Epigenetic analysis of Paget's disease of bone identifies differentially methylated loci that predict disease status.

Our skeleton stays healthy through an endless regeneration process, with specialized cells constantly absorbing and creating new bone tissue. Illnesses emerge when this breaking down and rebuilding cycle becomes imbalanced. For instance, in Paget's disease of bone (PDB for short) the skeleton becomes misshapen and fragile, with complications including pain, fractures, neurological problems, hearing loss and even cancer. For most patients however, symptoms are only present at an advanced stage, when irreversible damage to the skeleton has already occurred. Certain inherited genetic changes play a role in the development of PDB, but lifestyle and environmental factors are also thought to contribute. Indeed, accumulating evidence suggests that diet, pollution and infection may influence how genes involved in bone metabolism are activated. In this process, the environment may trigger chemical marks to be added onto DNA sequences, which ultimately switches specific genes on and off. To investigate whether the pattern of chemical marks in individuals with PDB may be characteristic, Diboun et al. scanned the genetic information of over 200 PDB patients, and compared it to healthy counterparts. Combining genomic analysis and machine learning revealed several chemical signatures that were remarkably different in the DNA of PDB individuals. These signatures affected sites close to genes involved in bone development, as well as response to mechanical loading and infection. This provides strong evidence that PDB could be, in part, triggered by the environment, as the placement of these marks is highly influenced by external factors. This research sheds light onto the underlying changes that trigger PDB. Future experiments should explore whether it may be possible to use these genetic changes to identify patients before the onset of irreversible and debilitating damage.