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How does nucleosome remodelling silence chromatin?


Project Description

Regulation of transcription through chromatin architecture is governed by nucleosome remodelers and is essential in 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 nucleosome remodelling and deacetylation complex SHREC, which is closely related to NuRD complexes in animals and plants. We have established architectural principles of this 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 we now want to understand how SHREC engages with chromatin to silence genes. The student 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 assemble 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).

Techniques that will be undertaken during the project

-Cloning
-Protein expression and purification
-Enzymatic assays
-Cryo-EM
-Chromatin reconstitution
-S. pombe genetics
-ChIP, RT-qPCR
-Nucleosome mapping

Available to UK/EU applicants only
Application information
https://www2.le.ac.uk/research-degrees/doctoral-training-partnerships/bbsrc

Funding Notes

BBSRC MIBTP 4 year studentship:
4 years of stipend at the Research Council rates and UK/EU Fee Waiver
Funds for research consumables, conference travel, laptop for use throughout the studies


This project is also advertised under a second/separate funding scheme ( Leicester Institute for Structural and Chemical Biology and the Molecular and Cell Biology) and so if you are interested in this project, it would be advisable for you to apply through both schemes to increase your chances of securing a studentship. View Website

References

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.

Leopold, K., and Schalch, T. (2018). Dedicated interaction between HP1 protein Chp2 and remodeling factor Mit1 regulates heterochromatin. Submitted.

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