Cindy Boer

52 | Chapter 1.2 developmental stage, the different enhancer regions are actively involved in regulation of expression, and different chromatin loops are established with the P1 and/or P2 pro- moter of RUNX2. The RUNX2 regulatory region carries all elements of a so‐called su- per‐enhancer region, which is a genomic region comprising multiple enhancers. These super‐enhancers are typically identified near genes important for cell‐identity/master transcription regulation genes, which require detailed regulation of expression, such as is the case for RUNX2. What Will the Future Hold? Advances in understanding the epigenomic mechanisms have greatly expanded our knowledge about the molecular mechanisms involved in the differentiation and activity of cells responsible for skeletal homeostasis, which are central players in the pathogen- esis of disorders such as osteoporosis and OA. Thus, we can anticipate that epigenetic mechanisms must also play an important role in these disorders and may become the foundation for new therapies. However, much more research is needed in order to use epigenetic marks as biomarkers of disease risk or progression and to introduce epigen- etic‐based therapies into the clinic. To date, association studies aimed to elucidate the association of epigenetic signals with bone phenotypes have had limited reproducibility, particularly regarding DNA methylation marks. Similarly, some miRNA signatures have been produced in a few small‐size studies, but replication in larger studies is still pending. Of course, this is critical before introducing the analysis of epigenetic markers as tools for diagnosis or prognosis of disease. It will likely require large collaborative, epigenome-wide studies. A major issue regarding therapy aimed at modulating epigenetic mechanisms is related to lack of specificity and undesired effects. Drugs interfering with DNA methyla- tion are already being used to treat some bone marrow disorders, but their widespread effects make them rather unsuitable for non‐neoplastic disorders. Thus, CRISPR‐based methods and other procedures to induce targeted DNA methylation changes to specific loci in somatic cells may greatly help to first delineate the effects of methylation marks and then to epigenetically modify the activity of specific genes[136]. SAHA‐PIPs are a novel class of histone modifiers made by conjugating selective DNA binding pyrrole‐ imidazole polyamides (PIPs) with the histone deacetylase inhibitor SAHA. They show some selectivity and modulate the transcription of certain clusters of genes[137]. Localized skeletal disorders, such as some forms of OA and delayed‐union frac- tures may be amenable to local therapies, such as agonists and antagonists of specific