DOCSLIB.ORG

Krüppel-Like Factors Integrin Targeted by 7Β Leukocyte

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Krüppel-Like Factors Integrin Targeted by 7Β Leukocyte Leukocyte β7 Integrin Targeted by Krüppel-like Factors Melanie Alles, Gleb Turchinovich, Pumin Zhang, Wolfgang Schuh, Fabien Agenès and Jörg Kirberg This information is current as of September 29, 2021. J Immunol 2014; 193:1737-1746; Prepublished online 11 July 2014; doi: 10.4049/jimmunol.1302613 http://www.jimmunol.org/content/193/4/1737 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2014/07/11/jimmunol.130261 Material 3.DCSupplemental References This article cites 69 articles, 32 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/193/4/1737.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 29, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Leukocyte b7 Integrin Targeted by Kruppel-like€ Factors Melanie Alles,* Gleb Turchinovich,†,‡ Pumin Zhang,x Wolfgang Schuh,{ Fabien Agene`s,‖,#,1 and Jo¨rg Kirberg* Constitutive expression of Kruppel-like€ factor 3 (KLF3, BKLF) increases marginal zone (MZ) B cell numbers, a phenotype shared with mice lacking KLF2. Ablation of KLF3, known to interact with serum response factor (SRF), or SRF itself, results in fewer MZ B cells. It is unknown how these functional equivalences result. In this study, it is shown that KLF3 acts as transcriptional repressor for the leukocyte-specific integrin b7 (Itgb7, Ly69) by binding to the b7 promoter, as revealed by chromatin immuno- precipitation. KLF2 overexpression antagonizes this repression and also binds the b7 promoter, indicating that these factors may compete for target sequence(s). Whereas b7 is identified as direct KLF target, its repression by KLF3 is not connected to the MZ B cell increase because b7-deficient mice have a normal complement of these and the KLF3-driven increase still occurs when b7 is deleted. Despite this, KLF3 overexpression abolishes lymphocyte homing to Peyer’s patches, much like b7 deficiency does. Furthermore, KLF3 expression alone overcomes the MZ B cell deficiency when SRF is absent. SRF is also dispensable for the Downloaded from KLF3-mediated repression of b7. Thus, despite the shared phenotype of KLF3 and SRF-deficient mice, cooperation of these factors appears neither relevant for the formation of MZ B cells nor for the regulation of b7. Finally, a potent negative regulatory feedback loop limiting KLF3 expression is shown in this study, mediated by KLF3 directly repressing its own gene promoter. In summary, KLFs use regulatory circuits to steer lymphocyte maturation and homing and directly control leukocyte integrin expression. The Journal of Immunology, 2014, 193: 1737–1746. http://www.jimmunol.org/ ruppel-like€ factors (KLFs) are zinc finger family tran- KLF3 may act exclusively in concert with other transcriptional scription factors with 17 members described for mam- regulators. K malian cells (1). KLFs have a highly conserved DNA In lymphocytes, KLFs play important roles in their development binding domain comprised of three C2H2 zinc fingers near or at the and function (7, 9, 13–20). When constitutively expressed under C terminus and share similarity to the transcription factors of the the B cell–specific CD19 promoter, KLF3 increases maturation specificity protein family (2–5). The KLF zinc fingers are thought toward marginal zone (MZ) B cells, resulting in a 5- to 10-fold to mediate binding to CACCC elements and GC-rich DNA increase of this subset, whereas, accordingly, MZ B cells were sequences in target genes. reduced in KLF3-deficient mice (7, 9). Interestingly, absence of by guest on September 29, 2021 In Drosophila Schneider cells, KLF3 (BKLF) had been shown KLF2 in B cells results in an increase of MZ B cells, mimicking to act as a weak transcriptional activator (6). However, more re- the effect of constitutive KLF3 expression (15, 16, 19). Although cent data in murine cells implicate KLF3 as a repressor of tran- the actual target genes mediating this effect are unknown, it has scription (7–9). Indeed, KLF3 has been shown to interact with the been demonstrated that the lymphocyte phenotypes of KLF2- common transcriptional corepressors C-terminal binding protein 2 deficient mice result from effects on the positioning, recircula- (CtBP2) and four and a half LIM domain protein 3 (FHL3) (8, 10, tion, and/or tissue-homing ability of these cells (13, 14, 19, 21– 11). A further KLF3-interacting transcription factor is serum 24). However, not all outcomes of KLF2 deficiency resulted response factor (SRF), as identified in muscle cells (12). Thus, from cell-autonomous processes (18). Integrins perform crucial functions for the positioning of leu- kocytes by acting both as signaling and signaling-responsive ad- *Division of Immunology (3/3), Paul-Ehrlich-Institut, 63225 Langen, Germany; hesion molecules (25). The functions of the leukocyte-specific b2 †Department of Biomedicine, Laboratory of Developmental Immunology, 4058 Basel, x b Switzerland; ‡Basel University Children’s Hospital, 4031 Basel, Switzerland; Department (CD18) and 7 (Ly69) integrin subunits have been elucidated of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX initially by blocking studies and subsequently by the respective { 77030; Division of Molecular Immunology, Department of Internal Medicine III, gene-deficient mice. This led to a mouse model of leukocyte ad- Nikolaus-Fiebiger-Center, University of Erlangen-Nurnberg,€ 91054 Erlangen, Germany; ‖INSERM U743, Montreal, Quebec H2X 1P1, Canada; and #INSERM ADR Paris V Saint hesion deficiency (LFA-A immunodeficiency, OMIM 116920) and Anne, 75014 Paris, France specific defects in the migration of leukocytes to tissues such as 1Current address: Office for Science and Technology, Consulate General of France, skin and gut, respectively (26–31). Indeed, whereas leukocyte Los Angeles, CA. migration via the afferent lymph and within lymph nodes is not Received for publication September 30, 2013. Accepted for publication June 6, 2014. affected in the absence of all integrins, their extravasation is Address correspondence and reprint requests to Dr. Jo¨rg Kirberg, Paul-Ehrlich- crucially dependent on them (32). With respect to b7 integrin, this Institut, Division of Immunology (3/3), D-63225 Langen, Germany. E-mail address: subunit can either pair with a (CD49d) to form lymphocyte [email protected] 4 Peyer’s patch (PP) adhesion molecule-1 (a /b ), mediating bind- The online version of this article contains supplemental material. 4 7 ing to VCAM-1, mucosal addressin cell adhesion molecule 1 Abbreviations used in this article: ChIP, chromatin immunoprecipitation; CtBP2, a C-terminal binding protein 2; KLF, Kruppel-like€ factor; MAdCAM-1, mucosal (MAdCAM-1; addressin), and fibronectin, or pair with E (CD103), addressin cell adhesion molecule 1; MLn, mesenteric lymph node; MZ, marginal a heterodimer found particularly among intestinal intraepithelial zone; PP, Peyer’s patch; QRT-PCR, quantitative real-time PCR; RIPA, radioimmu- lymphocytes mediating binding to E-cadherin. Thus, b expres- noprecipitation assay; SRF, serum response factor. 7 sion is considered a hallmark of mucosal lymphocytes because Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 a4/b7 allows for binding to the high endothelial venules of gut www.jimmunol.org/cgi/doi/10.4049/jimmunol.1302613 1738 KLF2/3-REGULATING LEUKOCYTE b7 INTEGRIN PP and mesenteric lymph nodes (MLn), and endothelial cells of streptomycin (Life Technologies), b-ME (50 mM), Gln (4 mM), 0.03% the lamina propria, all specifically expressing MAdCAM-1 (33), (w/v) Primatone RL (Quest, 5x59051, 10-kDa ultrafiltrate) (52), 5 mg/ml insulin (Sigma-Aldrich I5500), and 2% FCS (unless indicated differently) and aE/b7 mediating the retention within the tissue by binding to at 5–7.5% CO2, 37˚C. E-cadherin, expressed in the gut epithelial layer. Whereas aE (CD103) only pairs with b7, a4 (CD49d) can pair with either b7 or Retroviral transduction b a b 1 (CD29), the latter termed VLA-4 ( 4/ 1, CD49d/CD29), medi- Retroviral vector particles were obtained by transient transfection of ret- ating binding to VCAM-1, MAdCAM-1, and fibronectin. Whereas roviral vector plasmid DNA into Plat-E producer cells (53). Briefly, the day 3 6 binding specificities thus overlap, the ratio of a4/b7 and a4/b1 de- prior to transfection, 5 10 Plat-E cells were plated in a T75 flask in 8– 10 ml medium (10% FCS). The next afternoon, chloroquine (25 mM final) termines lymphocyte-homing specificity because a4/b7 preferentially (54) was added, and 1 h later cells were transfected using calcium- binds to MAdCAM-1 and a4/b1 has higher affinity for VCAM-1 phosphate [to 1 ml 20 mg plasmid DNA in 0.295 M CaCl2, 1 ml 50 mM (34–36). The relative expression of these integrins is set transcrip- N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES), 280 mM tionally but also depends on intracellular pairing preferences. Ap- NaCl, 1.5 mM Na2HPO4 (pH 7.16) was added, gassed with air for 20 s, and parently, under nonstimulated conditions, the expression of a4 and, immediately the mixture was added to the cells] (55). The next morning, medium was exchanged. Virus particle-containing supernatants were taken particularly, b1 is limited, such that the preferentially associating a4/b1 a b 42, 50, 66, and 72 h after transfection.
Load more

Recommended publications
  • FHL3 Contributes to EMT and Chemotherapy Resistance Through Inhibiting Ubiquitination of Slug and Activating Tgfβ/Smad-Independent Pathways in Gastric Cancer
    FHL3 Contributes to EMT and Chemotherapy Resistance Through Inhibiting Ubiquitination of Slug and Activating TGFβ/Smad-Independent Pathways in Gastric Cancer Guodong Cao First Aliated Hospital of Anhui Medical University Pengping Li Hangzhou Xiaoshan No 1 People's Hospital Qiang Sun Xuzhou Medical University Sihan Chen First Aliated Hospital of Anhui Medical University Xin Xu First Aliated Hospital of Anhui Medical University Xiaobo He First Aliated Hospital of Anhui Medical University Zhenyu Wang Hangzhou Xiaoshan No 1 People's Hospital Peng Chen First Aliated Hospital of Anhui Medical University Maoming Xiong ( [email protected] ) First Aliated Hospital of Anhui Medical University Bo Chen First Aliated Hospital of Anhui Medical University Research Keywords: EMT, Chemotherapy resistance, FHL3, Ubiquitination, Gastric cancer Posted Date: October 9th, 2020 DOI: https://doi.org/10.21203/rs.3.rs-87249/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. ReLoaadd iFngu l[Ml LaitchJeanxs]/ejax/output/CommonHTML/jax.js Page 1/28 Loading [MathJax]/jax/output/CommonHTML/jax.js Page 2/28 Abstract Background: Gastric cancer presents high risk of metastasis and chemotherapy resistance. Hence, the mechanistic understanding of the tumor metastasis and chemotherapy resistance is quietly important. Methods: TCGA database and clinical samples are used for exploring the role of FHL3 in disease progression and prognosis. The roles of FHL3 in metastasis and chemotherapy resistance are explored in vitro and in vivo by siRNA or shRNA treatment. Finally, we explore the FHL3-mediated EMT and chemotherapy resistance. Results: mRNA and protein level of FHL3 is signicantly up-regulated in gastric cancer tissues when compares with it in adjacent tissue.
    [Show full text]
  • In Vivo Studies Using the Classical Mouse Diversity Panel
    The Mouse Diversity Panel Predicts Clinical Drug Toxicity Risk Where Classical Models Fail Alison Harrill, Ph.D The Hamner-UNC Institute for Drug Safety Sciences 0 The Importance of Predicting Clinical Adverse Drug Reactions (ADR) Figure: Cath O’Driscoll Nature Publishing 2004 Risk ID PGx Testing 1 People Respond Differently to Drugs Pharmacogenetic Markers Identified by Genome-Wide Association Drug Adverse Drug Risk Allele Reaction (ADR) Abacavir Hypersensitivity HLA-B*5701 Flucloxacillin Hepatotoxicity Allopurinol Cutaneous ADR HLA-B*5801 Carbamazepine Stevens-Johnson HLA-B*1502 Syndrome Augmentin Hepatotoxicity DRB1*1501 Ximelagatran Hepatotoxicity DRB1*0701 Ticlopidine Hepatotoxicity HLA-A*3303 Average preclinical populations and human hepatocytes lack the diversity to detect incidence of adverse events that occur only in 1/10,000 people. Current Rodent Models of Risk Assessment The Challenge “At a time of extraordinary scientific progress, methods have hardly changed in several decades ([FDA] 2004)… Toxicologists face a major challenge in the twenty-first century. They need to embrace the new “omics” techniques and ensure that they are using the most appropriate animals if their discipline is to become a more effective tool in drug development.” -Dr. Michael Festing Quantitative geneticist Toxicol Pathol. 2010;38(5):681-90 Rodent Models as a Strategy for Hazard Characterization and Pharmacogenetics Genetically defined rodent models may provide ability to: 1. Improve preclinical prediction of drugs that carry a human safety risk 2.
    [Show full text]
  • Bioinformatic Analysis of Structure and Function of LIM Domains of Human Zyxin Family Proteins
    International Journal of Molecular Sciences Article Bioinformatic Analysis of Structure and Function of LIM Domains of Human Zyxin Family Proteins M. Quadir Siddiqui 1,† , Maulik D. Badmalia 1,† and Trushar R. Patel 1,2,3,* 1 Alberta RNA Research and Training Institute, Department of Chemistry and Biochemistry, University of Lethbridge, 4401 University Drive, Lethbridge, AB T1K 3M4, Canada; [email protected] (M.Q.S.); [email protected] (M.D.B.) 2 Department of Microbiology, Immunology and Infectious Disease, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive, Calgary, AB T2N 4N1, Canada 3 Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB T6G 2E1, Canada * Correspondence: [email protected] † These authors contributed equally to the work. Abstract: Members of the human Zyxin family are LIM domain-containing proteins that perform critical cellular functions and are indispensable for cellular integrity. Despite their importance, not much is known about their structure, functions, interactions and dynamics. To provide insights into these, we used a set of in-silico tools and databases and analyzed their amino acid sequence, phylogeny, post-translational modifications, structure-dynamics, molecular interactions, and func- tions. Our analysis revealed that zyxin members are ohnologs. Presence of a conserved nuclear export signal composed of LxxLxL/LxxxLxL consensus sequence, as well as a possible nuclear localization signal, suggesting that Zyxin family members may have nuclear and cytoplasmic roles. The molecular modeling and structural analysis indicated that Zyxin family LIM domains share Citation: Siddiqui, M.Q.; Badmalia, similarities with transcriptional regulators and have positively charged electrostatic patches, which M.D.; Patel, T.R.
    [Show full text]
  • Prox1regulates the Subtype-Specific Development of Caudal Ganglionic
    The Journal of Neuroscience, September 16, 2015 • 35(37):12869–12889 • 12869 Development/Plasticity/Repair Prox1 Regulates the Subtype-Specific Development of Caudal Ganglionic Eminence-Derived GABAergic Cortical Interneurons X Goichi Miyoshi,1 Allison Young,1 Timothy Petros,1 Theofanis Karayannis,1 Melissa McKenzie Chang,1 Alfonso Lavado,2 Tomohiko Iwano,3 Miho Nakajima,4 Hiroki Taniguchi,5 Z. Josh Huang,5 XNathaniel Heintz,4 Guillermo Oliver,2 Fumio Matsuzaki,3 Robert P. Machold,1 and Gord Fishell1 1Department of Neuroscience and Physiology, NYU Neuroscience Institute, Smilow Research Center, New York University School of Medicine, New York, New York 10016, 2Department of Genetics & Tumor Cell Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, 3Laboratory for Cell Asymmetry, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan, 4Laboratory of Molecular Biology, Howard Hughes Medical Institute, GENSAT Project, The Rockefeller University, New York, New York 10065, and 5Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724 Neurogliaform (RELNϩ) and bipolar (VIPϩ) GABAergic interneurons of the mammalian cerebral cortex provide critical inhibition locally within the superficial layers. While these subtypes are known to originate from the embryonic caudal ganglionic eminence (CGE), the specific genetic programs that direct their positioning, maturation, and integration into the cortical network have not been eluci- dated. Here, we report that in mice expression of the transcription factor Prox1 is selectively maintained in postmitotic CGE-derived cortical interneuron precursors and that loss of Prox1 impairs the integration of these cells into superficial layers. Moreover, Prox1 differentially regulates the postnatal maturation of each specific subtype originating from the CGE (RELN, Calb2/VIP, and VIP).
    [Show full text]
  • Clinical Utility of Recently Identified Diagnostic, Prognostic, And
    Modern Pathology (2017) 30, 1338–1366 1338 © 2017 USCAP, Inc All rights reserved 0893-3952/17 $32.00 Clinical utility of recently identified diagnostic, prognostic, and predictive molecular biomarkers in mature B-cell neoplasms Arantza Onaindia1, L Jeffrey Medeiros2 and Keyur P Patel2 1Instituto de Investigacion Marques de Valdecilla (IDIVAL)/Hospital Universitario Marques de Valdecilla, Santander, Spain and 2Department of Hematopathology, MD Anderson Cancer Center, Houston, TX, USA Genomic profiling studies have provided new insights into the pathogenesis of mature B-cell neoplasms and have identified markers with prognostic impact. Recurrent mutations in tumor-suppressor genes (TP53, BIRC3, ATM), and common signaling pathways, such as the B-cell receptor (CD79A, CD79B, CARD11, TCF3, ID3), Toll- like receptor (MYD88), NOTCH (NOTCH1/2), nuclear factor-κB, and mitogen activated kinase signaling, have been identified in B-cell neoplasms. Chronic lymphocytic leukemia/small lymphocytic lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, Burkitt lymphoma, Waldenström macroglobulinemia, hairy cell leukemia, and marginal zone lymphomas of splenic, nodal, and extranodal types represent examples of B-cell neoplasms in which novel molecular biomarkers have been discovered in recent years. In addition, ongoing retrospective correlative and prospective outcome studies have resulted in an enhanced understanding of the clinical utility of novel biomarkers. This progress is reflected in the 2016 update of the World Health Organization classification of lymphoid neoplasms, which lists as many as 41 mature B-cell neoplasms (including provisional categories). Consequently, molecular genetic studies are increasingly being applied for the clinical workup of many of these neoplasms. In this review, we focus on the diagnostic, prognostic, and/or therapeutic utility of molecular biomarkers in mature B-cell neoplasms.
    [Show full text]
  • Genome-Wide DNA Methylation Analysis of KRAS Mutant Cell Lines Ben Yi Tew1,5, Joel K
    www.nature.com/scientificreports OPEN Genome-wide DNA methylation analysis of KRAS mutant cell lines Ben Yi Tew1,5, Joel K. Durand2,5, Kirsten L. Bryant2, Tikvah K. Hayes2, Sen Peng3, Nhan L. Tran4, Gerald C. Gooden1, David N. Buckley1, Channing J. Der2, Albert S. Baldwin2 ✉ & Bodour Salhia1 ✉ Oncogenic RAS mutations are associated with DNA methylation changes that alter gene expression to drive cancer. Recent studies suggest that DNA methylation changes may be stochastic in nature, while other groups propose distinct signaling pathways responsible for aberrant methylation. Better understanding of DNA methylation events associated with oncogenic KRAS expression could enhance therapeutic approaches. Here we analyzed the basal CpG methylation of 11 KRAS-mutant and dependent pancreatic cancer cell lines and observed strikingly similar methylation patterns. KRAS knockdown resulted in unique methylation changes with limited overlap between each cell line. In KRAS-mutant Pa16C pancreatic cancer cells, while KRAS knockdown resulted in over 8,000 diferentially methylated (DM) CpGs, treatment with the ERK1/2-selective inhibitor SCH772984 showed less than 40 DM CpGs, suggesting that ERK is not a broadly active driver of KRAS-associated DNA methylation. KRAS G12V overexpression in an isogenic lung model reveals >50,600 DM CpGs compared to non-transformed controls. In lung and pancreatic cells, gene ontology analyses of DM promoters show an enrichment for genes involved in diferentiation and development. Taken all together, KRAS-mediated DNA methylation are stochastic and independent of canonical downstream efector signaling. These epigenetically altered genes associated with KRAS expression could represent potential therapeutic targets in KRAS-driven cancer. Activating KRAS mutations can be found in nearly 25 percent of all cancers1.
    [Show full text]
  • Mouse Population-Guided Resequencing Reveals That Variants in CD44 Contribute to Acetaminophen-Induced Liver Injury in Humans
    Downloaded from genome.cshlp.org on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Letter Mouse population-guided resequencing reveals that variants in CD44 contribute to acetaminophen-induced liver injury in humans Alison H. Harrill,1,2,12 Paul B. Watkins,3,12 Stephen Su,6 Pamela K. Ross,2 David E. Harbourt,5 Ioannis M. Stylianou,7 Gary A. Boorman,8 Mark W. Russo,3 Richard S. Sackler,9 Stephen C. Harris,11 Philip C. Smith,5 Raymond Tennant,8 Molly Bogue,7 Kenneth Paigen,7 Christopher Harris,9,10 Tanupriya Contractor,9 Timothy Wiltshire,5 Ivan Rusyn,1,2,14 and David W. Threadgill1,4,13,14,15 1Curriculum in Toxicology, University of North Carolina, Chapel Hill, North Carolina 27599, USA; 2Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina 27599, USA; 3Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, North Carolina 27599, USA; 4Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA; 5School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, USA; 6Department of Mouse Genetics, Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA; 7The Jackson Laboratory, Bar Harbor, Maine 04609, USA; 8National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA; 9Verto Institute Research Laboratories, New Brunswick, New Jersey 08903, USA; 10Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA; 11Purdue Pharma L.P., Stamford, Connecticut 06901, USA; 12Hamner-UNC Center for Drug Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709, USA; 13Department of Genetics, North Carolina State University, Raleigh, North Carolina 27695, USA Interindividual variability in response to chemicals and drugs is a common regulatory concern.
    [Show full text]
  • Functional Genomics Atlas of Synovial Fibroblasts Defining Rheumatoid Arthritis
    medRxiv preprint doi: https://doi.org/10.1101/2020.12.16.20248230; this version posted December 18, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Functional genomics atlas of synovial fibroblasts defining rheumatoid arthritis heritability Xiangyu Ge1*, Mojca Frank-Bertoncelj2*, Kerstin Klein2, Amanda Mcgovern1, Tadeja Kuret2,3, Miranda Houtman2, Blaž Burja2,3, Raphael Micheroli2, Miriam Marks4, Andrew Filer5,6, Christopher D. Buckley5,6,7, Gisela Orozco1, Oliver Distler2, Andrew P Morris1, Paul Martin1, Stephen Eyre1* & Caroline Ospelt2*,# 1Versus Arthritis Centre for Genetics and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK 2Department of Rheumatology, Center of Experimental Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland 3Department of Rheumatology, University Medical Centre, Ljubljana, Slovenia 4Schulthess Klinik, Zurich, Switzerland 5Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK 6NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, UK 7Kennedy Institute of Rheumatology, University of Oxford Roosevelt Drive Headington Oxford UK *These authors contributed equally #corresponding author: [email protected] NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. 1 medRxiv preprint doi: https://doi.org/10.1101/2020.12.16.20248230; this version posted December 18, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
    [Show full text]
  • Chain Gene Induced by GM-CSF Β Receptor Regulation of Human High-Affinity Ige Molecular Mechanisms for Transcriptional
    Molecular Mechanisms for Transcriptional Regulation of Human High-Affinity IgE Receptor β-Chain Gene Induced by GM-CSF This information is current as Kyoko Takahashi, Natsuko Hayashi, Shuichi Kaminogawa of September 23, 2021. and Chisei Ra J Immunol 2006; 177:4605-4611; ; doi: 10.4049/jimmunol.177.7.4605 http://www.jimmunol.org/content/177/7/4605 Downloaded from References This article cites 39 articles, 16 of which you can access for free at: http://www.jimmunol.org/content/177/7/4605.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 23, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Molecular Mechanisms for Transcriptional Regulation of Human High-Affinity IgE Receptor ␤-Chain Gene Induced by GM-CSF1 Kyoko Takahashi,*† Natsuko Hayashi,*‡ Shuichi Kaminogawa,† and Chisei Ra2* The ␤-chain of the high-affinity receptor for IgE (Fc␧RI) plays an important role in regulating activation of Fc␧RI-expressing cells such as mast cells in allergic reactions.
    [Show full text]
  • At the X-Roads of Sex and Genetics in Pulmonary Arterial Hypertension
    G C A T T A C G G C A T genes Review At the X-Roads of Sex and Genetics in Pulmonary Arterial Hypertension Meghan M. Cirulis 1,2,* , Mark W. Dodson 1,2, Lynn M. Brown 1,2, Samuel M. Brown 1,2, Tim Lahm 3,4,5 and Greg Elliott 1,2 1 Division of Pulmonary, Critical Care and Occupational Medicine, University of Utah, Salt Lake City, UT 84132, USA; [email protected] (M.W.D.); [email protected] (L.M.B.); [email protected] (S.M.B.); [email protected] (G.E.) 2 Division of Pulmonary and Critical Care Medicine, Intermountain Medical Center, Salt Lake City, UT 84107, USA 3 Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; [email protected] 4 Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, IN 46202, USA 5 Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA * Correspondence: [email protected]; Tel.: +1-801-581-7806 Received: 29 September 2020; Accepted: 17 November 2020; Published: 20 November 2020 Abstract: Group 1 pulmonary hypertension (pulmonary arterial hypertension; PAH) is a rare disease characterized by remodeling of the small pulmonary arteries leading to progressive elevation of pulmonary vascular resistance, ultimately leading to right ventricular failure and death. Deleterious mutations in the serine-threonine receptor bone morphogenetic protein receptor 2 (BMPR2; a central mediator of bone morphogenetic protein (BMP) signaling) and female sex are known risk factors for the development of PAH in humans.
    [Show full text]
  • Pig Antibodies
    Pig Antibodies gene_name sku Entry_Name Protein_Names Organism Length Identity CDX‐2 ARP31476_P050 D0V4H7_PIG Caudal type homeobox 2 (Fragment) Sus scrofa (Pig) 147 100.00% CDX‐2 ARP31476_P050 A7MAE3_PIG Caudal type homeobox transcription factor 2 (Fragment) Sus scrofa (Pig) 75 100.00% Tnnt3 ARP51286_P050 Q75NH3_PIG Troponin T fast skeletal muscle type Sus scrofa (Pig) 271 85.00% Tnnt3 ARP51286_P050 Q75NH2_PIG Troponin T fast skeletal muscle type Sus scrofa (Pig) 266 85.00% Tnnt3 ARP51286_P050 Q75NH1_PIG Troponin T fast skeletal muscle type Sus scrofa (Pig) 260 85.00% Tnnt3 ARP51286_P050 Q75NH0_PIG Troponin T fast skeletal muscle type Sus scrofa (Pig) 250 85.00% Tnnt3 ARP51286_P050 Q75NG8_PIG Troponin T fast skeletal muscle type Sus scrofa (Pig) 266 85.00% Tnnt3 ARP51286_P050 Q75NG7_PIG Troponin T fast skeletal muscle type Sus scrofa (Pig) 260 85.00% Tnnt3 ARP51286_P050 Q75NG6_PIG Troponin T fast skeletal muscle type Sus scrofa (Pig) 250 85.00% Tnnt3 ARP51286_P050 TNNT3_PIG Troponin T, fast skeletal muscle (TnTf) Sus scrofa (Pig) 271 85.00% ORF Names:PANDA_000462 EMBL EFB13877.1OrganismAiluropod High mobility group protein B2 (High mobility group protein a melanoleuca (Giant panda) ARP31939_P050 HMGB2_PIG 2) (HMG‐2) Sus scrofa (Pig) 210 100.00% Agpat5 ARP47429_P050 B8XTR3_PIG 1‐acylglycerol‐3‐phosphate O‐acyltransferase 5 Sus scrofa (Pig) 365 85.00% irf9 ARP31200_P050 Q29390_PIG Transcriptional regulator ISGF3 gamma subunit (Fragment) Sus scrofa (Pig) 57 100.00% irf9 ARP31200_P050 Q0GFA1_PIG Interferon regulatory factor 9 Sus scrofa (Pig)
    [Show full text]
  • Myt1l Safeguards Neuronal Identity by Actively Repressing Many Non-Neuronal Fates Moritz Mall1, Michael S
    LETTER doi:10.1038/nature21722 Myt1l safeguards neuronal identity by actively repressing many non-neuronal fates Moritz Mall1, Michael S. Kareta1†, Soham Chanda1,2, Henrik Ahlenius3, Nicholas Perotti1, Bo Zhou1,2, Sarah D. Grieder1, Xuecai Ge4†, Sienna Drake3, Cheen Euong Ang1, Brandon M. Walker1, Thomas Vierbuchen1†, Daniel R. Fuentes1, Philip Brennecke5†, Kazuhiro R. Nitta6†, Arttu Jolma6, Lars M. Steinmetz5,7, Jussi Taipale6,8, Thomas C. Südhof2 & Marius Wernig1 Normal differentiation and induced reprogramming require human Myt1l (Extended Data Fig. 1). Chromatin immunoprecipita- the activation of target cell programs and silencing of donor cell tion followed by DNA sequencing (ChIP–seq) of endogenous Myt1l programs1,2. In reprogramming, the same factors are often used to in fetal neurons (embryonic day (E) 13.5) and ectopic Myt1l in mouse reprogram many different donor cell types3. As most developmental embryonic fibroblasts (MEFs) two days after induction identified 3,325 repressors, such as RE1-silencing transcription factor (REST) and high-confidence Myt1l peaks that overlapped remarkably well between Groucho (also known as TLE), are considered lineage-specific neurons and MEFs (Fig. 1a, Extended Data Fig. 2, Supplementary repressors4,5, it remains unclear how identical combinations of Table 1). Thus, similar to the pioneer factor Ascl1, Myt1l can access transcription factors can silence so many different donor programs. the majority of its cognate DNA binding sites even in a distantly related Distinct lineage repressors would have to be induced in different cell type. However, unlike Ascl1 targets8, the chromatin at Myt1l donor cell types. Here, by studying the reprogramming of mouse fibroblasts to neurons, we found that the pan neuron-specific a Myt1l Myt1l b Myt1l Ascl1 Random Myt1l 6 Ascl1 + Brn2 endogenous transcription factor Myt1-like (Myt1l) exerts its pro-neuronal Closed 0.030 function by direct repression of many different somatic lineage k programs except the neuronal program.
    [Show full text]