Cindy Boer

Epigenomics in bone and cartilage disease | 33 1.2 Epigenomics as a Link Between Environment, Genotype, and Phenotype Phenotypic variation in skeletal traits and diseases is the product of genetic and en- vironmental factors. The extent to which genetics shapes the phenotype is different across the different skeletal conditions. Nevertheless, the genetic component of skel- etal traits is large, varying from 30% (knee osteoarthritis [OA]) to 80% (bone mineral density [BMD]). This does not mean there is no effect of the environment. In fact, these DNA‐sequence variants form the template upon which environmental factors can influ- ence the phenotype, by a number of mechanisms, including epigenetic marks. Wadding- ton coined the term epigenetics to describe the interactions between the environment and the genes leading to the development of phenotype[1]. The modern definition of epigenetic mechanisms includes information‐containing factors, other than DNA se- quence, that cause stable changes in gene expression and are maintained during cell divisions[2]. The main epigenetic factors are DNA methylation, posttranslational changes of histones, and higher‐order chromatin structure. Sometimes non‐coding RNAs, such as microRNAs (miRNAs) and long non‐coding RNAs (lncRNAs), are also included in the broad term of epigenetic factors. However, the exact definition of epigenetics and its components is still a matter of controversy[3]. Together these different epigenetic mechanisms are key factors behind the regulation, function, and cell fate of all tissues and cells. Not surprisingly, there is a large body of evidence supporting the role of epi- genetics in skeletal development, the maintenance of bone mass, and skeletal disorders. Our purpose here is to provide an overview and update of recent advances on the role of epigenomics in bone and cartilage diseases. Epigenomic marks DNA methylation DNA methylation refers to the covalent addition of a methyl group to cytosines in DNA, particularly when they are part of CpG dinucleotides. In somatic cells, more than 80% CpGs aremethylated, especially in repetitive sequences in intergenic regions and introns, whereas CpGs in gene promoters may be methylated or not. In general, the methylation of CpGs in gene promoters is associated with repression of gene expression, whereas the methylation of gene bodies and other regulatory regions (such as enhancers)[4] has a less predictable effect. Up to 20% of the variation in DNA methylation is influ-