About the Project
How does a cell decide whether a gene stays switched on or is silenced into heterochromatin? This project tests whether the speed at which RNA polymerase II travels along DNA is not merely a consequence of gene activity, but an instructive signal that determines it.
At the centre is H2B mono-ubiquitination, a histone mark written during transcription by a conserved E3 ubiquitin ligase complex (HULC in fission yeast, RNF20/40 in humans) that acts as a brake on polymerase. We have genetic evidence that this complex steers the balance between transcription and silencing through more than this one well-studied mark.
The project deliberately spans two disciplines. Using structural modelling and biochemistry, you will design mutations that tune the ligase's activity in graded steps, creating a molecular "dial" that sets polymerase speed without disturbing the surrounding chromatin machinery. Using functional genomics, you will read out the consequences genome-wide: elongation rates by nascent RNA sequencing, chromatin states by ChIP-seq, and new ligase targets by quantitative proteomics. Neither approach answers the question alone. The structural work builds the instrument, the genomics measures what it does, and each redirects the other. Findings will be tested for conservation in human cells using degron lines that strip out key factors within minutes.
You will be jointly supervised by Professor Thomas Schalch (structural mechanisms of chromatin regulation) and Dr Michael Tellier (transcription and genome-wide sequencing), and trained across protein structure, yeast and mammalian genetics, and computational genomics. Loss of H2Bub is linked to several cancers, giving the work a clear translational dimension.
Techniques that will be undertaken during the project
- Structural and biochemical: AlphaFold-based structural modelling; structure-guided mutagenesis; recombinant protein expression and purification; reconstitution of nucleosome complexes; in vitro ubiquitination assays; crosslinking mass spectrometry.
- Genetics and cell biology: fission yeast (S. pombe) genetics and strain construction; CRISPR genome editing; mammalian cell culture; degron-based rapid protein depletion; western blotting.
- Functional genomics: ChIP-seq and calibrated (spike-in) ChIP-seq; nascent RNA sequencing (TT-seq/PRO-seq) for elongation-rate measurement; RNA-seq; quantitative diGly ubiquitin proteomics.
- Computational: sequencing data analysis in R/Python; statistical modelling of rate–outcome relationships; reproducible pipeline development.
Enquiries
Project Enquiries to thomas.schalch@le.ac.uk
Programme enquiries to mibtp-admin@leicester.ac.uk
Funding Notes
All MIBTP students will be provided with a 4 year studentship. This includes: Tuition fees at the UK fee rate*, a tax free stipend which for 2026/7 is £21,805 per year (2027/8 stipend to be confirmed), a travel allowance over years 1-3, a travel/conference budget, a generous consumables budget, use of a laptop for the duration of the programme. The University of Leicester will provide full overseas fee waivers for the duration of their study to all international students accepted at Leicester. The funder, UKRI, allows us to appoint up to 30% overseas students.
