Computational Biology of Non- Coding RNA Methods and Protocols M ETHODS in M OLECULAR B IOLOGY
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Molecular Reprogramming in Tomato Pollen During Development And
Molecular reprogramming in tomato pollen during development and heat stress Dissertation zur Erlangung des Doktorgrades der Naturwissenschaften vorgelegt beim Fachbereich Biowissenschaften (FB15) der Goethe-Universität Frankfurt am Main von Mario Keller geboren in Frankfurt am Main (Hessen) Frankfurt am Main 2018 (D30) Vom Fachbereich Biowissenschaften (FB15) der Goethe-Universität als Dissertation angenommen. Dekan: Prof. Dr. Sven Klimpel Gutachter: Prof. Dr. Enrico Schleiff, Jun. Prof. Dr. Michaela Müller-McNicoll Datum der Disputation: 25.03.2019 Index of contents Index of contents Index of contents ....................................................................................................................................... i Index of figures ........................................................................................................................................ iii Index of tables ......................................................................................................................................... iv Index of supplemental material ................................................................................................................ v Index of supplemental figures ............................................................................................................... v Index of supplemental tables ................................................................................................................ v Abbreviations .......................................................................................................................................... -
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Published OnlineFirst November 11, 2014; DOI: 10.1158/0008-5472.CAN-14-1041 Cancer Tumor and Stem Cell Biology Research Loss of Estrogen-Regulated microRNA Expression Increases HER2 Signaling and Is Prognostic of Poor Outcome in Luminal Breast Cancer Shannon T. Bailey1,2,3, Thomas Westerling1,2,3, and Myles Brown1,2,3 Abstract Among the genes regulated by estrogen receptor (ER) are Genome Atlas (TCGA). Among luminal tumors, these miRNAs miRNAs that play a role in breast cancer signaling pathways. To are expressed at higher levels in luminal A versus B tumors. determine whether miRNAs are involved in ER-positive breast Although their expression is uniformly low in luminal B tumors, cancer progression to hormone independence, we profiled the they are lost only in a subset of luminal A patients. Interestingly, expression of 800 miRNAs in the estrogen-dependent human this subset with low expression of these miRNAs had worse breast cancer cell line MCF7 and its estrogen-independent deriv- overall survival compared with luminal A patients with high ative MCF7:2A (MCF7:2A) using NanoString. We found 78 expression. We confirmed that miR125b directly targets HER2 miRNAs differentially expressed between the two cell lines, and that let-7c also regulates HER2 protein expression. In addi- including a cluster comprising let-7c, miR99a, and miR125b, tion, HER2 protein expression and activity are negatively corre- which is encoded in an intron of the long noncoding RNA lated with let-7c expression in TCGA. In summary, we identified LINC00478. These miRNAs are ER targets in MCF7 cells, and an ER-regulated miRNA cluster that regulates HER2, is lost with nearby ER binding and their expression are significantly progression to estrogen independence, and may serve as a bio- þ decreased in MCF7:2A cells. -
Advances in Oligonucleotide Drug Delivery
REVIEWS Advances in oligonucleotide drug delivery Thomas C. Roberts 1,2 ✉ , Robert Langer 3 and Matthew J. A. Wood 1,2 ✉ Abstract | Oligonucleotides can be used to modulate gene expression via a range of processes including RNAi, target degradation by RNase H-mediated cleavage, splicing modulation, non-coding RNA inhibition, gene activation and programmed gene editing. As such, these molecules have potential therapeutic applications for myriad indications, with several oligonucleotide drugs recently gaining approval. However, despite recent technological advances, achieving efficient oligonucleotide delivery, particularly to extrahepatic tissues, remains a major translational limitation. Here, we provide an overview of oligonucleotide-based drug platforms, focusing on key approaches — including chemical modification, bioconjugation and the use of nanocarriers — which aim to address the delivery challenge. Oligonucleotides are nucleic acid polymers with the In addition to their ability to recognize specific tar- potential to treat or manage a wide range of diseases. get sequences via complementary base pairing, nucleic Although the majority of oligonucleotide therapeutics acids can also interact with proteins through the for- have focused on gene silencing, other strategies are being mation of three-dimensional secondary structures — a pursued, including splice modulation and gene activa- property that is also being exploited therapeutically. For tion, expanding the range of possible targets beyond example, nucleic acid aptamers are structured -
Timo Lassmann, Yoshiko Maida 2, Yasuhiro Tomaru, Mami Yasukawa
Int. J. Mol. Sci. 2015, 16, 1192-1208; doi:10.3390/ijms16011192 OPEN ACCESS International Journal of Molecular Sciences ISSN 1422-0067 www.mdpi.com/journal/ijms Article Telomerase Reverse Transcriptase Regulates microRNAs Timo Lassmann 1,†, Yoshiko Maida 2,†, Yasuhiro Tomaru 1, Mami Yasukawa 2, Yoshinari Ando 1, Miki Kojima 1, Vivi Kasim 2, Christophe Simon 1, Carsten O. Daub 1, Piero Carninci 1, Yoshihide Hayashizaki 1,* and Kenkichi Masutomi 2,3,* 1 RIKEN Omics Science Center, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan; E-Mails: [email protected] (T.L.); [email protected] (Y.T.); [email protected] (Y.A.); [email protected] (M.K.); [email protected] (C.S.); [email protected] (C.O.D.); [email protected] (P.C.) 2 Cancer Stem Cell Project, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; E-Mails: [email protected] (Y.M.); [email protected] (M.Y.); [email protected] (V.K.) 3 Precursory Research for Embryonic Science and Technology (PREST), Japan Science and Technology Agency, 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan † These authors contributed equally to this work. * Authors to whom correspondence should be addressed; E-Mails: [email protected] (Y.H.); [email protected] (K.M.); Tel.: +81-45-503-9248 (Y.H.); +81-3-3547-5173 (K.M.); Fax: +81-45-503-9216 (Y.H.); +81-3-3547-5123 (K.M.). Academic Editor: Martin Pichler Received: 22 November 2014 / Accepted: 26 December 2014 / Published: 6 January 2015 Abstract: MicroRNAs are small non-coding RNAs that inhibit the translation of target mRNAs. -
Targets for Antiviral Therapy of Hepatitis C
9 Targets for Antiviral Therapy of Hepatitis C Daniel Rupp, MD1,2 Ralf Bartenschlager, PhD1,2 1 Department for Infectious Diseases, Molecular Virology, University of Address for correspondence Ralf Bartenschlager, PhD, Department Heidelberg, Heidelberg, Germany for Infectious Diseases, Molecular Virology, University of Heidelberg, 2 German Centre for Infection Research, Heidelberg University Im Neuenheimer Feld 345, 69120 Heidelberg, Germany (e-mail: [email protected]). Semin Liver Dis 2014;34:9–21. Abstract Presently, interferon- (IFN-) containing treatment regimens are the standard of care for patients with hepatitis C virus (HCV) infections. Although this therapy eliminates the virus in a substantial proportion of patients, it has numerous side effects and contra- indications. Recent approval of telaprevir and boceprevir, targeting the protease residing in nonstructural protein 3 (NS3) of the HCV genome, increased therapy success when given in combination with pegylated IFN and ribavirin, but side effects are more frequent and the management of treatment is complex. This situation will change soon with the introduction of new highly potent direct-acting antivirals. They target, in Keywords addition to the NS3 protease, NS5A, which is required for RNA replication and virion ► NS3 protease assembly and the NS5B RNA-dependent RNA polymerase. Moreover, host-cell factors ► NS5A such as cyclophilin A or microRNA-122, essential for HCV replication, have been pursued ► NS5B as therapeutic targets. In this review, the authors briefly summarize the main features of ► miR-122 viral and cellular factors involved in HCV replication that are utilized as therapy targets ► cyclophilin A for chronic hepatitis C. Hepatitis C virus (HCV) infection still is a major health burden nonstructural protein 3 (NS3): boceprevir (BOC) and telap- affecting 130 to 170 million people worldwide. -
Charakterisierung Interindividueller Strahlenempfindlichkeit in Zellen Aus Tumorpatienten
Charakterisierung interindividueller Strahlenempfindlichkeit in Zellen aus Tumorpatienten Anne Maria Dietz Charakterisierung interindividueller Strahlenempfindlichkeit in Zellen aus Tumorpatienten Dissertation an der Fakultät für Biologie der Ludwig-Maximilians-Universität München zur Erlangung des Doktorgrades der Naturwissenschaften Angefertigt an der Klinik und Poliklinik für Strahlentherapie und Radioonkolgie in der Arbeitsgruppe Molekulare Strahlenbiologie unter der Leitung von PD. Dr. Anna Friedl Vorgelegt von Anne Maria Dietz München, den 03. Dezember 2014 Erstgutachter: PD Dr. Anna A. Friedl Zweitgutachter: Prof. Dr. Peter Becker Tag der mündlichen Prüfung: 05.05.2015 Meinem Vater Inhaltsverzeichnis Inhaltsverzeichnis 1 Zusammenfassung ........................................................................................................................... 5 2 Einleitung ......................................................................................................................................... 7 2.1 Individuelle Strahlenempfindlichkeit ...................................................................................... 7 2.2 Das Chromosomeninstabilitätssyndrom Ataxia Telangiectasia .............................................. 9 2.3 Biomarker-Entdeckung im Zeitalter der Omics-Technologien .............................................. 12 2.3.1 Charakterisierung eines validen Biomarkers ................................................................. 12 2.3.2 Biomarker für Strahlenempfindlichkeit ........................................................................ -
Antiviral Research 111 (2014) 53–59
Antiviral Research 111 (2014) 53–59 Contents lists available at ScienceDirect Antiviral Research journal homepage: www.elsevier.com/locate/antiviral Long-term safety and efficacy of microRNA-targeted therapy in chronic hepatitis C patients Meike H. van der Ree a, Adriaan J. van der Meer b, Joep de Bruijne a, Raoel Maan b, Andre van Vliet c, Tania M. Welzel d, Stefan Zeuzem d, Eric J. Lawitz e, Maribel Rodriguez-Torres f, Viera Kupcova g, ⇑ Alcija Wiercinska-Drapalo h, Michael R. Hodges i, Harry L.A. Janssen b,j, Hendrik W. Reesink a, a Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands b Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands c PRA International, Zuidlaren, The Netherlands d J.W. Goethe University Hospital, Frankfurt, Germany e The Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA f Fundacion de Investigacion, San Juan, Porto Rico g Department of Internal Medicine, Derer’s Hospital, University Hospital Bratislava, Slovakia h Medical University of Warsaw, Warsaw Hospital for Infectious Diseases, Warsaw, Poland i Santaris Pharma A/S, San Diego, USA j Liver Clinic, Toronto Western & General Hospital, University Health Network, Toronto, Canada article info abstract Article history: Background and aims: MicroRNA-122 (miR-122) is an important host factor for hepatitis C virus (HCV) Received 6 June 2014 and promotes HCV RNA accumulation. Decreased intra-hepatic levels of miR-122 were observed in Revised 28 July 2014 patients with hepatocellular carcinoma, suggesting a potential role of miR-122 in the development of Accepted 29 August 2014 HCC. -
Untersuchung Zur Rolle Des La-Verwandten Proteins LARP4B Im Mrna- Metabolismus
Untersuchung zur Rolle des La-verwandten Proteins LARP4B im mRNA-Metabolismus Dissertation zur Erlangung des naturwissenschaftlichen Doktorgrades der Julius-Maximilians-Universität Würzburg vorgelegt von Maritta Küspert aus Schwäbisch Hall Würzburg 2014 Eingereicht bei der Fakultät für Chemie und Pharmazie am: ....................................... Gutachter der schriftlichen Arbeit: 1. Gutachter: Prof. Dr. Utz Fischer 2. Gutachter: Prof. Dr. Alexander Buchberger Prüfer des öffentlichen Promotionskolloquiums: 1. Prüfer: Prof. Dr. Utz Fischer 2. Prüfer: Prof. Dr. Alexander Buchberger 3. Prüfer: Prof. Dr. Stefan Gaubatz Datum des öffentlichen Promotionskolloquiums: ......................................................... Doktorurkunde ausgehändigt am: ................................................................................ Zusammenfassung Eukaryotische messenger-RNAs (mRNAs) müssen diverse Prozessierungsreaktionen durchlaufen, bevor sie der Translationsmaschinerie als Template für die Proteinbiosynthese dienen können. Diese Reaktionen beginnen bereits kotranskriptionell und schließen das Capping, das Spleißen und die Polyadenylierung ein. Erst nach dem die Prozessierung abschlossen ist, kann die reife mRNA ins Zytoplasma transportiert und translatiert werden. mRNAs interagieren in jeder Phase ihres Metabolismus mit verschiedenen trans-agierenden Faktoren und bilden mRNA-Ribonukleoproteinkomplexe (mRNPs) aus. Dieser „mRNP-Code“ bestimmt das Schicksal jeder mRNA und reguliert dadurch die Genexpression auf posttranskriptioneller -
Gynecologic and Obstetric Pathology
ANNUAL MEETING ABSTRACTS 273A Design: From January 2011 to August 2013, 162 patients underwent robotic laparoscopic radical prostatectomy for clinically localized prostatic carcinoma at our institution. Gynecologic and Obstetric Pathology Periprostatic fat pads, yielded during defatting of the prostate, were dissected and sent to pathology for histopathologic examination in 133 cases. Clinical and pathological 1128 Recurrent Grade I, Stage Ia Endometrioid Carcinomas of the Uterus: staging was recorded according to the 2009 American Joint Committee on Cancer Analysis of Pathology and Correlation with Clinical Data (AJCC) criterion. SN Agoff. Virginia Mason Medical Center, Seattle, WA. Results: Of 133 patients whose periprostatic fat was examined, 32 (24%) patients had Background: Low-grade and low-stage endometrioid carcinoma of the uterus is thought lymph nodes in the periprostatic fat pads. Metastatic prostatic carcinoma to periprostatic to have an excellent prognosis in the vast majority of patients. However, despite the lack lymph nodes was detected in 5 individuals (3.8%). All 32 patients had bilateral pelvic of myometrial invasion or superfi cial invasion, some patients develop recurrent disease, lymphadenectomy. 3 of the 5 patients with positive periprostatic lymph nodes had no often in the vaginal apex. There is limited literature on these tumors, but recent analyses metastasis in pelvic lymph nodes, thereby upstaging 3 cases from T3N0 to T3N1. No have implicated the pattern of myoinvasion as a prognostic factor. The emphasis of relationship exists between the presences of periprostatic LNs and prostate weight, the current study is non-invasive or stage Ia, grade I endometrioid adenocarcinomas. patient age, pathological staging or Gleason score. -
The Promise and Challenges of Developing Mirna-Based Therapeutics for Parkinson’S Disease
cells Review The Promise and Challenges of Developing miRNA-Based Therapeutics for Parkinson’s Disease Simoneide S. Titze-de-Almeida 1 , Cristina Soto-Sánchez 2, Eduardo Fernandez 2,3 , James B. Koprich 4, Jonathan M. Brotchie 4 and Ricardo Titze-de-Almeida 1,* 1 Technology for Gene Therapy Laboratory, Central Institute of Sciences, FAV, University of Brasilia, Brasília 70910-900, Brazil; [email protected] 2 Neuroprosthetics and Visual Rehabilitation Research Unit, Bioengineering Institute, Miguel Hernández University, 03202 Alicante, Spain; [email protected] (C.S.-S.); [email protected] (E.F.) 3 Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine—CIBER-BBN, 28029 Madrid, Spain 4 Krembil Neuroscience Centre, Toronto Western Hospital, University Health Network, Toronto, Ontario M5T 2S8, Canada; [email protected] (J.B.K.); [email protected] (J.M.B.) * Correspondence: [email protected]; Tel.: +55-61-3107-7222 Received: 11 February 2020; Accepted: 18 March 2020; Published: 31 March 2020 Abstract: MicroRNAs (miRNAs) are small double-stranded RNAs that exert a fine-tuning sequence-specific regulation of cell transcriptome. While one unique miRNA regulates hundreds of mRNAs, each mRNA molecule is commonly regulated by various miRNAs that bind to complementary sequences at 3’-untranslated regions for triggering the mechanism of RNA interference. Unfortunately, dysregulated miRNAs play critical roles in many disorders, including Parkinson’s disease (PD), the second most prevalent neurodegenerative disease in the world. Treatment of this slowly, progressive, and yet incurable pathology challenges neurologists. In addition to L-DOPA that restores dopaminergic transmission and ameliorate motor signs (i.e., bradykinesia, rigidity, tremors), patients commonly receive medication for mood disorders and autonomic dysfunctions. -
The Discovery Potential of RNA Processing Profiles
bioRxiv preprint doi: https://doi.org/10.1101/049809; this version posted April 22, 2016. 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 4.0 International license. The discovery potential of RNA processing profiles Amadís Pagès1,2, Ivan Dotu1,3, Roderic Guigó1,2 and Eduardo Eyras1,4,* 1Universitat Pompeu Fabra (UPF), E08003 Barcelona, Spain. 2Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, E08003 Barcelona, Spain. 3IMIM - Hospital del Mar Medical Research Institute. E08003 Barcelona, Spain. 4Catalan Institution for Research and Advanced Studies, E08010 Barcelona, Spain *correspondence to: [email protected] Abstract Small non-coding RNAs are highly abundant molecules that regulate essential cellular processes and are classified according to sequence and structure. Here we argue that read profiles from size-selected RNA sequencing, by capturing the post-transcriptional processing specific to each RNA family, provide functional information independently of sequence and structure. SeRPeNT is a computational method that exploits reproducibility across replicates and uses dynamic time-warping and density-based clustering algorithms to identify, characterize and compare small non-coding RNAs, by harnessing the power of read profiles. SeRPeNT is applied to: a) generate an extended human annotation with 671 new RNAs from known classes and 131 from new potential classes, b) show pervasive differential processing between cell compartments and c) predict new molecules with miRNA-like behaviour from snoRNA, tRNA and long non-coding RNA precursors, dependent on the miRNA biogenesis pathway. -
Regulation of RNA Stability by Terminal Nucleotidyltransferases
Western University Scholarship@Western Electronic Thesis and Dissertation Repository 7-11-2019 10:30 AM Regulation of RNA stability by terminal nucleotidyltransferases Christina Z. Chung The University of Western Ontario Supervisor Heinemann, Ilka U. The University of Western Ontario Graduate Program in Biochemistry A thesis submitted in partial fulfillment of the equirr ements for the degree in Doctor of Philosophy © Christina Z. Chung 2019 Follow this and additional works at: https://ir.lib.uwo.ca/etd Part of the Biochemistry Commons Recommended Citation Chung, Christina Z., "Regulation of RNA stability by terminal nucleotidyltransferases" (2019). Electronic Thesis and Dissertation Repository. 6255. https://ir.lib.uwo.ca/etd/6255 This Dissertation/Thesis is brought to you for free and open access by Scholarship@Western. It has been accepted for inclusion in Electronic Thesis and Dissertation Repository by an authorized administrator of Scholarship@Western. For more information, please contact [email protected]. Abstract The dysregulation of RNAs has global effects on all cellular pathways. The regulation of RNA metabolism is thus tightly controlled. Terminal RNA nucleotidyltransferases (TENTs) regulate RNA stability and activity through the addition of non-templated nucleotides to the 3′-end. TENT-catalyzed adenylation and uridylation have opposing effects; adenylation stabilizes while uridylation silences or degrades RNA. All TENT homologs were initially characterized as adenylyltransferases; the identification of caffeine-induced death suppressor protein 1 (Cid1) in Schizosaccharomyces pombe as an uridylyltransferase led to the reclassification of many TENTs as uridylyltransferases. Cid1 uridylates mRNAs that are subsequently degraded by the exonuclease Dis-like 3′-5′ exonuclease 2 (Dis3L2), while the human homolog germline-development 2 (Gld2) has been associated with adenylation of mRNAs and miRNAs and uridylation of Group II pre-miRNAs.