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The term epigenetics refers to stable patterns of gene expression that are seen during differentiation or X chromosome inactivation and are not dependent on dynamic changes in coding DNA. These gene expression states are encoded in the epigenome - a collection of marks on DNA or on histone tails that are established during embryogenesis. Genome-wide studies in aging cells and tissues have uncovered stochastic DNA methylation drift (gradual increases or decreases at specific loci) that reflects imperfect maintenance of epigenetic marks. Drift creates epigenetic mosaicism in aging stem cells that could potentially restrict their plasticity and worsen phenotypes such as stem cell exhaustion and focal proliferative defects that can lead to cancer.
Epigenetics
The term epigenetics arose from a need to explain cellular phenotypic diversity in the face of a shared genetic make-up, as observed during differentiation in multicellular organisms (1). This is an extreme form of gene expression regulation, in which stability is key. Just as a lymphocyte does not spontaneously become an epithelial cell, an epigenetic pattern is stable through multiple rounds of cell division. While the concept arose to explain differentiation, epigenetic phenomena soon expanded to include other stable forms of gene expression regulation such as X chromosome inactivation in females (2) and imprinting, whereby a few hundred genes are expressed from only one of the two inherited alleles in a parent-of-origin manner (3). Our understanding of epigenetics has grown by leaps and bounds in the past decades as the mystery of stable gene expression in the absence of genetic change was solved through the discovery of DNA methylation- and chromatin-based gene regulation.
DNA methylation refers to the covalent addition of a methyl group (CH3) to a DNA base (4). In mammals, only cytosine can be normally methylated, and this most often happens in the context of the symmetrical dinucleotide CG (often referred to as CpG). About half of human promoters and transcription start sites are embedded in CpG islands (discrete regions rich in CpG sites and about 0.5 to 2 kilobases in length), and about half of all CpG islands are gene promoter associated. The 5-methylcytosine base can be further modified through sequential carboxylation by the ten-eleven translocation (TET) family of enzymes (5). These recently discovered modifications (e.g., 5-hydroxymethylcytosine) are...