DOCSLIB.ORG

120409 Thesis

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
120409 Thesis Mechanisms of Specificity in Neuronal Activity-regulated Gene Transcription by Michelle Renée Lyons Department of Neurobiology Duke University Date:_______________________ Approved: ___________________________ Anne West, Supervisor ___________________________ Dona Chikaraishi, Chair ___________________________ James O. McNamara ___________________________ Geoffrey Pitt ___________________________ Scott Soderling Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Neurobiology in the Graduate School of Duke University 2012 i v ABSTRACT Mechanisms of Specificity in Neuronal Activity-regulated Gene Transcription by Michelle Renée Lyons Department of Neurobiology Duke University Date:_______________________ Approved: ___________________________ Anne West, Supervisor ___________________________ Dona Chikaraishi, Chair ___________________________ James O. McNamara ___________________________ Geoffrey Pitt ___________________________ Scott Soderling An abstract of a dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Neurobiology in the Graduate School of Duke University 2012 Copyright by Michelle Renée Lyons 2012 Abstract In the nervous system, activity-regulated gene transcription is one of the fundamental processes responsible for orchestrating proper brain development – a process that in humans takes over 20 years. Moreover, activity-dependent regulation of gene expression continues to be important for normal brain function throughout life; for example, some forms of synaptic plasticity important for learning and memory are known to rely on alterations in gene transcription elicited by sensory input. In the last two decades, increasingly comprehensive studies have described complex patterns of gene transcription induced and/or repressed following different kinds of stimuli that act in concert to effect changes in neuronal and synaptic physiology. A key theme to emerge from these studies is that of specificity, meaning that different kinds of stimuli up- and downregulate distinct sets of genes. The importance of such signaling specificity in synapse-to-nucleus communication becomes readily apparent in studies examining the physiological effects of the loss of one or more forms of transcriptional specificity – often, such genetic manipulations result in aberrant synapse formation, neuronal cell death, and/or cognitive impairment in mutant mice. The two primary loci at which mechanisms of signaling specificity typically act are 1) at the synapse – in the form of calcium channel number, localization, and subunit composition – and 2) in the nucleus – in the form of transcription factor expression, localization, and post-translational modification. My dissertation research has focused on the mechanisms of specificity that govern the activity-regulated transcription of the gene encoding Brain- derived Neurotrophic Factor (Bdnf). BDNF is a secreted protein that has iv numerous important functions in nervous system development and plasticity, including neuronal survival, neurite outgrowth, synapse formation, and long- term potentiation. Due to Bdnf’s complex transcriptional regulation by various forms of neural stimuli, it is well positioned to function as a transducer through which altered neural activity states can lead to changes in neuronal physiology and synaptic function. In this dissertation, I show that different families of transcription factors, and even different isoforms or splice variants within a single family, can specifically regulate Bdnf transcription in an age- and stimulus- dependent manner. Additionally, I characterize another mechanism of synapse- to-nucleus signaling specificity that is dependent upon NMDA-type glutamate receptor subunit composition, and provide evidence that the effect this signaling pathway has on gene transcription is important for normal GABAergic synapse formation. Taken together, my dissertation research sheds light on several novel signaling mechanisms that could lend specificity to the activity-dependent transcription of Bdnf exon IV. My data indicate that distinct neuronal stimuli can differentially regulate the Calcium-Response Element CaRE1 within Bdnf promoter IV through activation of two distinct transcription factors: Calcium- Response Factor (CaRF) and Myocyte Enhancer Factor 2 (MEF2). Furthermore, individual members of the MEF2 family of transcription factors differentially regulate the expression of Bdnf, and different MEF2C splice variants are unequally responsive to L-type voltage-gated calcium channel activation. Additionally, I show here for the first time that the NMDA-type glutamate receptor subunit NR3A (also known as GluN3A) is capable of exerting an effect on NMDA receptor-dependent Bdnf exon IV transcription, and that changes in v the expression levels of NR3A may function to regulate the threshold for activation of synaptic plasticity-inducing transcriptional programs during brain development. Finally, I provide evidence that the transcription factor CaRF might function in the regulation of homeostatic programs of gene transcription in an age- and stimulus-specific manner. Together, these data describe multiple novel mechanisms of specificity in neuronal activity-regulated gene transcription, some of which function at the synapse, others of which function in the nucleus. vi Dedication This dissertation is dedicated to the memory of Violet Elaine Holman. She was my grandmother and a nurse; she inspired in me from a very early age a love of human anatomy and physiology and an interest in better understanding the world around me. vii Contents Abstract.............................................................................................................................iv List of Tables ..................................................................................................................xiii List of Figures ................................................................................................................xiv Abbreviations and Acronyms ....................................................................................xxii Acknowledgements ...................................................................................................xxvii 1. Introduction .................................................................................................................. 1 1.1 Activity-regulated gene transcription is critical for normal brain development and function ....................................................................................... 1 1.2 Brain-Derived Neurotrophic Factor (BDNF) regulates neuronal physiology and synaptic function........................................................................... 2 1.3 Fos: the archetypal member of a second class of activity-regulated genes. 7 1.3.1 Mechanisms of Fos transcriptional regulation: Association of transcription factors with stimulus-response elements in the proximal promoter ................................................................................................................... 9 1.3.2 Mechanisms of Fos transcriptional regulation: Stimulus-dependent recruitment of transcriptional co-activators and co-repressors that post- translationally modify histones........................................................................... 11 1.3.3 Mechanisms of Fos transcriptional regulation: Modulation of promoter function by distant enhancer elements............................................................... 12 1.3.4 Mechanisms of Fos transcriptional regulation: Regulation of transcriptional elongation .................................................................................... 14 1.4 Transcription factors regulated by neuronal activity................................... 14 1.4.1 Activation of prebound transcription factors........................................... 15 1.4.1.1 Calcium/cAMP-Response Element binding protein (CREB)......... 17 1.4.1.2 Serum-Response Factor (SRF) ............................................................. 18 1.4.1.3 Myocyte Enhancer Factor 2 (MEF2) ................................................... 20 1.4.2 Transcription factors that undergo regulated nucleocytoplasmic shuttling .................................................................................................................. 23 viii 1.4.2.1 Activity-dependent nuclear translocation......................................... 24 1.4.2.2 Synaptic activity-dependent nuclear export ..................................... 27 1.4.3 Transcription factors that show regulated binding................................. 28 1.4.4 Neuronal activity-regulated transcription factor expression................. 30 1.5 Calcium channel-dependent regulation of transcription ............................ 31 1.5.1 NMDA Receptors (NMDARs).................................................................... 33 1.5.1.1 NMDARs regulate transcription in vitro and in vivo ....................... 34 1.5.1.2 Molecular biology and patterns of expression of the NMDARs.... 35 1.5.1.3 Different pools of NMDARs differentially regulate transcription 39 1.5.1.4 Protein interactions that underlie NMDAR signaling specificity.. 44 1.5.2 L-type Voltage-Gated Calcium Channels (L-VGCCs) ............................ 51 1.5.2.1 Molecular biology of the L-VGCCs .................................................... 51 1.5.2.2 Physiological relevance of L-VGCCs for transcription
Load more

Recommended publications
  • Viewed Under 23 (B) Or 203 (C) fi M M Male Cko Mice, and Largely Unaffected Magni Cation; Scale Bars, 500 M (B) and 50 M (C)
    BRIEF COMMUNICATION www.jasn.org Renal Fanconi Syndrome and Hypophosphatemic Rickets in the Absence of Xenotropic and Polytropic Retroviral Receptor in the Nephron Camille Ansermet,* Matthias B. Moor,* Gabriel Centeno,* Muriel Auberson,* † † ‡ Dorothy Zhang Hu, Roland Baron, Svetlana Nikolaeva,* Barbara Haenzi,* | Natalya Katanaeva,* Ivan Gautschi,* Vladimir Katanaev,*§ Samuel Rotman, Robert Koesters,¶ †† Laurent Schild,* Sylvain Pradervand,** Olivier Bonny,* and Dmitri Firsov* BRIEF COMMUNICATION *Department of Pharmacology and Toxicology and **Genomic Technologies Facility, University of Lausanne, Lausanne, Switzerland; †Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts; ‡Institute of Evolutionary Physiology and Biochemistry, St. Petersburg, Russia; §School of Biomedicine, Far Eastern Federal University, Vladivostok, Russia; |Services of Pathology and ††Nephrology, Department of Medicine, University Hospital of Lausanne, Lausanne, Switzerland; and ¶Université Pierre et Marie Curie, Paris, France ABSTRACT Tight control of extracellular and intracellular inorganic phosphate (Pi) levels is crit- leaves.4 Most recently, Legati et al. have ical to most biochemical and physiologic processes. Urinary Pi is freely filtered at the shown an association between genetic kidney glomerulus and is reabsorbed in the renal tubule by the action of the apical polymorphisms in Xpr1 and primary fa- sodium-dependent phosphate transporters, NaPi-IIa/NaPi-IIc/Pit2. However, the milial brain calcification disorder.5 How- molecular identity of the protein(s) participating in the basolateral Pi efflux remains ever, the role of XPR1 in the maintenance unknown. Evidence has suggested that xenotropic and polytropic retroviral recep- of Pi homeostasis remains unknown. Here, tor 1 (XPR1) might be involved in this process. Here, we show that conditional in- we addressed this issue in mice deficient for activation of Xpr1 in the renal tubule in mice resulted in impaired renal Pi Xpr1 in the nephron.
    [Show full text]
  • Age-Dependent Myocardial Transcriptomic Changes in the Rat
    Revista Română de Medicină de Laborator Vol. 22, Nr. 1, Martie, 2014 9 Research article DOI: 10.2478/rrlm-2014-0001 Age-dependent myocardial transcriptomic changes in the rat. Novel insights into atrial and ventricular arrhythmias pathogenesis Modificări transcriptomice dependente de vârstă în miocardul de șobolan. Noi aspecte referitoare la patogeneza aritmiilor atriale și ventriculare Alina Scridon1,2, Emmanuelle Fouilloux-Meugnier3, Emmanuelle Loizon3, Marcel Perian1, Sophie Rome3, Claude Julien2, Christian Barrès2, Philippe Chevalier2,4 1.Physiology Department, University of Medicine and Pharmacy of Tîrgu Mureș, 540139, Tîrgu Mureș, Romania 2. Unité de Neurocardiologie, EA4612, Université Lyon 1, F-69008, Lyon, France 3. Unité 1060 INSERM CarMen, Université Lyon 1, F-69008, Lyon, France 4. Hospices Civils de Lyon, Hôpital Louis Pradel, Service de Rythmologie, 69500, Bron, France Abstract Background: Aging is associated with significantly increased prevalence of cardiac arrhythmias, but tran- scriptional events that underlie this process remain to be established. To gain deeper insight into molecular mech- anisms of aging-related cardiac arrhythmias, we performed mRNA expression analysis comparing atrial and ven- tricular myocardium from Wistar-Kyoto (WKY) rats of different ages. Methods: Atrial and ventricular sampling was performed in 3 groups (n=4 each) of young (14-week-old), adult (25-week-old), and aging (47-week-old) WKY rats. mRNA expressions of 89 genes involved in cardiac arrhythmogenicity were investigated using TaqMan Low Density Array analysis. Results: Of the 89 studied genes, 40 and 64 genes presented steady atrial and ventricu- lar expressions, respectively. All genes differentially expressed within the atria of WKY rats were up-regulated with advancing age, mainly the genes encoding for various K+, Ca2+, Na+ channels, and type 6 collagen.
    [Show full text]
  • Reversible Cardiac Disease Features in an Inducible CUG Repeat RNA–Expressing Mouse Model of Myotonic Dystrophy
    Reversible cardiac disease features in an inducible CUG repeat RNA–expressing mouse model of myotonic dystrophy Ashish N. Rao, … , Zheng Xia, Thomas A. Cooper JCI Insight. 2021;6(5):e143465. https://doi.org/10.1172/jci.insight.143465. Research Article Cardiology Cell biology Graphical abstract Find the latest version: https://jci.me/143465/pdf RESEARCH ARTICLE Reversible cardiac disease features in an inducible CUG repeat RNA–expressing mouse model of myotonic dystrophy Ashish N. Rao,1 Hannah M. Campbell,2,3 Xiangnan Guan,4 Tarah A. Word,2 Xander H.T. Wehrens,2,5 Zheng Xia,4,6 and Thomas A. Cooper1,2,5,7 1Department of Molecular and Cellular Biology, 2Department of Molecular Physiology and Biophysics, and 3Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas, USA. 4Computational Biology Program, Oregon Health & Science University, Portland, Oregon, USA. 5Cardiovascular Research Institute, Baylor College of Medicine, Houston, Texas, USA. 6Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, Oregon, USA. 7Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA. Myotonic dystrophy type 1 (DM1) is caused by a CTG repeat expansion in the DMPK gene. Expression of pathogenic expanded CUG repeat (CUGexp) RNA causes multisystemic disease by perturbing the functions of RNA-binding proteins, resulting in expression of fetal protein isoforms in adult tissues. Cardiac involvement affects 50% of individuals with DM1 and causes 25% of disease-related deaths. We developed a transgenic mouse model for tetracycline-inducible and heart-specific expression of human DMPK mRNA containing 960 CUG repeats. CUGexp RNA is expressed in atria and ventricles and induced mice exhibit electrophysiological and molecular features of DM1 disease, including cardiac conduction delays, supraventricular arrhythmias, nuclear RNA foci with Muscleblind protein colocalization, and alternative splicing defects.
    [Show full text]
  • Defining Functional Interactions During Biogenesis of Epithelial Junctions
    ARTICLE Received 11 Dec 2015 | Accepted 13 Oct 2016 | Published 6 Dec 2016 | Updated 5 Jan 2017 DOI: 10.1038/ncomms13542 OPEN Defining functional interactions during biogenesis of epithelial junctions J.C. Erasmus1,*, S. Bruche1,*,w, L. Pizarro1,2,*, N. Maimari1,3,*, T. Poggioli1,w, C. Tomlinson4,J.Lees5, I. Zalivina1,w, A. Wheeler1,w, A. Alberts6, A. Russo2 & V.M.M. Braga1 In spite of extensive recent progress, a comprehensive understanding of how actin cytoskeleton remodelling supports stable junctions remains to be established. Here we design a platform that integrates actin functions with optimized phenotypic clustering and identify new cytoskeletal proteins, their functional hierarchy and pathways that modulate E-cadherin adhesion. Depletion of EEF1A, an actin bundling protein, increases E-cadherin levels at junctions without a corresponding reinforcement of cell–cell contacts. This unexpected result reflects a more dynamic and mobile junctional actin in EEF1A-depleted cells. A partner for EEF1A in cadherin contact maintenance is the formin DIAPH2, which interacts with EEF1A. In contrast, depletion of either the endocytic regulator TRIP10 or the Rho GTPase activator VAV2 reduces E-cadherin levels at junctions. TRIP10 binds to and requires VAV2 function for its junctional localization. Overall, we present new conceptual insights on junction stabilization, which integrate known and novel pathways with impact for epithelial morphogenesis, homeostasis and diseases. 1 National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK. 2 Computing Department, Imperial College London, London SW7 2AZ, UK. 3 Bioengineering Department, Faculty of Engineering, Imperial College London, London SW7 2AZ, UK. 4 Department of Surgery & Cancer, Faculty of Medicine, Imperial College London, London SW7 2AZ, UK.
    [Show full text]
  • Genome-Wide Screening Identifies a KCNIP1 Copy Number Variant As a Genetic Predictor for Atrial Fibrillation
    ARTICLE Received 21 Oct 2014 | Accepted 16 Nov 2015 | Published 2 Feb 2016 DOI: 10.1038/ncomms10190 OPEN Genome-wide screening identifies a KCNIP1 copy number variant as a genetic predictor for atrial fibrillation Chia-Ti Tsai1,2,3, Chia-Shan Hsieh4,5, Sheng-Nan Chang2,3, Eric Y. Chuang4,5, Kwo-Chang Ueng6,7, Chin-Feng Tsai6,7, Tsung-Hsien Lin8, Cho-Kai Wu1, Jen-Kuang Lee1, Lian-Yu Lin1, Yi-Chih Wang1, Chih-Chieh Yu1, Ling-Ping Lai1, Chuen-Den Tseng1, Juey-Jen Hwang1, Fu-Tien Chiang1,9 & Jiunn-Lee Lin1 Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Previous genome- wide association studies had identified single-nucleotide polymorphisms in several genomic regions to be associated with AF. In human genome, copy number variations (CNVs) are known to contribute to disease susceptibility. Using a genome-wide multistage approach to identify AF susceptibility CNVs, we here show a common 4,470-bp diallelic CNV in the first intron of potassium interacting channel 1 gene (KCNIP1) is strongly associated with AF in Taiwanese populations (odds ratio ¼ 2.27 for insertion allele; P ¼ 6.23 Â 10 À 24). KCNIP1 insertion is associated with higher KCNIP1 mRNA expression. KCNIP1-encoded protein potassium interacting channel 1 (KCHIP1) is physically associated with potassium Kv channels and modulates atrial transient outward current in cardiac myocytes. Overexpression of KCNIP1 results in inducible AF in zebrafish. In conclusions, a common CNV in KCNIP1 gene is a genetic predictor of AF risk possibly pointing to a functional pathway. 1 Division of Cardiology, Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, No.
    [Show full text]
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • 4-6 Weeks Old Female C57BL/6 Mice Obtained from Jackson Labs Were Used for Cell Isolation
    Methods Mice: 4-6 weeks old female C57BL/6 mice obtained from Jackson labs were used for cell isolation. Female Foxp3-IRES-GFP reporter mice (1), backcrossed to B6/C57 background for 10 generations, were used for the isolation of naïve CD4 and naïve CD8 cells for the RNAseq experiments. The mice were housed in pathogen-free animal facility in the La Jolla Institute for Allergy and Immunology and were used according to protocols approved by the Institutional Animal Care and use Committee. Preparation of cells: Subsets of thymocytes were isolated by cell sorting as previously described (2), after cell surface staining using CD4 (GK1.5), CD8 (53-6.7), CD3ε (145- 2C11), CD24 (M1/69) (all from Biolegend). DP cells: CD4+CD8 int/hi; CD4 SP cells: CD4CD3 hi, CD24 int/lo; CD8 SP cells: CD8 int/hi CD4 CD3 hi, CD24 int/lo (Fig S2). Peripheral subsets were isolated after pooling spleen and lymph nodes. T cells were enriched by negative isolation using Dynabeads (Dynabeads untouched mouse T cells, 11413D, Invitrogen). After surface staining for CD4 (GK1.5), CD8 (53-6.7), CD62L (MEL-14), CD25 (PC61) and CD44 (IM7), naïve CD4+CD62L hiCD25-CD44lo and naïve CD8+CD62L hiCD25-CD44lo were obtained by sorting (BD FACS Aria). Additionally, for the RNAseq experiments, CD4 and CD8 naïve cells were isolated by sorting T cells from the Foxp3- IRES-GFP mice: CD4+CD62LhiCD25–CD44lo GFP(FOXP3)– and CD8+CD62LhiCD25– CD44lo GFP(FOXP3)– (antibodies were from Biolegend). In some cases, naïve CD4 cells were cultured in vitro under Th1 or Th2 polarizing conditions (3, 4).
    [Show full text]
  • Characterization of Glomerular Extracellular Matrix in Iga Nephropathy by Proteomic Analysis of Laser-Captured Microdissected Gl
    Paunas et al. BMC Nephrology (2019) 20:410 https://doi.org/10.1186/s12882-019-1598-1 RESEARCH ARTICLE Open Access Characterization of glomerular extracellular matrix in IgA nephropathy by proteomic analysis of laser-captured microdissected glomeruli Flavia Teodora Ioana Paunas1,2* , Kenneth Finne2, Sabine Leh2,3, Tarig Al-Hadi Osman2, Hans-Peter Marti2,4, Frode Berven5 and Bjørn Egil Vikse1,2 Abstract Background: IgA nephropathy (IgAN) involves mesangial matrix expansion, but the proteomic composition of this matrix is unknown. The present study aimed to characterize changes in extracellular matrix in IgAN. Methods: In the present study we used mass spectrometry-based proteomics in order to quantitatively compare protein abundance between glomeruli of patients with IgAN (n = 25) and controls with normal biopsy findings (n = 15). Results: Using a previously published paper by Lennon et al. and cross-referencing with the Matrisome database we identified 179 extracellular matrix proteins. In the comparison between IgAN and controls, IgAN glomeruli showed significantly higher abundance of extracellular matrix structural proteins (e.g periostin, vitronectin, and extracellular matrix protein 1) and extracellular matrix associated proteins (e.g. azurocidin, myeloperoxidase, neutrophil elastase, matrix metalloproteinase-9 and matrix metalloproteinase 2). Periostin (fold change 3.3) and azurocidin (3.0) had the strongest fold change between IgAN and controls; periostin was also higher in IgAN patients who progressed to ESRD as compared to patients who did not. Conclusion: IgAN is associated with widespread changes of the glomerular extracellular matrix proteome. Proteins important in glomerular sclerosis or inflammation seem to be most strongly increased and periostin might be an important marker of glomerular damage in IgAN.
    [Show full text]
  • Genetic Analysis of Indel Markers in Three Loci Associated with Parkinson’S Disease
    RESEARCH ARTICLE Genetic analysis of indel markers in three loci associated with Parkinson's disease Zhixin Huo1, Xiaoguang Luo2, Xiaoni Zhan1, Qiaohong Chu1, Qin Xu1, Jun Yao1, Hao Pang1* 1 Department of Forensic Genetics and Biology, China Medical University, Shenyang North New Area, Shenyang, P.R., China, 2 Department of Neurology, 1st Affiliated Hospital of China Medical University, Shenyang, P.R., China * [email protected] Abstract a1111111111 a1111111111 The causal mutations and genetic polymorphisms associated with susceptibility to Parkin- a1111111111 son's disease (PD) have been extensively described. To explore the potential contribution a1111111111 a1111111111 of insertion (I)/deletion (D) polymorphisms (indels) to the risk of PD in a Chinese population, we performed genetic analyses of indel loci in ACE, DJ-1, and GIGYF2 genes. Genomic DNA was extracted from venous blood of 348 PD patients and 325 age- and sex-matched controls without neurodegenerative disease. Genotyping of the indel loci was performed by fragment length analysis after PCR and DNA sequencing. Our results showed a statistically OPEN ACCESS significant association for both allele X (alleles without 5) vs. 5 (odds ratio = 1.378, 95% con- Citation: Huo Z, Luo X, Zhan X, Chu Q, Xu Q, Yao fidence interval = 1.112±1.708, P = 0.003) and genotype 5/X+X/X vs. 5/5 (odds ratio = J, et al. (2017) Genetic analysis of indel markers in three loci associated with Parkinson's disease. 1.681, 95% confidence interval = 1.174±2.407, P = 0.004) in the GIGYF2 locus; however, PLoS ONE 12(9): e0184269. https://doi.org/ no significant differences were detected for the ACE and DJ-1 indels.
    [Show full text]
  • A Genome-Wide Association Study Identifies Four Novel Susceptibility Loci Underlying Inguinal Hernia
    UCSF UC San Francisco Previously Published Works Title A genome-wide association study identifies four novel susceptibility loci underlying inguinal hernia. Permalink https://escholarship.org/uc/item/7g06z1k5 Journal Nature communications, 6(1) ISSN 2041-1723 Authors Jorgenson, Eric Makki, Nadja Shen, Ling et al. Publication Date 2015-12-21 DOI 10.1038/ncomms10130 Peer reviewed eScholarship.org Powered by the California Digital Library University of California ARTICLE Received 24 Aug 2015 | Accepted 6 Nov 2015 | Published 21 Dec 2015 DOI: 10.1038/ncomms10130 OPEN A genome-wide association study identifies four novel susceptibility loci underlying inguinal hernia Eric Jorgenson1,*, Nadja Makki2,3,*, Ling Shen1, David C. Chen4, Chao Tian5, Walter L. Eckalbar2,3, David Hinds5, Nadav Ahituv2,3 & Andrew Avins1 Inguinal hernia repair is one of the most commonly performed operations in the world, yet little is known about the genetic mechanisms that predispose individuals to develop inguinal hernias. We perform a genome-wide association analysis of surgically confirmed inguinal hernias in 72,805 subjects (5,295 cases and 67,510 controls) and confirm top associations in an independent cohort of 92,444 subjects with self-reported hernia repair surgeries (9,701 cases and 82,743 controls). We identify four novel inguinal hernia susceptibility loci in the regions of EFEMP1, WT1, EBF2 and ADAMTS6. Moreover, we observe expression of all four genes in mouse connective tissue and network analyses show an important role for two of these genes (EFEMP1 and WT1) in connective tissue maintenance/homoeostasis. Our findings provide insight into the aetiology of hernia development and highlight genetic pathways for studies of hernia development and its treatment.
    [Show full text]
  • Proteomics of Serum Extracellular Vesicles Identifies a Novel COPD Biomarker, Fibulin-3 from Elastic Fibres
    ORIGINAL ARTICLE COPD Proteomics of serum extracellular vesicles identifies a novel COPD biomarker, fibulin-3 from elastic fibres Taro Koba 1, Yoshito Takeda1, Ryohei Narumi2, Takashi Shiromizu2, Yosui Nojima 3, Mari Ito3, Muneyoshi Kuroyama1, Yu Futami1, Takayuki Takimoto4, Takanori Matsuki1, Ryuya Edahiro1, Satoshi Nojima5, Yoshitomo Hayama1, Kiyoharu Fukushima1, Haruhiko Hirata1, Shohei Koyama1, Kota Iwahori1, Izumi Nagatomo1, Mayumi Suzuki1, Yuya Shirai1, Teruaki Murakami1, Kaori Nakanishi 1, Takeshi Nakatani1, Yasuhiko Suga1, Kotaro Miyake1, Takayuki Shiroyama1, Hiroshi Kida 1, Takako Sasaki6, Koji Ueda7, Kenji Mizuguchi3, Jun Adachi2, Takeshi Tomonaga2 and Atsushi Kumanogoh1 ABSTRACT There is an unmet need for novel biomarkers in the diagnosis of multifactorial COPD. We applied next-generation proteomics to serum extracellular vesicles (EVs) to discover novel COPD biomarkers. EVs from 10 patients with COPD and six healthy controls were analysed by tandem mass tag-based non-targeted proteomics, and those from elastase-treated mouse models of emphysema were also analysed by non-targeted proteomics. For validation, EVs from 23 patients with COPD and 20 healthy controls were validated by targeted proteomics. Using non-targeted proteomics, we identified 406 proteins, 34 of which were significantly upregulated in patients with COPD. Of note, the EV protein signature from patients with COPD reflected inflammation and remodelling. We also identified 63 upregulated candidates from 1956 proteins by analysing EVs isolated from mouse models. Combining human and mouse biomarker candidates, we validated 45 proteins by targeted proteomics, selected reaction monitoring. Notably, levels of fibulin-3, tripeptidyl- peptidase 2, fibulin-1, and soluble scavenger receptor cysteine-rich domain-containing protein were significantly higher in patients with COPD.
    [Show full text]
  • Clonally Expanding Smooth Muscle Cells Promote Atherosclerosis by Escaping Efferocytosis and Activating the Complement Cascade
    Clonally expanding smooth muscle cells promote atherosclerosis by escaping efferocytosis and activating the complement cascade Ying Wanga,b, Vivek Nandaa,b,c, Daniel Direnzoa, Jianqin Yea, Sophia Xiaoa, Yoko Kojimaa, Kathryn L. Howea, Kai-Uwe Jarra, Alyssa M. Floresa, Pavlos Tsantilasa, Noah Tsaoa, Abhiram Raob,d, Alexandra A. C. Newmane, Anne V. Eberharda, James R. Priestf, Arno Ruusaleppg, Gerard Pasterkamph,i, Lars Maegdefesselj,k, Clint L. Millerl,m,n, Lars Lindo, Simon Koplevp, Johan L. M. Björkegrenp, Gary K. Owense, Erik Ingelssonb,o,q, Irving L. Weissmanr,1, and Nicholas J. Leepera,b,1 aDivision of Vascular Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305; bStanford Cardiovascular Institute, Stanford University, Stanford, CA 94305; cDepartment of Molecular and Cellular Pathology, University of Alabama at Birmingham, Birmingham, AL 35294; dDepartment of Bioengineering, Stanford University, Stanford, CA 94305; eRobert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22904; fDivision of Pediatric Cardiology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305; gDepartment of Cardiac Surgery, Tartu University Hospital, Tartu, Estonia 50406; hDepartment of Cardiology, University Medical Center Utrecht, 3584CX Utrecht, the Netherlands; iLaboratory of Clinical Chemistry, University Medical Center Utrecht, 3584CX Utrecht, the Netherlands; jDepartment for Vascular and Endovascular Surgery, Klinikum Rechts der Isar, Technical University
    [Show full text]