Mechanoepigenetics in musculoskeletal disease.

This review explores the intricate interplay between genetic variants, mechanical forces, and the epigenetic landscape (defined as 'mechanoepigenetics'), particularly in the context of musculoskeletal (MSK) diseases such as osteoarthritis. Whilst our understanding of Mendelian monogenic disease has progressed with exome sequencing and the generation of novel gene therapies, common complex diseases characterized by difficult-to-pinpoint non-coding genetic variants have posed significant challenges. The recent implementation of techniques such as ChIP-seq, ATAC-seq, and chromatin capture (Hi-C) has been pivotal in understanding how enhancers, promoters, and repressors interact with target genes to control gene expression. However, the data they generate are only more recently being used to filter non-coding variants for regulatory impacts. Even more pressing is that the epigenome and long-range interactions can be modified by environmental factors such as mechanical forces, and this is poorly understood, especially with respect to impacts on variant function. Here, we highlight the role of the dynamic mechanical environment in the regulation of the epigenome to identify mechanically mediated regulatory region interactions to streamline the identification of variant activity and how they might be impacted. We also explore the potential for targeting mechanically responsive loci with epigenome-modifying drugs. By integrating genetic, epigenetic, and mechanical insights, this review aims to advance understanding of disease mechanisms and propel the development of novel therapeutic strategies for MSK diseases, drawing parallels with emerging approaches in other fields.