Professor Gordon Simpson FRSB
What Genomes Really Encode - Processing the Transcriptome and Epitranscriptome
We are interested in very basic features of gene expression such as how are the ends of genes defined and what is the impact of mRNA methylation on gene expression?
Knowing where a gene ends is hugely important: First, it defines what a gene codes for, affecting the function of that gene and how it can be controlled. Second, if poly(A) site selection doesn’t happen properly, it can cause disease or be a feature of disease (recent work with human cells revealed global changes in poly(A) site choice in cancer tissue). Third, knowing where a gene ends is central to understanding genomes. Sequencing genomes has become relatively routine, but defining and annotating what they encode remains a huge challenge. Cleavage and polyadenylation effectively partitions the genome, maintaining expression of neighbouring genes. Knowing where cleavage and polyadenylation happens helps us tell where genes start and stop.
We became interested in this area almost by accident: We were studying how plants control the time at which they flower, a fundamental developmental transition carefully controlled to ensure that flowering takes place in conditions favourable for reproductive success. Underpinning the quantitative control of flowering time is a complex network of gene regulation. Working with late flowering mutants of the model plant Arabidopsis thaliana we discovered that the genes disrupted in these mutants encoded proteins that functioned to control the site of cleavage and polyadenylation of RNA. We therefore discovered that a biological consequence of controlling where genes end is the time at which plants flower.
Since the realisation that the regulation of alternative poly(A) site choice is widespread, there is now intense interest in understanding how this is controlled.
We have used third generation direct RNA sequencing to define where 3’ end formation occurs genome-wide using a range of Arabidopsis mutants to uncover this control. This first direct sequencing of RNA from any plant species has helped us to better understand how the genome is organised and how it should be annotated. It has also helped us to discover RNAs that aren’t translated into protein – so called non-coding RNAs that have previously been missed or disregarded because they are difficult to identify or predict what they do. Thus our RNA sequencing work has led us into several exciting new areas.
Most recently, our research has led us to mRNA methylation - the so called epitranscriptome.
We are passionate about discovering things that have never been found before. Working with Arabidopsis has helped us do that. As our experience in this area has grown we have become interested in translating our expertise and understanding of the impacts of poly(A) site choice on gene function and genome organisation to crop plants essential for food security and into biomedical contexts as well.
For the latest news from our lab - follow us on twitter @ggsimpsonrna.
I am a Principal Investigator in Plant Sciences and also within The Centre for Gene Expression & Regulation. My position is jointly supported by the University of Dundee and the James Hutton Institute. A film of the group being introduced to GRE is available here.
I teach Genetics (BS31005) and Gene Regulation & Expression to Level 3 biology students. I teach Advanced Gene Regulation & Expression (BS42010) and Advanced Plant Science (BS42005) to Level 4 Honours students. I am a tutor on the Level 3 Art, Science & Visual Thinking Course (DJ31001) and also on the Level 5 Integrated Masters (iMSci) course. I have taught connections between RNA and disease to Level 1 medical students, plant development to Level 3 biology students and taught on the MRes course Crops for the Future. My lab tutors Level 3 Gene Regulation and Expression (BS31006) and hosts Honours undergraduates and Masters students undertaking their research projects. My lab regularly hosts Masters and Erasmus Exchange students from overseas. I was the first Dundee University Mentor for the Gatsby Charitable Trust.
Parker MT, Knop K, Simpson GG. 2020. Making a mark: The role of RNA modifications in plant biology. Biochemist. 42(4):26-30. https://doi.org/10.1042/BIO20200046
Raxwal VK, Simpson CG, Gloggnitzer J, Entinze JC, Guo W, Zhang R, Brown JWS, Riha K. 2020. Nonsense-Mediated RNA Decay Factor UPF1 Is Critical for Posttranscriptional and Translational Gene Regulation in Arabidopsis. Plant Cell. 32(9):2725-2741. https://doi.org/10.1105/tpc.20.00244
Parker MT, Knop K, Sherwood AV, Schurch NJ, Mackinnon K, Gould PD, Hall AJW, Barton GJ, Simpson GG. 2020. Nanopore direct RNA sequencing maps the complexity of Arabidopsis mRNA processing and m6A modification. eLife. 9:1-35. https://doi.org/10.7554/eLife.49658
Froussios K, Schurch N, Mackinnon K, Gierlinski M, Duc C, Simpson G, Barton G. 2019. How well do RNA-Seq differential gene expression tools perform in a complex eukaryote? A case study in A. thaliana. Bioinformatics. https://doi.org/10.1093/bioinformatics/btz089
Froussios K, Mourao K, Simpson G, Barton G, Schurch N. 2019. Relative Abundance of Transcripts (RATs): Identifying differential isoform abundance from RNA-seq [version 1; referees: 1 approved, 2 approved with reservations]. F1000 Research. 8:1-20. https://doi.org/10.12688/f1000research.17916.1
Mourão K, Schurch NJ, Lukoszek R, Froussios K, Mackinnon K, Duc C, Simpson G, Barton G. 2019. Detection and Mitigation of Spurious Antisense RNA-seq Reads with RoSA. F1000 Research. 8:1-7. https://doi.org/10.1101/425900, https://doi.org/10.12688/f1000research.18952.1
Schurch, N.J, Schofield, P., Gierliński, M., Cole, C., Sherstnev, A., Singh, V., Wrobel, N., Gharbi, K., Simpson, G.G., Owen-Hughes, T., Blaxter, M., and Barton, G.J. (2016) How many biological replicates are needed in an RNA-Seq experiment and which differential expression tool should you use? (2016) RNA published 28 March 2016; doi:10.1261/rna.053959.115. PMID: 27022035.
Fray, R.G. and Simpson, G.G. (2015) The Arabidopsis Epitranscriptome. Current Opinion in Plant Biology. 27: 17-21 (doi :10.1016/j.pbi.201505.015) view paper
Duc,C., Sherstnev, A.,Cole, C., Barton, G.J. and Simpson, G.G. (2013) Transcription termination and chimeric RNA formation controlled by Arabidopsis thaliana FPA. PLOS Genetics. 9: e1003867. DOI:10.1371/journal.pgen.1003867 view paper
Vanholme, R., Cesarino, I., Rataj, K., Xiao, Y., Sundin, L., Goeminne, G., Kim, H., Cross, J., Morreel, K., Araujo, P., Welsh, L., Haustraete, J., McClellan, C., Vanholme, B., Ralph, J., Simpson, G.G., Halpin, C. and Boerjan, W. (2013) Caffeoyl Shikimate Esterase (CSE) Is an Enzyme in the Lignin Biosynthetic Pathway. Science 341:1103-1106 view paper
Shertsnev, A., Duc, C., Cole, C., Zacharaki, I. V., Hornyik, C., Ozsolak, F., Milos, P., Barton, G.J. Simpson, G. G. (2012) Direct Sequencing of Arabidopsis thaliana RNA Reveals Patterns of Cleavage and Polyadenylation. Nature Structural & Molecular Biology. 19, 845-852. PMCID: PMC3533403. view paper
Simpson, G.G., Laurie, R.E., Dijkwel, P.P., Quesada, V., Stockwell, P.A., Dean, C. and Macknight, R.C. (2010) Non-Canonical Translation Initiation of the Flowering Time and Alternative Polyadenylation Regulator, FCA. The Plant Cell 22: 3764-77 view paper
Hornyik, C., Terzi, L.C. and Simpson, G.G. (2010) The Spen Family Protein FPA Controls Alternative Cleavage and Polyadenylation of RNA. Developmental Cell 18:203-213 view paper
Quesada, V., Macknight, R., Dean, C. and Simpson, G. G. Autoreglation of FCA pre-mRMA processing controls Arabidopsis flowering time. (2003) EMBO J. 22, 3142-2152. PMID: 12805228
PMCID: PMC162157. view paper
Simpson, G. G., Dijkwel, P.P., Quesada, V., Henderson, I. and Dean C. FY is a 3'-end-RNA-processing factor that interacts with FCA to control the floral transition. (2003). Cell, 113, 671-672. PMID: 12809608. view paper
Simpson, G. G. and Dean, C. Arabidopsis, The Rosetta stone of flowering time? (2002) Science. 296, 285-289. PMID: 11951029. view paper
I led the impact activities of Dundee Plant Sciences from 2009-2015 and in that time developed close working links with colleagues at Dundee Botanic Garden. A very high proportion of our staff take part in public engagement activities every year, such as Doors Open Day, Botanic Garden Family Fun Day, Fascination of Plants Day and the Edinburgh International Science Festival. In 2013, we used funding from the College of Life Sciences’ BBSRC Excellence with Impact winners’ award to create a Genetics Garden at Dundee Botanic Garden. This sustainable display has been a hub for our activities throughout the year, from sowing, to opening talks and harvesting, we have used it to engage children and adults alike in the molecular genetic work that underpins the science we do. In this way we have directly engaged with thousands of members of the public on plant science. BBC's Beechgrove Garden was introduced from our Genetics Garden in 2013 and our Genetics Garden was the subject of a focus piece by Jim McColl and The Beechgrove Garden broadcast on BBC2 in August 2015. I was a partner in Dundee University’s Excellence with Impact Group.
We have commisioned the scientific animation company Vivomotion to develop an animation to accompany and explain the utility of our direct RNA sequencing database: polyAdb. And we also use social media to communicate our work, for example, you can follow us on twitter.
Our research focuses on new discoveries in basic science, but reflecting its importance, our patent on a gene controlling flowering time was sold to the agricultural biotechnology company DuPont Pioneer and more recently our collaboration with Claire Halpin (Dundee) and Wout Boerjan (Ghent) led to the discovery and patenting of a previously undiscovered enzyme in the lignin biosynthesis pathway that has potentially important implications for biofuel development.
Current core member of the BBSRC’s Research Committee B (Plants, Microbes, Food and Sustainability) and a previous member of the BBSRC Bioinformatics and Biological Resources Fund Assessment Panel (2014).
Grant panel member and assessor for The Carnegie Trust for the Universities of Scotland.
Science Strategy Group of The James Hutton Institute 2016-
Dundee University's Botanic Garden's Advisory Group.
Chair, HCERES Evaluation Committee, IBMP, Strasbourg, France, 2017.
Scientific Advisory Board "Micro and Metabolic Regulators of Plants" The first EMBO meeting on plant biology ever held in India, 2017.
I have held the first position jointly funded by the University of Dundee and the James Hutton Institute since 2004. My lab is also associated with The Centre for Gene Regulation & Expression where I am an Associate PI.