Cardiovascular Epigenetics: Basic Concepts and Results From Animal and Human Studies

Abstract

Epigenetics is the study of heritable alterations in phenotypes and gene expression that occur without changes in the DNA sequence. Epigenetic mechanisms are flexible genomic factors that not only can change genome function under exogenous influence, but also can provide a molecular substrate that allows for the stable propagation of gene expression states from one generation of cells to the next. The best understood of the epigenetic mechanisms is DNA methylation,1 a covalent modification that, in mammals, occurs predominantly at cytosines followed by guanines (ie, CpG dinucleotides) to form 5-methylcytosines. CpG methylation generally is associated with gene silencing. DNA methylation states may vary over an individual's lifetime, and have been shown to regulate biological processes underlying cardiovascular disease, such as atherosclerosis, inflammation, hypertension, and diabetes.6,12,13 Methylation within gene promoters and CpG-dense sequences (CpG islands, usually unmethylated) has long been held to have the highest functional relevance to gene expression control (Figure 1). However, recent work has identified regions up to 2 kb from the islands (ie, on the island edges), termed CpG island shores, that have variable methylation and are the most enriched with functional CpG sites.2 DNA methylation also is believed to play important roles in the maintenance of genome integrity by transcriptional silencing of retrotransposons, that is, retrovirus-like DNA sequences that can duplicate and transpose themselves across the genome. In particular, some retrotransposons, such as Alu and long-interspersed nucleotide elements-1 (LINE-1) have up to 1 million copies in the human genome, are heavily methylated, and have been extensively investigated in human epigenetics studies. DNA methylation is mitotically stable and can be transmitted through cell division and, in some loci identified in animal experiments, transgenerationally.