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The term epigenetics was first coined by Waddington in 1942, as he sought to explain how changes in phenotype could occur throughout development independent of any changes to genotype. Appending the prefix epi- (Greek, meaning “over, outside of, around”) to genetics aptly describes the numerous mechanisms by which gene expression and phenotypes are influenced, independent of any changes to the underlying DNA sequence. Today, epigenetics occupies one of the most exciting topics in biology and medicine, offering profound opportunities for discovery, as well as promise for the development of new therapies for disease. Interdisciplinary by nature, the field crosses virtually all areas of science and medicine: chemistry and genetics, development and differentiation, immunology, cancer, aging, and neuroscience.

The continuous introduction of ever more powerful techniques for interrogating the epigenome has led epigenetics to become one of the most innovative fields within the biomedical sciences. Given the vast expanse of the topic and limitations of space, in this chapter we provide a broad overview of the field and highlight key areas from across the landscape of biomedicine where epigenetics plays critical roles in disease, and importantly, where epigenetics-based therapies have demonstrated success in clinical medicine.


Fundamental to epigenetic regulation is the intricate organization of each cell’s genome into chromatin (Chap. 456). The fundamental unit of the packaging into chromatin is the nucleosome, consisting of 147 base pairs of DNA wrapped around an octamer of 8 histone proteins (two copies of each of the four core histone proteins: H2A, H2B, H3, and H4). The level of compaction of this chromatin structure determines the accessibility of the DNA strand to transcription factors, the DNA repair machinery, and other DNA-binding entities. Thus, compaction has a profound influence on gene expression levels and on local DNA mutation rates. Open regions of chromatin (euchromatin) tend to be transcriptionally active, whereas compacted chromatin (heterochromatin) tends to be transcriptionally repressed.

Histones include the four core histones, which are the most abundant and most frequently found throughout the genome, and variant histones of H2A, H2B, and H3. The structure of core and variant histones include amino- and carboxyl-terminal “tails,” which are extended and unstructured, and highly conserved globular domains. The x-ray crystal structure of the nucleosome particle has illuminated the dynamic alterations of chromatin by an astounding range of regulatory mechanisms, summarized below.

The three main processes that regulate chromatin compaction, and thus access to the DNA template, include direct methylation modifications of the DNA strand itself, post-translational modifications of histones, and remodeling of nucleosomes to alter their location and composition with variant histones (Fig. 471-1). The major modification of DNA is cytosine methylation of CpG dinucleotides (5-mC), associated with gene repression and catalyzed by the DNMT1, DNMT3A, and DNMT3B enzymes. DNMT3A and 3B catalyze the addition of methyl groups on unmethylated DNA de novo at ...

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