Projects are available to study the molecular function of chromatin regulators such as MOZ/KAT6A or MORF/KAT6B and their contribution to the development of cancer. These proteins function as histone acetyltransferases and are thus of interest as potential therapeutic targets. In addition to being involved in acute myeloid leukaemia, they are also implicated in several developmental syndromes in humans. We currently use a range of techniques such as molecular & cell biology, CRISPR-CAS9 technology, RNA Seq and structural biology to study the function and malfunction of these proteins in normal and cancer cells. To achieve these goals we have a network of collaborators both locally and internationally.
Specific projects include:
• Use of CRISPR-CAS9 technology for genome editing of the KAT6A and KAT6B genes in cell lines and mouse embryonic stem cells. Transcription profiling by RNA seq and validation of differentially expressed genes. This will identify genes that are mis-expressed due to mutations in KAT6A and KAT6B that are associated with cancers or developmental syndromes.
• Structural studies of the complex between the Double PHD Finger domains of KAT6A and KAT6B with the histone N-terminal tails. This will build on our recent finding that histone tails adopt alpha-helical structures in complex with MOZ/KAT6A, demonstrating how chromatin regulators manipulate histone structure to ‘read’ signaling information in the histone tail.
• How do mutations in the N-terminal tail of histone variant H3.3 affect interactions with chromatin regulators? How does this contribute to the development of brain tumours?
The project will be carried out within the Gene Regulation & RNA Biology Group (30+ researchers) within the Division of Molecular & Cellular Sciences. The School of Pharmacy provides excellent cross-disciplinary support and training facilities for PG students.
Applications are welcome from motivated students with a good honours BSc. or Masters degree in Science subjects. International applicants should visit our University pages for information regarding fees and funding at the University. Sponsored and self-funded students are welcome, and all applicants should contact the supervisor to discuss funding.
Dreveny, I., Deeves, S.E., Fulton, J., Yue, B., Messmer, M., Bhattacharya, A., Collins, H.M., and Heery, D.M. (2014). The double PHD finger domain of MOZ/MYST3 induces alpha-helical structure of the histone H3 tail to facilitate acetylation and methylation sampling and modification. Nucleic acids research 42, 822-835.
Kindle, K.B., Collins, H.M., and Heery, D.M. (2010). MOZ-TIF2-mediated destruction of CBP/p300 is blocked by calpain inhibitor 2. Leukemia 24, 1359-1361.
Heery, D.M., and Fischer, P.M. (2007). Pharmacological targeting of lysine acetyltransferases in human disease: a progress report. Drug discovery today 12, 88-99.