Epigenetic, genetic and functional analysis of growth differentiation factor 5 gene GDF5 in developmental dysplasia of the hip and in osteoarthritis; development of the musculoskeletal system through to ageing.

Genetics and epigenetics are core drivers of the formation and the subsequent maintenance of organ systems, including articulating joints and their tissues. Healthy musculoskeletal ageing is dependent on the correct symmetry of the joint and on its ability to maintain and repair itself by responding appropriately to changing environmental conditions. The growth factor GDF5 is one of the key proteins in this regard, having a pivotal role in joint formation and subsequent joint homeostasis.

DNA polymorphism in the GDF5 gene has been genetically associated with a number of musculoskeletal diseases, ranging from early-onset conditions such as developmental dysplasia of the hip (our data, currently under review for publication) through to late-onset diseases, including osteoarthritis. These studies have focused on two SNPs in the genes 5’UTR, but it is now known that other regulatory elements of GDF5, including enhancer sequences, harbour potentially functional polymorphisms.

This studentship will therefore employ a range of molecular and cellular techniques to comprehensively investigate the molecular genetics and epigenetics of GDF5 as risk factors for musculoskeletal disease. The techniques to be employed include eQTL analysis, luciferase reporter studies, CRISPR/cas9 genome modulation, and DNA CpG methylation quantitation. The student will also use bioinformatics tools to scrutinise public databases and to analyse their data. The Newcastle Bioinformatics Support Unit (BSU) will train the student in this regard, and through the BSU the student will undertake relevant bioinformatics courses. The student will also utilise the patient tissue and cell resources made available through the CIMA biobank and will therefore liaise closely with the biobank technician, based in Newcastle.

This is a collaboration between the universities of Newcastle and Sheffield, with the student based in Newcastle. The Newcastle and Sheffield teams are both extremely well equipped and have experienced postdoctoral scientists and technicians able to offer day-to-day support to the student. The student’s PI will be Professor John Loughlin (Newcastle) whilst their laboratory supervisor will be Dr Sarah Rice, a postdoctoral scientist in Professor Loughlin’s group. The student will meet with Loughlin and Rice fortnightly whilst Skype meetings with the Sheffield supervisor, Professor Mark Wilkinson, will take place each month. Informal interactions outside of this formalised structure will be encouraged, as will supervisory meetings at CIMA gatherings.