Genetic and epigenetic effects in development and disease of the human hip

For over a decade, genome wide association studies (GWAS) have been successfully applied to identify risk variants in common diseases, including osteoarthritis (OA) and osteoporosis (OP). However, there remains an enormous disparity between the reporting of variants and functional follow-up studies.

A growing body of evidence indicates that these genetic variants lead to epigenetic changes, namely DNA methylation (DNAm), which in turn alter gene expression, leading to disease. In musculoskeletal disease, the key recurring GWAS locus is at chromosome 6p21.1. This region will be my primary research focus during this fellowship.

Here, distinct variants can predispose an individual to OA, OP, and other skeletal traits.

This locus harbours RUNX2, a gene encoding a transcription factor essential for skeletal mineralisation and long bone development. RUNX2 levels change in both OA and OP, due to a heritable dysregulation in gene expression. My previous studies have shown that OA-associated genetic influences affect DNAm, which can alter expression of RUNX2.

I have recently made the remarkable discovery that these DNAm changes leading to age-associated disease also operate in human foetal cartilage. This indicates that the epigenetic risk of poor musculoskeletal ageing is established during development.

Using state-of-the-art epigenetic technologies, including targeted Methyl-seq and dCas9 epigenome editing, I will carefully examine the role of human RUNX2 enhancers in two key hip tissues (bone and cartilage) during development and identify how this regulation becomes aberrant in common, age-associated disease.

Using subnuclear proteomic profiling, I will identify the proteins binding to prioritised regulatory elements and characterise the molecular mechanisms leading to altered RUNX2 expression.

Together, this innovative combination of techniques will elucidate the epigenetic regulation of RUNX2 in musculoskeletal disease and probe the developmental origins of disease risk.

This will pave the way for the identification and development of novel therapies by pharmacological targeting of the epigenome.