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Conrad Hal Waddington is usually credited with modifying the Greek word “epigenesis,” which described a theory of development, into a new term “epigenetics” to mean “the causal interactions between genes and their products which bring the phenotype into being.”1 Waddington described an “epigenetic landscape” usually as a system of bifurcating valleys through which a cell, depicted alternatively as water or a roulette ball, flows or rolls toward the sea constantly making binary choices on its way.2 Waddington explained how genes were responsible for creating this “epigenetic landscape” of valleys since these genes were positioned on the underside of the landscape and attached to it by a series of “guy ropes” much like how pegs with ropes determine the shape of a tent's canopy. Thus, genes were ultimately responsible for the motley array of crevices, valleys, and hills in the canopy through which a ball could follow downhill as it embarked on its developmental pathway of differentiation. In addition to Waddington, other leading biologists of the time, including Ernest Hadorn, Richard Goldschmidt, and Julian Huxley, also saw a relationship between genes and their action to development during a period when embryology and developmental biology were very disparate disciplines.4 Thus, the term “epigenetics” proved durable not only because it provided a convenient explanation of how expressed genes informed developmental decisions of a cell, but also because it brought together the two disciplines of Mendelian genetics and embryology. In time, epigenetics has become used not only to explain heritable changes in development, but also to understand diverse biological processes including normal aging, maternal X chromosome inactivation, as well as pathological states, such as cancer and neurodegenerative diseases.

In our modern experimental, scientific era, it has become apparent that it is not only the information contained within genes that is important (the so-called “hardware”), but also how genes are organized or packaged within the cell (the “software”) that is critical. This is because the precise, compact folding of the DNA into its chromatin structure has a significant effect on which genes are actively transcribed by DNA polymerase and which are not (largely, it can be thought of as an accessibility problem—the more compactly folded or closed the DNA, the more inaccessible to being read or transcribed). The contemporary definition of epigenetics as “a hereditable change in gene expression that occurred without a change in the DNA sequence”5 can also be attributed to work done by both Robin Holliday and Arthur Riggs in the 1970s. Both authors independently published papers suggesting that DNA methylation may be responsible for an epigenetic switch between activity and inactivity of genetic transcription that affected cell development.6,7 In 1987, Holliday revisited Waddington's original terminology and applied it to changes in gene expression caused by DNA methylation.8 Riggs followed in 1996 stating more broadly that epigenetics was “the study of mitotically and/or meiotically heritable changes in gene function ...

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