Prof Vicky Cowling, FRSE - Gene Regulation

Introduction

Cowling Vicky 2021

In every human cell, the expression of 25,000 genes is precisely regulated to generate the spectrum of cell types required through development and into the adult. We are interested in the signalling pathways that coordinate and regulate gene expression, and how dysregulation of these pathways is a cause or consequence of disease. Our aim is to understand how gene expression is regulated in health and disease, and to use this knowledge to develop and refine therapeutic approaches.

Our focus is on the RNA cap, a structure found on pre-mRNA and non-coding RNA that protects RNA and recruits factors involved in processing and translation. A series of RNA capping enzymes catalyses cap formation, predominantly as the transcript is being synthesised. We are interested in how these RNA capping enzymes are regulated during development and in the adult, and the impact that this has on gene expression. Currently, we are investigating RNA cap regulation in embryonic stem cell differentiation, during T cell activation and following oncogene dysregulation in cancer models.

Regulation of the RNA cap can have potent effects on cell function and fate decisions via the regulation of specific gene families. We characterise the biochemical configuration of capping enzyme complexes in different cell types or disease states, follow how these configurations change during differentiation and disease, and determine the impact on gene expression and cell function and fate decisions.


Current funding:
LOGO ERC 2020   Wellcome Trust logo  ChineseScholarship logo UKRI MR Council-Logo Horiz-RGB
 
 
Royal Society logo    

Lab Report

Key Publications

Galloway A, Kaskar A, Ditsova D, Atrih A, Yoshikawa H, Gomez-Moreira C, Suska O, Warminski M, Grzela R, Lamond AI, Darzynkiewicz E, Jemielity J, Cowling VH. Upregulation of RNA cap methyltransferase RNMT drives ribosome biogenesis during T cell activation. Nucleic Acids Res. 2021;49(12):6722-6738.

Varshney D, Lombardi O, Schweikert G, Dunn S, Suska O, Cowling VH. mRNA Cap Methyltransferase, RNMT-RAM, Promotes RNA Pol II-Dependent Transcription. Cell Rep. 2018;23(5):1530-1542.

Varshney D, Petit AP, Bueren-Calabuig JA, Jansen C, Fletcher DA, Peggie M, Weidlich S, Scullion P, Pisliakov AV, Cowling VH. Molecular basis of RNA guanine-7 methyltransferase (RNMT) activation by RAM. Nucleic Acids Res. 2016;44(21):10423-10436.

Grasso L, Suska O, Davidson L, Gonatopoulos-Pournatzis T, Williamson R, Wasmus L, Wiedlich S, Peggie M, Stavridis MP, Cowling VH. mRNA Cap Methylation in Pluripotency and Differentiation. Cell Rep. 2016;16(5):1352-1365.

Aregger M, Kaskar A, Varshney D, Fernandez-Sanchez ME, Inesta-Vaquera FA, Weidlich S, Cowling VH. CDK1-Cyclin B1 Activates RNMT, Coordinating mRNA Cap Methylation with G1 Phase Transcription. Mol Cell. 2016;61(5):734-746.

Biography

Education and qualifications

2002: PhD, Cancer Research UK London Research Institute/UCL - Caspase activation during programmed cell death
1997: BA Natural Sciences, Cambridge University

Appointments

2022-present: Senior Group Leader, CRUK Beatson Institute, Glasgow, UK and Chair of Biology (Full Professor), University of Glasgow, UK
2017-2022: Deputy Head of Centre for Gene Regulation and Expression, University of Dundee, UK
2016: Chair of Biology (Full Professor), University of Dundee, UK
2007-2022: Group Leader, School of Life Sciences, University of Dundee, UK - Regulation of RNA cap in health and disease
2003-2007: Postdoctoral research at Princeton University and Darmouth College, USA - Myc oncogenes: mechanisms and function in breast cancers

Awards and fellowships

Wellcome Trust Investigator Award, 2020
Fellow of the Royal Society of Edinburgh, 2019
Wolfson Royal Society Research Merit Award, 2018
European Research Council (ERC) Consolidator Award, 2017
Fellow of the Royal Society of Biology (UK), 2016
British Society of Cell Biology Women in Cell Biology Award, 2015
European Molecular Biology Organisation (EMBO) Young Investigator, 2014
Medical Research Council UK (MRC) Senior Fellowship, 2013
Lister Institute Prize Fellowship, 2011
Medical Research Council UK (MRC) Career Development Award, 2007

Current committee membership

British Society of Cell Biology Committee
Wellcome Trust Expert Review Group
Volkswagen Foundation Momentum Panel
Royal Society of Edinburgh Fellow Selection Panel

Recent Publications

2021

Bage MG, Almohammed R, Cowling VH, Pisliakov AV. A novel RNA pol II CTD interaction site on the mRNA capping enzyme is essential for its allosteric activation. Nucleic Acids Res. 2021;49(6):3109-3126.

Basu S, Mak T, Ulferts R, Wu M, Deegan T, Fujisawa R, Tan KW, Lim CT, Basier C, Canal B, Curran JF, Drury LS, McClure AW, Roberts EL, Weissmann F, Zeisner TU, Beale R, Cowling VH, Howell M, Labib K, Diffley JFX. Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp14 RNA cap methyltransferase. Biochem J. 2021;478(13):2481-2497.

Galloway A, Kaskar A, Ditsova D, Atrih A, Yoshikawa H, Gomez-Moreira C, Suska O, Warminski M, Grzela R, Lamond AI, Darzynkiewicz E, Jemielity J, Cowling VH. Upregulation of RNA cap methyltransferase RNMT drives ribosome biogenesis during T cell activation. Nucleic Acids Res. 2021;49(12):6722-6738.

Pearson L-A, Green CJ, Lin D, Petit A-P, Gray DW, Cowling VH, Fordyce EAF. Development of a High-Throughput Screening Assay to Identify Inhibitors of the SARS-CoV-2 Guanine-N7-Methyltransferase Using RapidFire Mass Spectrometry. SLAS DISCOVERY: Advancing the Science of Drug Discovery. 2021;26(6):749-756.

Borden KLB, Culjkovic-Kraljacic B, Cowling VH. To Cap it all Off, Again: Dynamic Capping and Recapping of Coding and Non-coding RNAs to Control Transcript Fate and Biological Activity Cell Cycle. 2021; 20(14):1347-1360.

2020

Culjkovic-Kraljacic B, Skrabanek L, Revuelta MV, Gasiorek J, Cowling VH, Cerchietti L, Borden KLB. The eukaryotic translation initiation factor eIF4E elevates steady-state m7G capping of coding and noncoding transcripts. Proceedings of the National Academy of Sciences. 2020;117(43):26773-26783.

Galloway A, Atrih A, Grzela R, Darzynkiewicz E, Ferguson MAJ, Cowling VH. CAP-MAP: cap analysis protocol with minimal analyte processing, a rapid and sensitive approach to analysing mRNA cap structures. Open Biol. 2020;10(2):190306.

Kasprzyk R, Fido M, Mamot A, Wanat P, Smietanski M, Kopcial M, Cowling VH, Kowalska J, Jemielity J. Direct High-Throughput Screening Assay for mRNA Cap Guanine-N7 Methyltransferase Activity. Chemistry. 2020;26(49):11266-11275.

2019

Bueren-Calabuig JA, M GB, Cowling VH, Pisliakov AV. Mechanism of allosteric activation of human mRNA cap methyltransferase (RNMT) by RAM: insights from accelerated molecular dynamics simulations. Nucleic Acids Res. 2019;47(16):8675-8692.

Dunn S, Lombardi O, Lukoszek R, Cowling VH. Oncogenic PIK3CA mutations increase dependency on the mRNA cap methyltransferase, RNMT, in breast cancer cells. Open Biol. 2019;9(4):190052.

Cowling VH. CAPAM: The mRNA Cap Adenosine N6-Methyltransferase. Trends in Biochemical Sciences. 2019;44:183-185.

Galloway A, Cowling VH. mRNA cap regulation in mammalian cell function and fate. Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms. 2019;1862:270-279.

2018

Inesta-Vaquera F, Chaugule VK, Galloway A, Chandler L, Rojas-Fernandez A, Weidlich S, Peggie M, Cowling VH. DHX15 regulates CMTR1-dependent gene expression and cell proliferation. Life Sci Alliance. 2018;1(3):e201800092.

Kelner A, Tinti M, Guther MLS, Foth BJ, Chappell L, Berriman M, Cowling VH, Ferguson MAJ. The mRNA cap methyltransferase gene TbCMT1 is not essential in vitro but is a virulence factor in vivo for bloodstream form Trypanosoma brucei. PLoS One. 2018;13(7):e0201263.

Varshney D, Lombardi O, Schweikert G, Dunn S, Suska O, Cowling VH. mRNA Cap Methyltransferase, RNMT-RAM, Promotes RNA Pol II-Dependent Transcription. Cell Rep. 2018;23(5):1530-1542.

Jantsch MF, Quattrone A, O'Connell M, Helm M, Frye M, Macias-Gonzales M, Ohman M, Ameres S, Willems L, Fuks F, Oulas A, Vanacova S, Nielsen H, Bousquet-Antonelli C, Motorin Y, Roignant JY, Balatsos N, Dinnyes A, Baranov P, Kelly V, Lamm A, Rechavi G, Pelizzola M, Liepins J, Holodnuka Kholodnyuk I, Zammit V, Ayers D, Drablos F, Dahl JA, Bujnicki J, Jeronimo C, Almeida R, Neagu M, Costache M, Bankovic J, Banovic B, Kyselovic J, Valor LM, Selbert S, Pir P, Demircan T, Cowling V, Schäfer M, Rossmanith W, Lafontaine D, David A, Carre C, Lyko F, Schaffrath R, Schwartz S, Verdel A, Klungland A, Purta E, Timotijevic G, Cardona F, Davalos A, Ballana E, D OC, Ule J, Fray R. Positioning Europe for the EPITRANSCRIPTOMICS challenge. RNA Biol.2018; 15:829-831.

2017

Dunn S, Lombardi O, Cowling VH. c-Myc co-ordinates mRNA cap methylation and ribosomal RNA production. Biochem J. 2017;474(3):377-384.

Aregger M, Cowling VH. Regulation of mRNA capping in the cell cycle. RNA biology. 2017:14:11-14.

Inesta-Vaquera F, Cowling VH. Regulation and function of CMTR1-dependent mRNA cap methylation. Wiley Interdiscip Rev RNA. 2017; 8:ed2017.

2016

Aregger M, Kaskar A, Varshney D, Fernandez-Sanchez ME, Inesta-Vaquera FA, Weidlich S, Cowling VH. CDK1-Cyclin B1 Activates RNMT, Coordinating mRNA Cap Methylation with G1 Phase Transcription. Mol Cell. 2016;61(5):734-746.

Grasso L, Suska O, Davidson L, Gonatopoulos-Pournatzis T, Williamson R, Wasmus L, Wiedlich S, Peggie M, Stavridis MP, Cowling VH. mRNA Cap Methylation in Pluripotency and Differentiation. Cell Rep. 2016;16(5):1352-1365.

Lombardi O, Varshney D, Phillips NM, Cowling VH. c-Myc deregulation induces mRNA capping enzyme dependency. Oncotarget. 2016;7(50):82273-82288.

Varshney D, Petit AP, Bueren-Calabuig JA, Jansen C, Fletcher DA, Peggie M, Weidlich S, Scullion P, Pisliakov AV, Cowling VH. Molecular basis of RNA guanine-7 methyltransferase (RNMT) activation by RAM. Nucleic Acids Res. 2016;44(21):10423-10436.

Young DF, Andrejeva J, Li X, Inesta-Vaquera F, Dong C, Cowling VH, Goodbourn S, Randall RE. Human IFIT1 Inhibits mRNA Translation of Rubulaviruses but Not Other Members of the Paramyxoviridae Family. J Virol. 2016;90(20):9446-9456.

Lab Members

 

Research

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