DNA MODIFICATION AND EPIGENETICS

    DNA contains four units of information: adenine, guanine, thymine and cytosine, collectively known as bases, and abbreviated to A,G,T and C. A fifth base is produced when some cytosines are modified to methyl cytosine. It was proposed in 1975 by Robin Holliday and John Pugh, and independently by Arthur Riggs, that methyl cytosine may have an important role in controlling gene activity. It was also proposed that the pattern of methylated cytosine could be inherited through cell divisions. In 1975 there was no direct evidence for these proposals.

    Since that time a huge amount of direct evidence has accumulated which shows that DNA methylation can turn off or silence genes. This means that genes can be active without DNA methylation and inactive with DNA methylation, and that both states are heritable from cell to cell. This is what is necessary for complex organisms, where some specialised genes are expressed and others are not. For example, a brain cell does not make haemoglobin, although the gene is present. A blood cell has haemoglobin but not many components of brain cells.

    Epigenetics is the bridge between genetics - the inheritance of DNA - and development from the fertilised egg to the adult organism. It can be defined in a broad sense as the unfolding of the genetic programme for development. It also has a more narrow meaning: the inheritance of gene activities which do not depend on any changes in DNA base sequences. As well as DNA modification, there are other epigenetic mechanisms, notably the modification of proteins (histones) associated with DNA. However, any mechanism for the heritability of protein modification has not been clearly demonstrated.

    In 1987 Robin Holliday published a paper on "The heritability of epigenetic defects." In a later review another author wrote that the 1987 paper was "the critical paper that lit the fuse for the explosion in the use of the term 'epigenetic' in the 1990s." Today there is a huge literature on epigenetics and it has become a discipline in its own right. Almost all this work relates to the more narrow meaning of epigenetics. A full understanding of development undoubtedly depends on the broad meaning, and that is a very important field for future research.

Historical references:

Holliday, R. A different kind of inheritance. Scientific American, 260,
60-73 (1989).
Holliday, R. Epigenetics: a historical overview. Epigenetics, 1, 76-80 (2006).