Osteoarthritis as an Enhanceropathy: Gene Regulation in Complex Musculoskeletal Disease.

Advances in technologies such as ATAC-seq have facilitated our understanding of chromatin states in specific cell types, bolstering the interpretation of GWAS and the identification of effector genes. Their application to osteoarthritis research has revealed enhancers as the principal regulatory element driving disease-associated changes in gene expression. However, tissue-specific effects in gene regulatory mechanisms can contribute added complexity to biological interpretation. Understanding gene enhancers and their altered activity in specific cell and tissue types is the key to unlocking the genetic complexity of osteoarthritis. The use of single-cell technologies in osteoarthritis research is still in its infancy. However, such tools offer great promise in improving our functional interpretation of osteoarthritis GWAS and the identification of druggable targets. Large-scale collaborative efforts will be imperative to understand tissue and cell-type specific molecular mechanisms underlying enhancer function in disease.