About the Project
Histone deacetylase complexes play a role in many cellular processes, such as cancer, cell cycle progression and DNA repair. Investigating how these HDAC complexes act to control gene expression and their interactions with other proteins should lead to an understanding of their influence in the cell. HDAC inhibitors are currently used to treat some cancers. An understanding of the structure and function of the various histone deacetylase complexes should mean that inhibitors can be designed to specific complexes to reduce side effects.
The Schwabe group have been successful in expressing and purifying the core of many HDAC complexes in HEK293F cells in sufficient quantity for structural studies. This has led to a number of structures of HDAC complexes using X-ray crystallography and negative stain electron microscopy. In addition the structure of the HDAC3/SMRT complex led to the discovery that class I histone deacetylases are activated by inositol phosphates.
There has recently been a revolution in Cryo-Electron Microscopy, which means that large protein and protein complex structures that previously could not be crystallised can now be solved at atomic resolution. The aim of this PhD project is to solve the structure of histone deacetylase complexes using Cryo-electron microscopy and to fully understand the structure of the different HDAC complexes, their interaction with chromatin and their interaction with other components involved in transcription. An understanding of the structure of the different HDAC complexes may lead to the design of more specific histone deacetylase inhibitors.
UK/EU applicants only.
Applicants are required to hold/or expect to obtain a UK Bachelor Degree 2:1 or better in a relevant subject.
The University of Leicester English language requirements apply where applicable: https://le.ac.uk/study/research-degrees/entry-reqs/eng-lang-reqs/ielts-65
How to apply:
To apply for the PhD please refer to the guidelines and use the application link at https://le.ac.uk/study/research-degrees/funded-opportunities/bbsrc-mibtp
Please also submit your MIBTP notification form at https://warwick.ac.uk/fac/cross_fac/mibtp/pgstudy/phd_opportunities/application/
Project / Funding Enquiries: [Email Address Removed]
Application enquiries to [Email Address Removed]
UK/EU fees and stipend at UKRI rates. For 2020 this will be £15,285 pa
Watson PJ, Millard CJ, Riley AM, Robertson NS, Wright LC, Godage HY, Cowley SM, Jamieson AG, Potter BVL & Schwabe JWR (2016) Insights into the activation mechanism of class I HDAC complexes by inositol phosphates. Nature Communications 7: 11262
Kalin, J.H., Wu, M., Gomez, A.V., Song, Y., Das, J., Hayward, D., Adejola, N., Wu, M., Panova, I., Chung, H.J., Kim, E., Roberts, H.J., Roberts, J.M., Prusevich, P., Jeliazkov, J.R., Roy Burman, S.S., Fairall, L., Milano, C., Eroglu, A., Proby, C.M., Dinkova-Kostova, A.T., Hancock, W.W., Gray, J.J., Bradner, J.E., Valente, S., Mai, A., Anders, N.M., Rudek, M.A., Hu, Y., Ryu, B., Schwabe, J.W.R., Mattevi, A., Alani, R.M., Cole, P.A., (2018). Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors. Nature Communications 9, 53.
Zhang, T., Wei, G., Millard, C.J., Fischer, R., Konietzny, R., Kessler, B.M., Schwabe, J.W.R., Brockdorff, N., (2018). A variant NuRD complex containing PWWP2A/B excludes MBD2/3 to regulate transcription at active genes. Nature Communications 9, 3798.
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