Epigenetic regulation of the cardiovascular system: introduction to a review series.

Our genes code for the building blocks of our body, and variations in our genome predispose us to distinct traits, including disease. To add complexity to the interpretation and regulation of our genetic code, the DNA packed into the chromatin forming our chromosomes is modified by factors that alter its expressivity but without changing its sequence. These factors are referred to as epigenetic factors. A recent definition states: “An epigenetic trait is a stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence.”1 Many factors are involved in establishing epigenetic traits, including DNA methylation, histone variants, chemical modification of histones, position of nucleosomes, and 3D organization of genes in the nucleus, for example. These modifications often act in concert to alter the expression of genes, or to effect allele-specific inheritance. Epigenetic regulation can be established cell-autonomously, through intercellular signaling, and by environmental influences. All cells in the body are subject to epigenetic regulation, and thus understanding this important layer of regulation is key to elucidating mechanisms of cardiovascular development, physiology, and disease (Figure). This review series in Circulation Research will explore recent advances in epigenetic research, with an outlook toward the cardiovascular system. The reviews will explore the current state of the art and will focus on the exciting future of epigenetic research as it relates to the cardiovascular system. Epigenetic regulation is commonly considered to include the chemical modification of histone residues that accompany regulated gene expression. Many have noted that the definition of epigenetics quoted above implies heritability of a phenotype through either mitosis or meiosis. At first glance, this might seem to exclude the changes in histone modifications that are established during gene regulation but are thought to be transient because of histone turnover. However, some of these changes are in fact actively maintained,2 and thus histone modifications can be included in a broader definition of epigenetics. To enact a concerted phenotypic program during differentiation, or remodeling in disease, several broad programs of gene expression must be coregulated. Epigenetic regulation through histone modifications is an important aspect of this coregulation.3 The unstructured tails of histones (the proteins that assemble into the nucleosomes around which chromosomal DNA is wound) are subject to myriad chemical modifications, including acetylation, methylation, phosphorylation, ubiquitinylation, and sumoylation. In combination, these modifications are thought to result in a histone “code” that is read and translated into signals for activation or repression of associated genes.3,4 For example, certain histone modifications are most often associated with repressed genes, and others with active genes. The widespread coordinated deployment of particular histone modifications ensures a stable and efficiently enacted