University of Dundee

Professor Victoria Cowling

mRNA cap regulation of T cells, embryonic stem cells and cancer cells
Position: 
Professor of Biology, Lister Institute Fellow, MRC Senior Fellow and Deputy-Head of The Centre for Gene Regulation and Expression
Address: 
School of Life Sciences, University of Dundee, Dundee
Full Telephone: 
+44 (0) 1382 386997, int ext 86997
Email: 

Biography

2017    ERC Consolidator Award

2015    British Society of Cell Biology Women in Cell Biology Award

2014    EMBO Young Investigator

2013    MRC Senior Fellowship

2011    Lister Institute Prize Fellowship

2007    MRC Career Development Award

2007    Research Group Leader, Life Sciences, University of Dundee

2003-2007       Post-doctoral research with Prof. Michael Cole, Dartmouth College, NH, USA and Princeton University, NJ, USA.  “Regulation and Function of c-Myc”

1997-2002       PhD Biochemistry with Prof. Julian Downward and Prof. Gerard Evan.  Imperial Cancer Research Fund, London, UK.   Thesis “Regulation of Caspase Activation during Programmed Cell Death”

1994-1997       Emmanuel College, Cambridge University, UK.  B.A. (Hons) Natural Sciences. Part II Zoology

Research

Investigating the regulation and function of the mRNA cap

We investigate the regulation and function of the mRNA cap, and use this information to develop new therapies targeted at inhibiting tumour cell and parasite growth and proliferation.

Human cells contain about 25000 protein-encoding genes.  We are only beginning to understand how the cell co-ordinately controls expression of these genes.  Our focus is on a modification of mRNA called the mRNA cap.  The mRNA cap structure protects transcripts from degradation and recruits factors which mediate processing events.  We have found that different signals which the cell encounters (developmental, immunological, oncogenic) can alter the rate and extent to which the mRNA cap forms, either across the transcriptome or on specific transcripts.  Thus the mRNA cap is an integrator of cellular signalling information, which directs reshaping of the cellular proteome in response to external and internal signals.

Nitty Gritty

The mRNA cap describes a collection of structures which form on the 5’ end of RNA pol II transcripts.   Capping enzymes catalyse modification of the first few nucleotides to form the cap.  Most of these enzymes are recruited to phosphorylated RNA pol II at the early stages of transcription, thus capping the transcript as it is being synthesised.  One cap structure and the enzymes involved in its synthesis are shown below.  Our research involves investigating how these capping enzymes function biochemically and how they influence gene expression.  We look at how cellular signalling pathways influence the expression or activity of these enzymes to change the genes which are expressed.

 

 mRNA cap regulation

How does the cell regulate formation of the mRNA cap?

We strive to understand the function of mRNA cap regulation in mammals, in health and disease. The mRNA cap is an important but poorly understood structure which recruits the enzymes and co-factors involved in RNA processing and translation initiation. We have recently discovered mechanisms by which mRNA cap formation is regulated by oncogenes, signalling pathways and developmental pathways, resulting in changes in transcription and translation, which impact on cellular fate and function. The enzymes which catalyse mRNA cap synthesis are emerging as integrators of cellular signals which govern cell physiology. Our challenge now is to understand how the regulation of the mRNA cap impacts on specific mechanisms of gene expression and cell function.

Currently we are investigating how mRNA cap formation is regulated during embryonic stem cell differentiation, in T cells and in response to oncogenes.

mRNA cap regulation in T cells: We are using mouse models to investigate how the mRNA capping enzymes are regulated following T cell activation.  We investigate how T cell activation is dependent on the different cap methyltransferases.  We use the latest gene expression analyses technologies to investigate the impact of the mRNA cap on gene expression. We use immunological techniques to investigate the impact of the cap on T cell activation and function.  Project funded by an ERC grant.

mRNA cap regulation in embryonic stem cells:  We investigate how the mRNA cap is regulated during different differentiation pathways. We investigate the impact of mRNA cap regulation on pluripotency and differentiation.  We use the latest transcriptomic and proteomic analyses to understand the mechanisms by which the capping enzymes impact on cell function.  Project funded by MRC Senior Fellowship and Lister Fellowship

 

Figure 2 RAM-RNMT

Considering mRNA capping enzymes as therapeutic targets?

We are currently asking whether cancer cells with deregulated gene expression pathways are more sensitive to inhibition of mRNA capping than healthy cells.  We have found that particular oncogenes sensitise breast cancer cell lines to inhibition of RNMT.  This suggests use of RNMT inhibitors may be most successful therapeutically at treating cancers with these oncogenic mutations.

We are working with the Dundee Drug Discovery Unit to screen for inhibitors of the mRNA capping enzymes.  Small molecule inhibitors will be critical to discern the most suitable cancers to treat with mRNA capping inhibitors.

We are working with Mike Ferguson to consider the mRNA capping enzymes as therapeutic targets in T.brucei, the parasite which causes Human African Trypanosomiasis. We are extending this work to other parasites with the Dundee Drug Discovery Unit.

 

Publications

 Lombardi O, Varshney D, Phillips NM and Cowling VH (2016)  c-Myc deregulation induces mRNA capping enzyme dependency Oncotarget 2016 DOI: 10.18632/oncotarget.12701 PMID: 27756891

Grasso L, Suska O, Davidson L, Gonatopoulos-Pournatzis T, Williamson R, Wasmus L, Wiedlich S, Peggie M, Stavridis MP, Cowling VH. (2016)  mRNA Cap Methylation in Pluripotency and Differentiation.  Cell Rep. 2016 Jul 20. pii: S2211-1247(16)30858-0. doi: 10.1016/j.celrep.2016.06.089. [Epub ahead of print] PMID:27452456

Varshney D, Petit AP, Bueren-Calabuig JA, Jansen C, Fletcher DA, Peggie M, Weidlich S, Scullion P, Pisliakov AV, Cowling VH. (2016) Molecular basis of RNA guanine-7 methyltransferase (RNMT) activation by RAM. Nucleic Acids Res. 2016 Jul 15. pii: gkw637. [Epub ahead of print] PMID:27422871

Aregger M, Kaskar A, Fernandez-Sanchez ME, Simone Weidlich S and Cowling VH  (2016) CDK1-cyclinB activates RNMT co-ordinating mRNA cap methylation with G1 phase transcription Mol Cell. 2016 Mar 3;61(5):734-46. doi: 10.1016/j.molcel.2016.02.008.   View Paper

Preston GC, Sinclair LV, Kaskar A, Hukelmann JL, Navarro MN, Ferrero I, MacDonald HR, Cowling VH and Cantrell DA  (2015)  Single Cell Tuning of Myc Expression by Antigen Receptor Signal Strength and Interleukin 2 in T Lymphocytes  EMBO J. 2015 Jul 1. pii: e20149025  View Paper

Cowling VH, Turner S and Cole MD (2014) Burkitt's lymphoma-associated c-Myc mutations converge on a dramatically altered target gene response and implicate ribosome biogenesis in oncogenesis  Oncogene. 2014 Jul 3;33(27):3519-27. doi: 10.1038/onc.2013.338. Epub 2013 Sep 9.  View Paper

Gonatopoulos-Pournatzis T and Cowling VH (2014)  RAM function is dependent on Kapb2–mediated nuclear entry Biochemical J 2013 2014 Feb 1;457(3):473-84. doi: 10.1042/BJ20131359  View Paper

Aregger M and Cowling VH (2013) Human cap methyltransferase (RNMT) N-terminal non-catalytic domain mediates recruitment to transcription initiation sites  Biochem J. 2013 Oct 1;455(1):67-73. doi: 10.1042/BJ20130378  View Paper

Gonatopoulos-Pournatzis T, Dunn S, Bounds R, and Cowling VH (2011) RAM/Fam103a1 is required for mRNA cap methylation  Molecular Cell 2011 Nov18;44(4):585-596  View Paper

Cowling VH (2010) Enhanced mRNA cao methylation increases Cyclin D1 expression and promotes cell transformation Oncogene. 2010 Feb 11;29(6):930-6. Epub 2009 Nov 16. View Paper

Fernandez-Sanchez ME, Gonatopoulos-Pournatzis T, Preston G, Lawlor MA, and Cowling VH (2009) S-Adenosyl Homocysteine Hydrolase (SAHH) is required for Myc-induced mRNA cap methylation, protein synthesis and cell proliferation Mol Cell Biol 2009, Dec;29(23):6182-91. Epub 2009 Oct 5.  View Paper