Professor of Molecular Biology
Jean is Professor of Molecular Biology at the University of Edinburgh. She obtained a BSc Hons in Biochemistry and PhD at Glasgow University. Following a postdoc with the late Professors Ken and Noreen Murray in the Dept of Molecular Biology, University of Edinburgh, she was awarded a Beit Memorial Fellowship for Medical Research and moved to the Plant Breeding Institute, Cambridge. There she completed work to develop yeast two micron plasmid cloning vectors for highly efficient yeast transformation. She then moved to a lectureship at the Dept of Biochemistry, Imperial College London, where she began her long-term study of yeast splicing machinery. In 1985 she returned to Edinburgh funded by a Royal Society University Research Fellowship and then by a Royal Society Cephalosporin Fund Senior Research Fellowship and, subsequently, the Royal Society Darwin Trust Research Professorship. She was awarded the Royal Society Gabor Medal in 2003, the Biochemical Society Novartis Medal and Prize in 2004, and the RNA Society Lifetime Achievement Award in 2018. She is a Fellow of the Royal Society and of the Royal Society of Edinburgh where she was Vice President for Life Sciences from 2009 til 2012. In 2006 was appointed CBE for services to science. The laboratory is mainly funded by the Wellcome Trust and in 2015 Jean was awarded Wellcome Trust Investigator status.
Regulation of splicing and functional links between splicing, transcription and chromatin
Transcription and RNA splicing are at the centre of gene expression in eukaryotes, controlling gene expression levels and removing introns from primary transcripts. The mechanisms and machineries involved in both transcription and RNA splicing are highly conserved throughout eukaryotes, and the budding yeast Saccharomyces cerevisiae makes an excellent model system. Using biochemistry, cell biology and genetics, we have investigated the functions of a number of key splicing factors, characterising their molecular interactions in the spliceosome. In addition, we use more quantitative systems biology approaches to study the flow of RNA through the various RNA processing pathways.
Currently, our focus is on links between RNA splicing and other metabolic processes, especially transcription and chromatin. For example, to investigate how speed of transcription elongation affects pre-mRNA splicing, we used mutant RNA polymerases that elongate faster or slower. We found that slow transcription elongation increases both co-transcriptional splicing and splicing efficiency and that faster elongation has the opposite effect, suggesting that splicing is more efficient when co-transcriptional. Moreover, we demonstrated that altering the polymerase elongation rate in either direction compromises splicing fidelity. These effects are notably stronger for the highly expressed ribosomal protein coding transcripts, which are spliced with much higher fidelity than other transcripts (Figure 1). We propose that transcription by RNA polymerase II is tuned to optimize the efficiency and accuracy of ribosomal protein gene expression, while allowing flexibility in splice site choice with the non-ribosomal protein transcripts (Aslanzadeh et al., 2018).
We are also studying links between splicing and chromatin modifications, using an auxin inducible degron (AID) system to rapidly deplete splicing factors and investigate the effect on histone methylation. To this end, we developed a ß-estradiol-inducible AID system that permits the depletion rate of the target protein to be tuned, and also minimises secondary effects (Mendoza-Ochoa et al., 2019). By depleting individual splicing factors that function at different stages of the splicing cycle we find that different steps of the splicing pathway influence trimethylation of lysine 4 or lysine 36 on histone H3. Our ongoing efforts are focused on trying to unravel the reciprocal effects of transcription, splicing and chromatin modification on each other, to determine who does what directly (Figure 2).
Wallace, E. and Beggs, J.D. (2017) Extremely fast and incredibly close: co-transcriptional splicing in budding yeast. RNA 23, doi: 10.1261/rna.060830
Aslanzadeh, V., Huang, Y., Sanguinetti, G. and Beggs, J.D. (2018) Transcription rate strongly affects splicing fidelity and co-transcriptionality in budding yeast. Genome Res. 28, 203-213, doi:10.1101/gr.225615.117.
Mendoza-Ochoa, G.I., Barrass, J.D., Terlouw, B.R., Maudlin, I.E., de Lucas, S., Sani, E., Aslanzadeh, V., Reid, J.A.E. and Beggs, J.D. (2019) A fast and tuneable auxin-inducible degron for depletion of target proteins in budding yeast. Yeast, 36, 75-81, doi: 10.1002/yea.3362.