Bone Abstracts

Epigenetic mechanisms regulate gene expression and are heritable through cell divisions even though they do not involve modifications in the gene sequence. They include methylation and other chemical modifications of cytosine nucleotides, histone posttranslational modifications, microRNAs and other non-coding RNAs. Most cytosines in the human genome are methylated, particularly in the inactive, tightly packed, heterochromatin of autosomes, and the inactivated X-chromosome in females. This is thought to contribute to DNA stability. However, the promoters and enhancers of many genes contain CpG-rich regions that may remain unmethylated. The methylation of cytosines in CpG dinucleotides in gene promoters tends, in association with specific histone modifications, to repress gene transcription. This allows body cells to display a whole variety of phenotypes despite them all having the same gene sequence. Thus, the methylation/demethylation of specific cytosines plays a central role in embryogenesis, and in cell differentiation needed for normal tissue homeostasis and turnover, as well as in cancer and other diseases. It also represents a pathway by which environmental influences, either in the uterus or after birth, impact on the phenotype of the individual. The role of DNA methylation in the differentiation of cells of the osteoblastic lineage has been well demonstrated. Thus, the expression of genes playing a major role in bone homeostasis (such as those encoding alkaline phosphatase, os teoprotegerin, RANKL or sclerostin) is associated with the demethylation of CpG-rich regions in their promoters. Modern technologies permit the use of genome-wide approaches to study DNA methylation. Investigators comparing the methylation patterns in patients with osteoporosis and other skeletal disorders have found several differentially methylated regions. However, the interpretation of these studies has inherent complexities because, unlike the genome, the epigenome of the individual is tissue and cell-specific and may change with time.