Wellcome Principal Research Fellow, Professor of RNA Biology and Director, Wellcome Centre for Cell Biology
David Tollervey studied for a BSc in Microbiology in Edinburgh and then for a PhD in Genetics at Cambridge in the lab of Herb Arst. He then moved to the University of California, San Francisco, as a postdoctoral fellow in the laboratory of Christine Guthrie. In 1983 he relocated to a permanent post at the Institut Pasteur in Paris, which he left in 1988 to move to the European Molecular Biology Laboratory (EMBL) in Heidelberg as a group leader. He returned to Edinburgh in 1997 as Professor of RNA Biology and a Wellcome Trust Principal Research Fellow. Since 2011 he has served as Director of the Wellcome Centre for Cell Biology. He is a Fellow of the Royal Society, and of the Royal Society of Edinburgh, a member of EMBO and Past President of the international RNA Society. The aim of the Tollervey group is to understand the nuclear pathways that process newly transcribed RNAs and assemble RNA-protein complexes, the mechanisms that regulate these pathways and the surveillance activities that monitor their fidelity. His current research combines in vivo UV crosslinking and high-throughput sequencing to precisely identify sites of RNA-protein interaction and RNA-RNA basepairing, with genetics, biochemistry, transcriptomics and bioinformatics.
Nuclear RNA processing and surveillance
We aim to understand the nuclear pathways that synthesise and process newly transcribed RNAs, the assembly of RNA-protein complexes and the surveillance activities that monitor their fidelity.
Over the past year, we discovered novel functional links between chromatin structure, transcription and RNA metabolism in baker’s yeast Saccharomyces cerevisiae. Reversible phosphorylation of the C-terminal domain of RNA polymerase II (RNAPII) provides a flow of information from transcribing RNAPII to the RNA processing and surveillance machinery, acting on the nascent transcript. We recently reported that the catalytic RNAPII subunit is ubiquitinated close to the DNA entry path (Ref. 1). This provides a reverse flow of information linking events on the nascent transcript back to transcribing RNAPII. In particular, we proposed that splicing-associated transcriptional pausing is enforced by RNAPII ubiquitination (Figure 1). This promotes co-transcriptional splicing of the nascent pre-mRNA, which is the norm in both yeast and humans.
We also discovered links between the nascent transcript and major chromatin modifications; methylation of histone H3 at lysine 4 (H3K4) and lysine 36 (H3K36), catalysed by the Set1 and Set2 methyltransferases, respectively. We reported that both Set1 and Set2 bind nascent RNA transcripts (Ref 2). Interactions between Set1 and RNA are predominately mediated by RRM2 and deletion of this region reduced the chromatin association of Set1, accompanied by reduced levels of H3K4 tri-methylation and increased di-methylation on protein coding genes. Notably, a class of non-coding RNAs (ncRNAs), termed CUTs, failed to bind Set1 and their genes showed high levels of H3K4 mono-methylation rather than tri-methylation that characterises protein coding genes. H3K4 mono-methylation is also a feature of human enhancers, which are transcribed into ncRNAs, termed eRNAs. Both yeast CUTs and human eRNAs are highly unstable, due to rapid degradation by the exosome complex, which is potentially linked to their histone modification status.
Long-standing observations by the group indicated that the activity of nuclear RNA degradation by the exosome nuclease complex is responsive to nutrient availability. We have now discovered that alterations in the targeting of nuclear surveillance pathways function, together with transcriptional changes, to rapidly remodel gene expression following nutrient shift - acting both positively and negatively (Ref. 3). This identified nuclear RNA surveillance as an actively regulated step in gene expression. It seems likely that changes in nuclear RNA degradation pathways will play important roles in other situations that require large scale reprogramming of gene expression, such as developmental steps in metazoans.
Milligan, L., Sayou, C., Tuck, A., Auchynnikava, T., Reid, J.E.A., Alexander, R., de Lima Alves, F., Allshire, R., Spanos, C., Rappsilber, J., Beggs, J.D. Kudla, G., and Tollervey, D. (2017). RNA polymerase II stalling at pre-mRNA splice sites is enforced by ubiquitination of the catalytic subunit. eLife, 6, e27082. PMCID:PMC5673307
Sayou, C., Millán-Zambrano, G., Santos-Rosa, H., Petfalski, E., Robson, S., Houseley, J., Kouzarides, T., and Tollervey, D. (2017). RNA binding by the histone methyltransferases Set1 and Set2. Mol. Cell Biol. doi: 10.1128/MCB.00165-17. PMID: PMC28483910
Bresson, S., Tuck, A., Staneva, D., and Tollervey, D. (2017). Nuclear RNA decay pathways aid rapid remodeling of gene expression in yeast. Mol. Cell, 65, 787-800. PMCID: PMC5344683