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Revealing molecular mechanisms of gene silencing

Primary Supervisor: Professor Thomas Schalch

Secondary Supervisor: Professor Shaun Cowley

PhD project title: Revealing molecular mechanisms of gene silencing

University of Registration: University of Leicester

Project outline: 

Regulation of transcription through chromatin architecture is governed by nucleosome remodelers and chromatin modifying complexes. These macromolecular machines are essential for establishing the transcriptional programs of eukaryotic cells, which underpin survival, cellular identity and many disease states. We aim to understand the mechanisms that silence genomic regions and use the powerful yeast model system S. pombe to study the histone H3K9 methyltransferase complex CLRC and the nucleosome remodelling and deacetylation complex SHREC. We have established architectural principles of the SHREC complex (Job et al., 2016) and have shown how its nucleosome remodelling subunit is recruited by a member of the HP1 family (Leopold and Schalch, 2018). Using a comprehensive structure-function approach you will be involved in revealing how SHREC or CLRC engage with chromatin to silence genes. You will learn both structural biology (emphasis on Cryo-EM, but X-ray crystallography and NMR are also available) to understand how the molecules perform their function and will use genetic manipulation of the same molecules in yeast to establish a comprehensive view of the molecular mechanism by monitoring genome structure and gene expression (nucleosome mapping, chromatin immunoprecipitation (ChIP) and measuring transcript levels by quantitative PCR).

 

References:

  1. Job, G., Brugger, C., Xu, T., Lowe, B.R., Pfister, Y., Qu, C., Shanker, S., Baños Sanz, J.I., Partridge, J.F., and Schalch, T. (2016). SHREC Silences Heterochromatin via Distinct Remodeling and Deacetylation Modules. Mol. Cell 62, 207–221.
  2. Leopold, K., and Schalch, T. (2018). Dedicated interaction between HP1 protein Chp2 and remodeling factor Mit1 regulates heterochromatin. Submitted.


BBSRC Strategic Research Priority: Understanding the Rules of Life: Structural Biology

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Techniques that will be undertaken during the project:

  • Cloning
  • Protein expression and purification
  • Enzyme kinetics
  • Cryo-EM, S. pombe genetics
  • Chromatin Immunoprecipitation
  • RT-qPCR

 Contact: Professor Thomas Schalch, University of Leicester