Nuclear receptors (NRs) are one of the largest families of gene regulators in humans and they have fundamental roles in most physiological processes. Many NRs are ligand-regulated such as steroid, retinoid and vitamin D receptors, while others function independent of ligand (orphan NRs). Mutations/alterations in genes encoding specific nuclear receptor genes or their cofactors are implicated in human diseases including cancer, diabetes and retinopathies. Understanding molecular mechanisms of NR interactions with ligands or protein cofactors can facilitate drug development of precision medicines.
Our work has identified short sequence motifs (LXXLL) that mediate interactions of cofactors with NRs. More recently, we discovered new versions of this motif that are specific for subfamilies of NRs important in breast, brain and ovarian cancers. This facilitates the discovery of NR-selective drugs and provides molecular insight into functions of NRs in vivo.
Projects are available to study the interactions of NRs and their specific cofactors
Specific projects include:
• Use of CRISPR-CAS9 technology for genome editing of the NR genes in cell lines and mouse embryonic stem cells. Transcription profiling by RNA seq and validation of differentially expressed genes. This approach will be used to identify genes co-regulated by a novel NR heterodimer complex discovered in our laboratory.
• Mutations in the PNR gene in humans are associated with visual loss through failure of rod cell development in the retina. CRISPR-CAS9 editing techniques will be used to introduce such mutations in PNR in cell lines and mouse embryonic stem cells. Functional impacts of these mutations will be assessed in a variety of assays including EMSA, western blots, RTqPCR, reporter assays, confocal microscopy, RNA Seq. This will shed light on the pathology of PNR gene mutations.
• BCL11A is a co-repressor protein that interacts with a subfamily of NRs including PNR, TLX and COUP-TFs. Mutations in BCL11A are associated with sickle cell disease, and it is overexpressed in some cancers, including triple negative breast cancer (TNBC). This project will build on our discovery of a signature motif in BCL11A that is needed for its binding to NRs. The project will use a range of techniques (including genome editing) to discover how this protein regulates expression of estrogen receptor in TNBC derived cell lines.
The project will be carried out within the Gene Regulation & RNA Biology Group (30+ researchers) in 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.
Heery, D.M., Kalkhoven, E., Hoare, S., and Parker, M.G. (1997). A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature 387, 733-736
Coulthard, V.H., Matsuda, S., and Heery, D.M. (2003). An extended LXXLL motif sequence determines the nuclear receptor binding specificity of TRAP220. The Journal of biological chemistry 278, 10942-10951.
Chan, C.M., Fulton, J., Montiel-Duarte, C., Collins, H.M., Bharti, N., Wadelin, F.R., Moran, P.M., Mongan, N.P., and Heery, D.M. (2013). A signature motif mediating selective interactions of BCL11A with the NR2E/F subfamily of orphan nuclear receptors. Nucleic acids research 41, 9663-9679.
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