There are hundreds of tissue-specific nuclear membrane proteins, many of which have been shown to cause a wide range of diseases when mutated. The host lab has shown that for nuclear envelope-linked muscular dystrophy and lipodystrophy there are many metabolic changes due to disruption of the normal muscle or fat-specific connections between these tissue-specific nuclear membrane proteins and genes they regulate. Separately, we found that nuclear membrane proteins whose expression alters nuclear size are linked to lower survival in cancer patients and in vitro correcting this nuclear size reduces cell migration and invasion. In both cases we are interested in better understanding how genome organisation is altered respectively by the mutated nuclear membrane proteins and the nuclear size changes. Thus, there are 2 separate core projects available with multiple variations. For the muscle/fat metabolism project we are interested in understanding the mechanism underlying the tethering complex using biochemistry, mass spectrometry, biophysics, CRISPR/Cas9-genome editing, and fluorescence in situ hybridisation/ live-cell imaging. This will enable both deciphering the complex itself and asking fundamental questions regarding complex stability and dynamics, how the nuclear envelope can control the positioning of both genes and their regulatory elements, and how tension on DNA from distal tethering points can direct the dynamics, speed, and transcriptional fitness of promoter-enhancer complexes, which will further involve bioinformatic analysis of genome organisation datasets from the host lab and others. This project could also investigate using metabolic drugs to treat muscle disorders using in vitro assays for muscle differentiation and metabolism using human muscular dystrophy patient mutations and/or could involve a different focus on muscle damage-repair. For the latter, we found genes normally recruited to the nuclear envelope to be repressed during differentiation (and failing to do so in muscular dystrophy patients) are released when inducing muscle damage to promote fusion of myoblasts with the damaged myotubes. The cancer project could focus either on specific nuclear membrane proteins that can alter nuclear size and are often altered in expression and/or by mutation in more metastatic cancers or on drugs we found can reverse nuclear size changes associated with increased metastasis. Both will involve microscopy assays for nuclear size, cell migration and invasion plus mass spectrometry to identify partners of involved nuclear membrane proteins and bioinformatics analysis of cancer expression and mutation datasets and for the drug aspect the known chemical-genetic interactions of relevant drugs. For both project directions there would be the possibility of doing animal work (e.g. testing metabolic drugs on a mouse Emery-Dreifuss muscular dystrophy model or testing drugs for reducing metastasis using a xenograft model) pending availability of funds.
For more information on the project, eligibility and how to apply for the School's PhD programme, please click on the 'Visit Institutional Website' link.
Applicants should apply to the School's Biological Sciences PhD programme via the University’s admissions portal (EUCLID) with a start date of 01 October 2026.
In the EUCLID application, applicants should state the project “Nuclear Envelope Directed Genome Organisation in Health and Disease”, the research supervisor (Eric Schirmer) and their anticipated funding source (e.g. Darwin Trust).