Shikhar Sharma,^1,2 Theresa K. Kelly,¹ and  Peter A. Jones^1,*

Introduction

Chromatin structure defines the state in which genetic information in the form of DNA is organized within a cell. This organization of the genome into a precise compact structure greatly influences the abilities of genes to be activated or silenced. Epigenetics, originally defined by C.H.Waddington (1) as ‘the causal interactions between genes and their products, which bring the phenotype into being’, involves understanding chromatin structure and its impact on gene function. Waddington’s definition initially referred to the role of epigenetics in embryonic development; however, the definition of epigenetics has evolved over time as it is implicated in a wide variety of biological processes. The current definition of epigenetics is ‘the study of heritable changes in gene expression that occur independent of changes in the primary DNA sequence’. Most of these heritable changes are established during differentiation and are stably maintained through multiple cycles of cell division, enabling cells to have distinct identities while containing the same genetic information. This heritability of gene expression patterns is mediated by epigenetic modifications, which include methylation of cytosine bases in DNA, posttranslational modifications of histone proteins as well as the positioning of nucleosomes along the DNA. The complement of these modifications, collectively referred to as the epigenome, provides a mechanism for cellular diversity by regulating what genetic information can be accessed by cellular machinery. Failure of the proper maintenance of heritable epigenetic marks can result in inappropriate activation or inhibition of various signaling pathways and lead to disease states such as cancer (2,3).

Recent advances in the field of epigenetics have shown that human cancer cells harbor global epigenetic abnormalities, in addition to numerous genetic alterations (3,4). These genetic and epigenetic alterations interact at all stages of cancer development, working together to promote cancer progression (5). The genetic origin of cancer is widely accepted; however, recent studies suggest that epigenetic alterations may be the key initiating events in some forms of cancer (6). These findings have led to a global initiative to understand the role of epigenetics in the initiation and propagation of cancer (7). The fact that epigenetic aberrations, unlike genetic mutations, are potentially reversible and can be restored to their normal state by epigenetic therapy makes such initiatives promising and therapeutically relevant (8).

In this review, we take a comprehensive look at the current understanding of the epigenetic mechanisms at work in normal mammalian cells and their comparative aberrations that occur during carcinogenesis. We also discuss the idea of cancer stem cells as the originators of cancer and the prospect of epigenetic therapy in designing efficient strategies for cancer treatment.