Osteoarthritis (OA) and osteoporosis (OP) are common diseases affecting a large proportion of our ageing population. Both diseases carry a heritability factor of over 50%. Hundreds of independent genetic signals have been identified conferring risk to each of the respective diseases. One particular genetic risk locus at chromosome 6p21.1 has been reported in a number of genome wide association studies (GWAS), at which distinct variants can predispose an individual to either OA or OP. This locus harbours the gene RUNX2, encoding the transcription factor RUNX2. Correct spatiotemporal expression of RUNX2 expression is required for skeletal mineralisation and the development of the long bones, and becomes aberrantly up-regulated in OA articular cartilage. My previous studies have shown that a trait-associated interplay between genetics and epigenetics at the RUNX2 locus can alter gene expression. I have recently identified that these methylation changes operate in human foetal cartilage, laying down the risk of age-associated diseases during key skeletal developmental processes.

Using the latest technology in epigenetic research, including targeted Methyl-seq and dCas9 epigenome editing, I will scrutinise the distinct role of RUNX2 enhancers in developmental and aged bone and cartilage, and identify how this regulation becomes aberrant in disease. Using subnuclear proteomic profiling I will determine the proteins binding to regulatory elements. Finally, I will use small molecules targeting the epigenome to modulate RUNX2 expression in joint tissues. Together, these techniques will resolve the epigenetic landscape of RUNX2 throughout hip development, ageing, and in musculoskeletal disease.