Platform/Plenary

Total Page:16

File Type:pdf, Size:1020Kb

Platform/Plenary Platform Session 18: Plenary Session 1 †1 †3 Dissection of a Modifier Network in Marfan Syndrome Reveals New A Global Mechanism for Non-coding RNA Dependent Chromatin For- Therapeutic Targets. J. Doyle1, J. Pardo Habashi1, T. Holm1, D. Bedja1,H. mation in Mammals. A. Khalil1, 2, M. Guttman1, M. Huarte1, L. Goff1,M. Dietz1,2. 1) Institute of Genetic Medicine, Johns Hopkins School of Medicine, Kellis1, E. Lander1, 2, J. Rinn1, 2. 1) The Broad Institute of Harvard and MIT, Baltimore, MD; 2) Howard Hughes Medical Institute. Cambridge, MA; 2) Harvard Medical School, Boston, MA. Excessive TGFβ activity causes many of the manifestations of Marfan One of the most fundamental and unsolved problems in biology is: how syndrome (MFS), including aortic aneurysm, that can be attenuated by TGFβ does the same genome present in every cell of an organism encode a antagonism with neutralizing antibody or the angiotensin II (Ang II) type 1 multitude of different cellular states? While epigenetic regulation by chroma- receptor (AT1) blocker (ARB) losartan in MFS mice (Fbn1 genotype C1039G/ tin modifying complexes plays a key role in this process, it is not currently +). TGFβ signals through both canonical (pSmad2/3) and noncanonical known how these complexes are targeted to specific regions of the genome. (MAPK: Jnk, Erk, p38) cascades. To determine their relative contribution, Recently, we and others have found two large intergenic non-coding RNAs we introduced haploinsufficiency for Smad4 (a mediator of Smad-dependent (lincRNAs) known as HOTAIR and XIST to physically associate with the signaling) on the C1039G/+ background (S4+/-:C1039G/+). Unexpectedly, chromatin modifying complex PRC2 and guide it to specific genomic loci. S4+/-:C1039G/+ mice showed synthetic lethality due to aortic rupture com- Thus, we hypothesized that association of lincRNAs with chromatin modi- pared to S4+/+:C1039G/+ littermates. Both S4+/+:C1039G/+ and S4+/- fying complexes may be a general theme in the establishment and mainte- :C1039G/+ mice show marked and equivalent activation of the Smad2/3 nance of epigenetic states. To assay lincRNA interactions with chromatin and Erk1/2 cascades, which could not account for synthetic lethality. S4+/- modifying complexes on a genome-wide scale we developed RIP-Chip tech- :C1039G/+ mice uniquely show activation of Jnk, and a Jnk antagonist fully nology: RNA co-immunoprecipitation followed by hybridization to tilling rescues synthetic lethality. Both an Erk1/2 and Jnk1 antagonist protected arrays. Remarkably, we found that 20% of expressed lincRNAs are bound against aneurysm progression in S4+/+:C1039G/+ mice despite the fact by PRC2 in several human cell types. By examining several other chromatin that only Erk shows activation in this strain. Activation of MAPKs is dependent modifying complexes, we found that 56% of lincRNAs are associated with on both AT1 and TGFβ. These data show that Erk and Jnk signaling is these complexes. We then confirmed the localization of these lincRNAs to additive and interchangeable in the pathogenesis of ascending aortic aneu- chromatin by RNA in situ hybridization. Through loss-of-function experi- rysm. AngII signals through both the AT1 and AT2 receptors. Use of ACE ments, we found PRC2-associated lincRNAs to be required for proper inhibitors (ACEi, e.g. enalapril) inhibits both receptors, whereas selective expression of specific regions of the genome which are known to be regu- AT1 blockade is achieved with ARBs. AT2 signaling can induce apoptosis, lated by PRC2. We have also profiled lincRNAs across multiple cancer prompting the proposal that ACEi are preferable. To address this controversy types and discovered numerous lincRNAs that are both misregulated in we knocked out the AT2 gene in C1039G/+ mice (AT2KO:C1039G/+) and cancer and bound to chromatin modifying complexes. Moreover, p53 directly showed larger aortas and worsened vessel architecture compared to and temporally induces several chromatin-associated lincRNAs in response AT2+:C1039G/+ animals. A trial of enalapril in the MFS mice did not attenu- to DNA damage. Remarkably, these lincRNAs serve to regulate many key ate aortic growth, while losartan led to regression of aortic size. Much of genes in the p53 pathway. Together, these results point to a general mecha- the protection by losartan was lost in AT2KO:C1039G/+ mice, suggesting nism of lincRNA mediated regulation in key cancer processes via the guid- that shunting of signaling through AT2 upon AT1 blockade contributes to ance of chromatin modifying complexes. Furthermore, RIP-seq technology aortic rescue. Finally, we show that AT2 signaling mediates protection has revealed a plethora of small RNAs that map to peaks of various chroma- through inhibition of activation of Erk, which is increased in AT2KO:C1039G/ tin modifications. Our results are significant since: 1) This is the first genome- + mice. In contrast to losartan, enalapril fails to reduce Erk1/2 activation in wide characterization of ncRNAs interaction with chromatin modifying com- C1039G/+ mice. Taken together, these data define MAPK and AT2 signaling plexes, 2) They suggest that both small and large ncRNAs can establish as prognostic and therapeutic modifiers of vascular disease in MFS and epigenetic landscapes by guiding chromatin modifying complexes to specific provide rationale and incentive for a clinical trial of Erk and Jnk antagonists regions of the genome, and disruption of these interactions may represent and AT2 agonists in MFS. a novel paradigm in cancer etiology. 2 Next-Generation Mendelian Genetics by Exome Sequencing. J. Shend- ure1, S.B. Ng1, E.H. Turner1, P.D. Robertson1, A.W. Bigham2,C.Lee1, E.E. Eichler1, M. Bamshad2, D.A. Nickerson1. 1) Department of Genome Sciences, University of Washington, Seattle, WA; 2) Department of Pediat- rics, University of Washington, Seattle, WA. Rare monogenic diseases have been of incredible value to biomedical research, as the identification of the genes underlying phenotypes of interest has yielded fundamental, medically relevant insights into human biology. However, many rare disorders have yet to be solved. In many cases, this is because only a small number of cases/families are available, limiting the power of traditional gene mapping strategies. As most disease-causing variants affect coding sequences, comprehensive resequencing of all human genes has the potential to serve as a genome-wide scan for the underlying cause of a rare monogenic disease. While the routine sequencing of full human genomes continues to be cost prohibitive, the cost of sequencing all protein-coding regions (i.e., the “exome”, ~1% of a human genome) may soon be on par with that of dense genotyping arrays. We evaluated whether second-generation methods for targeted sequencing of the human exome could serve as a genome-wide scan for monogenic diseases that is indepen- dent of linkage data or other a priori assumptions. To that end, we carried out targeted capture and massively parallel sequencing of the exomes of twelve humans. These include eight HapMap individuals representing three populations, and four unrelated individuals with a rare dominantly inherited disorder, Freeman-Sheldon syndrome (FSS). We successfully interrogated ~96% of each human exome and demonstrate the sensitive and specific identification of rare and common variants in over 300 megabases (Mb) of coding sequence, capturing both single nucleotide substitutions and small insertion-deletions. Importantly, using FSS as a proof-of-concept, we show that candidate genes for monogenic disorders can be identified by exome sequencing of a small number of unrelated, affected individuals. Notably, however, this approach is critically dependent on the availability of adequate filters for common variants. In our analysis of FSS, the availability of the 8 HapMap exomes provided an essential supplement to dbSNP. Low-cost, high throughput technologies for exome resequencing have the potential to rapidly accelerate the discovery of candidate gene(s) and mutations that underlie rare monogenic diseases that have been resistant to conventional approaches. This strategy may also be applicable to diseases with more complex genetics through larger sample sizes and appropriate weighting of nonsynonymous variants by predicted functional impact. † Trainee Award Finalist Copyright © 2009 The American Society of Human Genetics. All rights reserved. 2 Platform Session 18: Plenary Session 4 5 Meta-analysis of >100,000 individuals identifies 63 new loci associated Long Range Effects of CNVs Mediated by cis-Acting Promoter Competi- with serum lipid concentrations. T.M. Teslovich1, K. Musunuru2,3, A.V. tion. K. Lower1, J. Hughes1, M. De Gobbi1, S. Henderson2, V. Viprakasit3, Smith4, S. Ripatti5,6, C. van Duijn7, J. Rotter8, D. Chasman9, E. Boerwinkle10, C. Fisher1, A. Goriely1, H. Ayyub1, J. Sloane-Stanley1, D. Vernimmen1,C. L.A. Cupples11, R. Krauss12, V. Gudnason4, D. Rader13, M. Sandhu14,15,J. Langford4, D. Garrick1, R. Gibbons1, D. Higgs1. 1) MRC Molecular Haematol- Kooner16, I. Borecki17, P. Munroe18, L. Pentonen2,5,19, M. Boehnke1,G. ogy Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Abecasis1, S. Kathiresan2,3, Global Lipids Genetics Consortium. 1) Center Oxford, UK; 2) National Haemoglobinopathy Reference Laboratory, Oxford for Statistical Genetics, Department of Biostatistics, University of Michigan, Radcliffe Hospitals NHS Trust, Oxford, UK; 3) Department of Paediatrics, Ann Arbor, MI; 2) Program in Medical and
Recommended publications
  • Peripheral Nervous System……………………………………………….9
    PhD School in Integrative Biomedical Research Department of Pharmacological and Biomolecular Sciences Curriculum: Neuroscience Molecular basis for the development of innovative therapies for peripheral neuropathies treatment: role and cross-regulation of the GABAergic system and neuroactive steroids SDD BIO/09 - Physiology Luca Franco Castelnovo Badge number R10402 PhD Tutor: Prof. Valerio Magnaghi PhD School Coordinator: Prof. Chiarella Sforza Academic year 2015/2016 INDEX Abstract…………………………………………………………………...page 1 Abbreviations list…………………………………………………………….....5 Introduction………………………………………………………………….....8 Peripheral nervous system……………………………………………….9 General concepts……………...……….……………………………........……..9 Sensory system and nociceptive fibers.………………..………….…………..12 Schwann cells and myelination……….……..………………...………………15 Peripheral neuropathies…….…………………………………………...26 General concepts……………………………………………………...……….26 Neuropathic pain……………………………………...……………………….27 Nerve regeneration…………………………………………………………….28 The GABAergic system………….……………………………………...32 GABA……………….…………………………………………………..……..32 GABA-A receptors…………………………………………………………….33 GABA-B receptors…………………………………………………………….42 GABAergic system in the peripheral nervous system…………………………47 Protein kinase C – type ε……………………….………………………..51 General concepts…………………………………………………….…………51 Cross-talk with allopregnanolone and GABA-A………………………………54 Neuroactive steroids…………......………………………………………57 General concepts…………………………………….…………………………57 Mechanism of action…………………………….……………………………..59 Progesterone derivatives………………………………….……………………60
    [Show full text]
  • Nicotinic Signalling and Neurosteroid Modulation in Principal Neurons of the Hippocampal Formation and Prefrontal Cortex
    Nicotinic Signalling and Neurosteroid Modulation in Principal Neurons of the Hippocampal Formation and Prefrontal Cortex by Beryl Yik Ting Chung A Thesis presented to The University of Guelph In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Sciences and Neuroscience Guelph, Ontario, Canada © Beryl Yik Ting Chung, April, 2018 ABSTRACT NICOTINIC SIGNALLING AND NEUROSTEROID MODULATION IN PRINCIPAL NEURONS OF THE HIPPOCAMPAL FORMATION AND PREFRONTAL CORTEX Beryl Yik Ting Chung Advisor: University of Guelph, 2018 Dr. Craig D.C. Bailey Nicotinic signalling plays an important role in coordinating the response of neuronal networks in many brain regions. During pre- and postnatal circuit formation, neurotransmission mediated by nicotinic acetylcholine receptors (nAChRs) influences neuronal survival and regulates neuronal excitability, synaptic transmission, and synaptic plasticity. Nicotinic signalling is also necessary for the proper function of the hippocampal formation (HF) and prefrontal cortex (PFC), which are anatomically and functionally connected and facilitate higher-order cognitive functions. The decline or dysfunction in nicotinic signalling and nAChR function has been observed in various neurological disorders, and the disruption or alteration of nicotinic signalling in the HF and/or PFC can impair learning and memory. While the location and functional role of the α4β2* nAChR isoform has been well characterized in the medial portion of the PFC, this is not well-established in the HF. What is the role of α4β2* nAChRs in excitatory principal neurons of the HF during early development? Growing evidence suggests that the progesterone metabolite allopregnanolone (ALLO) plays a role in mediating the proper function of the HF and the PFC, and that it may also inhibit nAChR function.
    [Show full text]
  • In Silico Prediction of High-Resolution Hi-C Interaction Matrices
    ARTICLE https://doi.org/10.1038/s41467-019-13423-8 OPEN In silico prediction of high-resolution Hi-C interaction matrices Shilu Zhang1, Deborah Chasman 1, Sara Knaack1 & Sushmita Roy1,2* The three-dimensional (3D) organization of the genome plays an important role in gene regulation bringing distal sequence elements in 3D proximity to genes hundreds of kilobases away. Hi-C is a powerful genome-wide technique to study 3D genome organization. Owing to 1234567890():,; experimental costs, high resolution Hi-C datasets are limited to a few cell lines. Computa- tional prediction of Hi-C counts can offer a scalable and inexpensive approach to examine 3D genome organization across multiple cellular contexts. Here we present HiC-Reg, an approach to predict contact counts from one-dimensional regulatory signals. HiC-Reg pre- dictions identify topologically associating domains and significant interactions that are enri- ched for CCCTC-binding factor (CTCF) bidirectional motifs and interactions identified from complementary sources. CTCF and chromatin marks, especially repressive and elongation marks, are most important for HiC-Reg’s predictive performance. Taken together, HiC-Reg provides a powerful framework to generate high-resolution profiles of contact counts that can be used to study individual locus level interactions and higher-order organizational units of the genome. 1 Wisconsin Institute for Discovery, 330 North Orchard Street, Madison, WI 53715, USA. 2 Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI 53715, USA. *email: [email protected] NATURE COMMUNICATIONS | (2019) 10:5449 | https://doi.org/10.1038/s41467-019-13423-8 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-019-13423-8 he three-dimensional (3D) organization of the genome has Results Temerged as an important component of the gene regulation HiC-Reg for predicting contact count using Random Forests.
    [Show full text]
  • Proteomic Identification of the Transcription Factors Ikaros And
    European School of Molecular Medicine (SEMM) University of Milan and University of Naples “Federico II” PhD degree in Systems Medicine (curriculum in Molecular Oncology) Settore disciplinare: BIO/11 Proteomic identification of the transcription factors Ikaros and Aiolos as new Myc interactors on chromatin Chiara Veronica Locarno Matricola: R10755 Center for Genomic Science IIT@SEMM, Milan Supervisor: Bruno Amati, PhD IEO, Milan Added Supervisor: Arianna Sabò, PhD IEO, Milan Academic year 2017-2018 Table of contents List of abbreviations ........................................................................................................... 4 List of figures ....................................................................................................................... 8 List of tables ....................................................................................................................... 11 Abstract .............................................................................................................................. 12 1. INTRODUCTION ......................................................................................................... 13 1.1 Myc ........................................................................................................................................ 13 1.1.1 Myc discovery and structure ........................................................................................... 13 1.1.2. Role of Myc in physiological and pathological conditions ...........................................
    [Show full text]
  • TASOR Is a Pseudo-PARP That Directs HUSH Complex Assembly and Epigenetic Transposon Control
    bioRxiv preprint doi: https://doi.org/10.1101/2020.03.09.974832; this version posted March 11, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. TASOR is a pseudo-PARP that directs HUSH complex assembly and epigenetic transposon control Christopher H. Douse1,‡, Iva A. Tchasovnikarova2,‡, Richard T. Timms2,‡, Anna V. Protasio2, Marta Seczynska2, Daniil M. Prigozhin1, Anna Albecka1,2, Jane Wagstaff3, James C. Williamson2, Stefan M.V. Freund3, Paul J. Lehner2*, Yorgo Modis1,2* 1 Molecular Immunity Unit, Department of Medicine, University of Cambridge, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge, CB2 0QH, UK 2 Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Department of Medicine, University of Cambridge, Cambridge CB2 0AW, UK 3 Structural Studies Division, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge, CB2 0QH, UK Current addresses: Department of Experimental Medical Science, Lund University, Sölvegatan 19, Lund, Sweden (C.H.D.); The Gurdon Institute, Tennis Court Road, Cambridge, UK (I.A.T.); Department of Pathology, Tennis Court Road, Cambridge, UK (A.V.P.); Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA (D.M.P.) ‡These authors contributed equally *co-corresponding authors Keywords: Transcriptional repression; epigenetic silencing; antiretroviral response; genome stability; histone H3 lysine 9 methylation (H3K9me3); transposable element (TE); long interspersed nuclear element-1 (LINE-1); poly-ADP ribose polymerase (PARP); RNA-binding protein; RNA-induced transcriptional silencing; CUT&RUN; CUT&Tag; genome profiling 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.03.09.974832; this version posted March 11, 2020.
    [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]
  • 1 UST College of Science Department of Biological Sciences
    UST College of Science Department of Biological Sciences 1 Pharmacogenomics of Myofascial Pain Syndrome An Undergraduate Thesis Submitted to the Department of Biological Sciences College of Science University of Santo Tomas In Partial Fulfillment of the Requirements for the Degree of Bachelor of Science in Biology Jose Marie V. Lazaga Marc Llandro C. Fernandez May 2021 UST College of Science Department of Biological Sciences 2 PANEL APPROVAL SHEET This undergraduate research manuscript entitled: Pharmacogenomics of Myofascial Pain Syndrome prepared and submitted by Jose Marie V. Lazaga and Marc Llandro C. Fernandez, was checked and has complied with the revisions and suggestions requested by panel members after thorough evaluation. This final version of the manuscript is hereby approved and accepted for submission in partial fulfillment of the requirements for the degree of Bachelor of Science in Biology. Noted by: Asst. Prof. Marilyn G. Rimando, PhD Research adviser, Bio/MicroSem 602-603 Approved by: Bio/MicroSem 603 panel member Bio/MicroSem 603 panel member Date: Date: UST College of Science Department of Biological Sciences 3 DECLARATION OF ORIGINALITY We hereby affirm that this submission is our own work and that, to the best of our knowledge and belief, it contains no material previously published or written by another person nor material to which a substantial extent has been accepted for award of any other degree or diploma of a university or other institute of higher learning, except where due acknowledgement is made in the text. We also declare that the intellectual content of this undergraduate research is the product of our work, even though we may have received assistance from others on style, presentation, and language expression.
    [Show full text]
  • Redefining the Specificity of Phosphoinositide-Binding by Human
    bioRxiv preprint doi: https://doi.org/10.1101/2020.06.20.163253; this version posted June 21, 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 4.0 International license. Redefining the specificity of phosphoinositide-binding by human PH domain-containing proteins Nilmani Singh1†, Adriana Reyes-Ordoñez1†, Michael A. Compagnone1, Jesus F. Moreno Castillo1, Benjamin J. Leslie2, Taekjip Ha2,3,4,5, Jie Chen1* 1Department of Cell & Developmental Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801; 2Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205; 3Department of Biophysics, Johns Hopkins University, Baltimore, MD 21218; 4Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21205; 5Howard Hughes Medical Institute, Baltimore, MD 21205, USA †These authors contributed equally to this work. *Correspondence: [email protected]. bioRxiv preprint doi: https://doi.org/10.1101/2020.06.20.163253; this version posted June 21, 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 4.0 International license. ABSTRACT Pleckstrin homology (PH) domains are presumed to bind phosphoinositides (PIPs), but specific interaction with and regulation by PIPs for most PH domain-containing proteins are unclear. Here we employed a single-molecule pulldown assay to study interactions of lipid vesicles with full-length proteins in mammalian whole cell lysates.
    [Show full text]
  • Análise Integrativa De Perfis Transcricionais De Pacientes Com
    UNIVERSIDADE DE SÃO PAULO FACULDADE DE MEDICINA DE RIBEIRÃO PRETO PROGRAMA DE PÓS-GRADUAÇÃO EM GENÉTICA ADRIANE FEIJÓ EVANGELISTA Análise integrativa de perfis transcricionais de pacientes com diabetes mellitus tipo 1, tipo 2 e gestacional, comparando-os com manifestações demográficas, clínicas, laboratoriais, fisiopatológicas e terapêuticas Ribeirão Preto – 2012 ADRIANE FEIJÓ EVANGELISTA Análise integrativa de perfis transcricionais de pacientes com diabetes mellitus tipo 1, tipo 2 e gestacional, comparando-os com manifestações demográficas, clínicas, laboratoriais, fisiopatológicas e terapêuticas Tese apresentada à Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo para obtenção do título de Doutor em Ciências. Área de Concentração: Genética Orientador: Prof. Dr. Eduardo Antonio Donadi Co-orientador: Prof. Dr. Geraldo A. S. Passos Ribeirão Preto – 2012 AUTORIZO A REPRODUÇÃO E DIVULGAÇÃO TOTAL OU PARCIAL DESTE TRABALHO, POR QUALQUER MEIO CONVENCIONAL OU ELETRÔNICO, PARA FINS DE ESTUDO E PESQUISA, DESDE QUE CITADA A FONTE. FICHA CATALOGRÁFICA Evangelista, Adriane Feijó Análise integrativa de perfis transcricionais de pacientes com diabetes mellitus tipo 1, tipo 2 e gestacional, comparando-os com manifestações demográficas, clínicas, laboratoriais, fisiopatológicas e terapêuticas. Ribeirão Preto, 2012 192p. Tese de Doutorado apresentada à Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo. Área de Concentração: Genética. Orientador: Donadi, Eduardo Antonio Co-orientador: Passos, Geraldo A. 1. Expressão gênica – microarrays 2. Análise bioinformática por module maps 3. Diabetes mellitus tipo 1 4. Diabetes mellitus tipo 2 5. Diabetes mellitus gestacional FOLHA DE APROVAÇÃO ADRIANE FEIJÓ EVANGELISTA Análise integrativa de perfis transcricionais de pacientes com diabetes mellitus tipo 1, tipo 2 e gestacional, comparando-os com manifestações demográficas, clínicas, laboratoriais, fisiopatológicas e terapêuticas.
    [Show full text]
  • Expression Signatures of the Lipid-Based Akt Inhibitors Phosphatidylinositol Ether Lipid Analogues in NSCLC Cells
    Published OnlineFirst May 6, 2011; DOI: 10.1158/1535-7163.MCT-10-1028 Molecular Cancer Therapeutic Discovery Therapeutics Expression Signatures of the Lipid-Based Akt Inhibitors Phosphatidylinositol Ether Lipid Analogues in NSCLC Cells Chunyu Zhang1, Abdel G. Elkahloun2, Hongling Liao3, Shannon Delaney1, Barbara Saber1, Betsy Morrow1, George C. Prendergast4, M. Christine Hollander1, Joell J. Gills1, and Phillip A. Dennis1 Abstract Activation of the serine/threonine kinase Akt contributes to the formation, maintenance, and therapeutic resistance of cancer, which is driving development of compounds that inhibit Akt. Phosphatidylinositol ether lipid analogues (PIA) are analogues of the products of phosphoinositide-3-kinase (PI3K) that inhibit Akt activation, translocation, and the proliferation of a broad spectrum of cancer cell types. To gain insight into the mechanism of PIAs, time-dependent transcriptional profiling of five active PIAs and the PI3K inhibitor LY294002 (LY) was conducted in non–small cell lung carcinoma cells using high-density oligonucleotide arrays. Gene ontology analysis revealed that genes involved in apoptosis, wounding response, and angiogen- esis were upregulated by PIAs, whereas genes involved in DNA replication, repair, and mitosis were suppressed. Genes that exhibited early differential expression were partitioned into three groups; those induced by PIAs only (DUSP1, KLF6, CENTD2, BHLHB2, and PREX1), those commonly induced by PIAs and LY (TRIB1, KLF2, RHOB, and CDKN1A), and those commonly suppressed by PIAs and LY (IGFBP3, PCNA, PRIM1, MCM3, and HSPA1B). Increased expression of the tumor suppressors RHOB (RhoB), KLF6 (COPEB), and CDKN1A (p21Cip1/Waf1) was validated as an Akt-independent effect that contributed to PIA-induced cytotoxicity. Despite some overlap with LY, active PIAs have a distinct expression signature that contributes to their enhanced cytotoxicity.
    [Show full text]
  • WO 2019/079361 Al 25 April 2019 (25.04.2019) W 1P O PCT
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2019/079361 Al 25 April 2019 (25.04.2019) W 1P O PCT (51) International Patent Classification: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, C12Q 1/68 (2018.01) A61P 31/18 (2006.01) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, C12Q 1/70 (2006.01) HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, (21) International Application Number: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, PCT/US2018/056167 OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (22) International Filing Date: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 16 October 2018 (16. 10.2018) TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (26) Publication Language: English GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, (30) Priority Data: UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 62/573,025 16 October 2017 (16. 10.2017) US TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, ΓΕ , IS, IT, LT, LU, LV, (71) Applicant: MASSACHUSETTS INSTITUTE OF MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TECHNOLOGY [US/US]; 77 Massachusetts Avenue, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Cambridge, Massachusetts 02139 (US).
    [Show full text]
  • A Multi-Stage Genome-Wide Association Study of Uterine Fibroids in African Americans
    UCLA UCLA Previously Published Works Title A multi-stage genome-wide association study of uterine fibroids in African Americans. Permalink https://escholarship.org/uc/item/0mc5r0xh Journal Human genetics, 136(10) ISSN 0340-6717 Authors Hellwege, Jacklyn N Jeff, Janina M Wise, Lauren A et al. Publication Date 2017-10-01 DOI 10.1007/s00439-017-1836-1 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Hum Genet (2017) 136:1363–1373 DOI 10.1007/s00439-017-1836-1 ORIGINAL INVESTIGATION A multi‑stage genome‑wide association study of uterine fbroids in African Americans Jacklyn N. Hellwege1,2,3 · Janina M. Jef4 · Lauren A. Wise5,6 · C. Scott Gallagher7 · Melissa Wellons8,9 · Katherine E. Hartmann3,9 · Sarah F. Jones1,3 · Eric S. Torstenson1,2 · Scott Dickinson10 · Edward A. Ruiz‑Narváez6 · Nadin Rohland7 · Alexander Allen7 · David Reich7,11,12 · Arti Tandon7 · Bogdan Pasaniuc13,14 · Nicholas Mancuso13 · Hae Kyung Im10 · David A. Hinds15 · Julie R. Palmer6 · Lynn Rosenberg6 · Joshua C. Denny16,17 · Dan M. Roden2,16,17,18 · Elizabeth A. Stewart19 · Cynthia C. Morton12,20,21,22 · Eimear E. Kenny4 · Todd L. Edwards1,2,3 · Digna R. Velez Edwards2,3,9 Received: 12 April 2017 / Accepted: 16 August 2017 / Published online: 23 August 2017 © Springer-Verlag GmbH Germany 2017 Abstract Uterine fbroids are benign tumors of the uterus imaging, genotyped and imputed to 1000 Genomes. Stage 2 afecting up to 77% of women by menopause. They are the used self-reported fbroid and GWAS data from 23andMe, leading indication for hysterectomy, and account for $34 bil- Inc.
    [Show full text]