The human genome found in each cell of the body consists of ~6 billion bases of DNA forming a sequence unique to each individual. This sequence contributes to differences in phenotypic traits among individuals, such as height, as well as risks of developing different diseases. However, the DNA sequence alone cannot account for the phenotypic identity that discriminates between different cell types and tissues of a human being, because (with few exceptions) the DNA sequence is largely identical in each cell. Thus, cell type–specific gene expression programs require an additional system of control to achieve this phenotypic diversity, a system commonly referred to as epigenetics.
Epigenetics relates to heritable changes that impact DNA templated processes, such as gene expression, that are not encoded in the primary linear DNA sequence. These processes are mediated by the covalent attachment of chemical groups (eg, methyl or acetyl groups) to DNA and associated proteins, histones and chromatin that together establish “chromatin states.” Each state consists of a unique combination of DNA and histone modifications that demarcate DNA sequences with specific functions such as transcripts, silent genes, or cis-regulatory elements involved in modulating gene expression. Remarkably, through these layers of regulation, a single human genome, of which only ~1.5% encodes proteins, gives rise to hundreds of cell types with distinct gene expression patterns and functional phenotypes. Although the DNA and histone modifications that determine each chromatin state are conserved across cell types, the distribution of each state along the DNA varies from one cell type to another (Ernst et al, 2011) and is subject to change across development. Alterations to these chromatin states have been linked to the development and progression of various human disorders, including cancer (Feinberg, 2018). The sensitivity of chromatin states to cell-extrinsic factors also imparts an opportunity for therapeutic interventions aimed either to correct pathogenic alterations or to exploit vulnerabilities of the cancer cells (Pfister and Ashworth, 2017; Bates, 2020). In this chapter, the mechanisms of epigenetic regulation will be reviewed, with a focus on processes for which dysregulation contributes to malignancy and on opportunities to leverage modifiable chromatin states for anticancer therapy.
3.2 EPIGENETIC MECHANISMS AND REGULATION
Epigenetic modifications occur in the context of chromatin, a macromolecular complex composed of DNA bases wrapped around nucleosomes (Fig. 3–1). Nucleosomes are the basic units of chromatin, with each consisting of 147 base pairs of DNA winding around histone octamers that comprise pairs of the core H2A, H2B, H3, and H4 histone proteins. Although histone variants can replace these core proteins on the chromatin to delineate distinct chromatin states (Henikoff and Smith, 2015), the most commonly reported epigenetic modifications consist of DNA methylation and posttranslational modifications of histones. Chromatin is compacted to varying degrees to minimize the space needed to store the genetic information encoded within the human genome. Chromatin ...