Cindy Boer

46 | Chapter 1.2 teoclast differentiation and activity in vitro[100]. Because of these seemingly key roles, HDACs, HAT, and BET have been suggested as novel therapeutic targets in a range of skeletal diseases[97, 102]. Thus, JQ1 and other inhibitors of BET proteins ameliorate bone loss in ovariectomized mice and several preclinical models of inflammatory disor- ders, such as arthritis and periodontitis[102, 103]. However, it is important to keep in mind that most histone remodelers and read- ers also fulfil essential roles in other tissues and cell types[104]. For example, DOT1L is not only essential for chondrogenesis and cartilage homeostasis[99] but, also for telo- mere silencing, meiotic checkpoint control, and DNA damage response[105, 106]. Mu- rine knockout models of DOT1L show multiple developmental abnormalities, not only restricted to skeletal abnormalities[106]. Similar observations can be made for most histone remodelers associated with skeletal development and disease, such as the sir- tuins (SirT1)[107], KDM6B[108], and BET proteins[109]. Because histone remodelers and readers are involved in a plethora of cellular processes in diverse cell types[110], globally administered therapeutic targeting may produce off‐target and side effects, il- lustrating the need to examine such histone remodelers and readers in careful detail. The chromatin structure itself can also modulate gene regulation and expression. For example, disruption of the TAD structure near certain genes can cause congenital skeletal disorders. Depending on the type and size of the of TAD disruption, brachy- dactyly, syndactyly, and polydactyly may be caused by changes in enhancer‐promoter regulation in the WNT6/IHH/EPHA4/PAX3 locus[111]. Further, the deletion of a TAD boundary as a disease mechanism has also been proposed for Liebenberg syndrome, a rare disorder where the arms of the patient acquire morphological characteristics similar to those of the legs[112]. For a comprehensive review regarding the disruption of TADs and skeletal disorders, see Lupiáñez and colleagues[7]. Up to now, only small‐scale data are available on histone modifications and 3D chromatin structure of chondrocytes and bone. This may reflect the novelty of these data, the costs, material amounts, and skills needed to perform such experiments and analysis. However, recent large‐scale efforts from the ROADMAP consortium[113] and the encyclopedia of DNA elements (ENCODE)[114] have built genome-wide maps of several histone modifications and chromatin conformations inmultiple human cells and tissues, including bone and cartilage[4]. Those data are freely accessible ( Table 3 ) and can be used as an epigenomic reference map for the locations of regulatory elements in osteoblasts and chondrogenic cells. To our knowledge, no chromatin conformation capture data of chondrocyte or osteoblast is available. However, TADs have been shown to be stable across cells, tissues, and even species, which highlights biological relevance and suggests that they function as a general 3D framework to determine domains of