. St-Germain1, Audrey Astori*1, Payman Samavarchi-Tehrani*2, Hala Abdouni2, Vinitha Macwan1, Dae-Kyum Kim2, Jennifer J. Knapp2, Frederick P. Roth2,3,4, Anne-Claude Gingras†2,3 and Brian Raught†1,5 1. Princess Margaret Cancer Centre, University Health Network, 101 College St., Toronto, ON, Canada 2. Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada 3. Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada 4. Department of Computer Science, University of Toronto, Toronto, ON, Canada 5. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada *these authors contributed equally † corresponding authors bioRxiv preprint doi: https://doi.org/10.1101/2020.08.28.269175; this version posted August 28, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Summary Key steps of viral replication take place at host cell membranes, but the detection of membrane- associated protein-protein interactions using standard affinity-based approaches (e.g.
    [Show full text]
  • Autocrine IFN Signaling Inducing Profibrotic Fibroblast Responses By
    Downloaded from http://www.jimmunol.org/ by guest on September 23, 2021 Inducing is online at: average * The Journal of Immunology , 11 of which you can access for free at: 2013; 191:2956-2966; Prepublished online 16 from submission to initial decision 4 weeks from acceptance to publication August 2013; doi: 10.4049/jimmunol.1300376 http://www.jimmunol.org/content/191/6/2956 A Synthetic TLR3 Ligand Mitigates Profibrotic Fibroblast Responses by Autocrine IFN Signaling Feng Fang, Kohtaro Ooka, Xiaoyong Sun, Ruchi Shah, Swati Bhattacharyya, Jun Wei and John Varga J Immunol cites 49 articles Submit online. Every submission reviewed by practicing scientists ? is published twice each month by Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://jimmunol.org/subscription Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html http://www.jimmunol.org/content/suppl/2013/08/20/jimmunol.130037 6.DC1 This article http://www.jimmunol.org/content/191/6/2956.full#ref-list-1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material References Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 23, 2021. The Journal of Immunology A Synthetic TLR3 Ligand Mitigates Profibrotic Fibroblast Responses by Inducing Autocrine IFN Signaling Feng Fang,* Kohtaro Ooka,* Xiaoyong Sun,† Ruchi Shah,* Swati Bhattacharyya,* Jun Wei,* and John Varga* Activation of TLR3 by exogenous microbial ligands or endogenous injury-associated ligands leads to production of type I IFN.
    [Show full text]
  • Coexpression Networks Based on Natural Variation in Human Gene Expression at Baseline and Under Stress
    University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations Fall 2010 Coexpression Networks Based on Natural Variation in Human Gene Expression at Baseline and Under Stress Renuka Nayak University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Computational Biology Commons, and the Genomics Commons Recommended Citation Nayak, Renuka, "Coexpression Networks Based on Natural Variation in Human Gene Expression at Baseline and Under Stress" (2010). Publicly Accessible Penn Dissertations. 1559. https://repository.upenn.edu/edissertations/1559 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/1559 For more information, please contact [email protected]. Coexpression Networks Based on Natural Variation in Human Gene Expression at Baseline and Under Stress Abstract Genes interact in networks to orchestrate cellular processes. Here, we used coexpression networks based on natural variation in gene expression to study the functions and interactions of human genes. We asked how these networks change in response to stress. First, we studied human coexpression networks at baseline. We constructed networks by identifying correlations in expression levels of 8.9 million gene pairs in immortalized B cells from 295 individuals comprising three independent samples. The resulting networks allowed us to infer interactions between biological processes. We used the network to predict the functions of poorly-characterized human genes, and provided some experimental support. Examining genes implicated in disease, we found that IFIH1, a diabetes susceptibility gene, interacts with YES1, which affects glucose transport. Genes predisposing to the same diseases are clustered non-randomly in the network, suggesting that the network may be used to identify candidate genes that influence disease susceptibility.
    [Show full text]
  • An Integrative Genomic Analysis of the Longshanks Selection Experiment for Longer Limbs in Mice
    bioRxiv preprint doi: https://doi.org/10.1101/378711; this version posted August 19, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Title: 2 An integrative genomic analysis of the Longshanks selection experiment for longer limbs in mice 3 Short Title: 4 Genomic response to selection for longer limbs 5 One-sentence summary: 6 Genome sequencing of mice selected for longer limbs reveals that rapid selection response is 7 due to both discrete loci and polygenic adaptation 8 Authors: 9 João P. L. Castro 1,*, Michelle N. Yancoskie 1,*, Marta Marchini 2, Stefanie Belohlavy 3, Marek 10 Kučka 1, William H. Beluch 1, Ronald Naumann 4, Isabella Skuplik 2, John Cobb 2, Nick H. 11 Barton 3, Campbell Rolian2,†, Yingguang Frank Chan 1,† 12 Affiliations: 13 1. Friedrich Miescher Laboratory of the Max Planck Society, Tübingen, Germany 14 2. University of Calgary, Calgary AB, Canada 15 3. IST Austria, Klosterneuburg, Austria 16 4. Max Planck Institute for Cell Biology and Genetics, Dresden, Germany 17 Corresponding author: 18 Campbell Rolian 19 Yingguang Frank Chan 20 * indicates equal contribution 21 † indicates equal contribution 22 Abstract: 23 Evolutionary studies are often limited by missing data that are critical to understanding the 24 history of selection. Selection experiments, which reproduce rapid evolution under controlled 25 conditions, are excellent tools to study how genomes evolve under strong selection. Here we 1 bioRxiv preprint doi: https://doi.org/10.1101/378711; this version posted August 19, 2018.
    [Show full text]