Coveney Clarissa R, Capellini Terence D
Department of Human Evolutionary Biology, Harvard University, United States; Broad Institute of Harvard and MIT, United States.
Osteoarthritis Cartilage. 2025 Jun 4. doi: 10.1016/j.joca.2025.05.012.
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.
本综述探讨了基因变异、机械力和表观遗传景观（定义为“机械表观遗传学”）之间的复杂相互作用，特别是在骨关节炎等肌肉骨骼（MSK）疾病的背景下。虽然我们通过外显子组测序和新型基因疗法的开发，对孟德尔单基因疾病的理解取得了进展，但以难以确定的非编码基因变异为特征的常见复杂疾病带来了重大挑战。ChIP-seq、ATAC-seq和染色质捕获（Hi-C）等技术的近期应用，对于理解增强子、启动子和阻遏物如何与靶基因相互作用以控制基因表达起到了关键作用。然而，它们产生的数据直到最近才被用于筛选具有调控影响的非编码变异。更紧迫的是，表观基因组和长程相互作用会受到机械力等环境因素的影响，而这一点目前还知之甚少，尤其是对变异功能的影响。在这里，我们强调动态机械环境在表观基因组调控中的作用，以识别机械介导的调控区域相互作用，从而简化变异活性的识别以及它们可能受到的影响。我们还探讨了用表观基因组修饰药物靶向机械反应性位点的潜力。通过整合遗传学、表观遗传学和机械学方面的见解，本综述旨在增进对疾病机制的理解，并推动MSK疾病新型治疗策略的开发，同时与其他领域的新兴方法进行比较。
