Free The Epigenetics Revolution by Nessa Carey Page A

epigenetic modification to be identified was DNA methylation. Methylation means the addition of a methyl group to another chemical, in this case DNA. A methyl group is very small. It’s just one carbon atom linked to three hydrogen atoms. Chemists describe atoms and molecules by their ‘molecular weight’, where the atom of each element has a different weight. The average molecular weight of a base-pair is around 600 Da (the Da stands for Daltons, the unit that is used for molecular weight). A methyl group only weighs 15 Da. By adding a methyl group the weight of the base-pair is only increased by 2.5 per cent. A bit like sticking a grape on a tennis ball.
    Figure 4.1 shows what DNA methylation looks like chemically.
    The base shown is C – cytosine. It’s the only one of the four DNA bases that gets methylated, to form 5-methylcytosine. The ‘5’ refers to the position on the ring where the methyl is added, not to the number of methyl groups; there’s always only one of these. This methylation reaction is carried out in our cells, and those of most other organisms, by one of three enzymes called DNMT1, DNMT3A or DNMT3B. DNMT stands for DN A m ethyl t ransferase. The DNMTs are examples of epigenetic ‘writers’ – enzymes that create the epigenetic code. Most of the time these enzymes will only add a methyl group to a C that is followed by a G. C followed by G is known as CpG.

    Figure 4.1 The chemical structures of the DNA base cytosine and its epigenetically modified form, 5-methylcytosine. C: carbon; H: hydrogen; N: nitrogen; O: oxygen. For simplicity, some carbon atoms have not been explicitly shown, but are present where there is a junction of two lines.
    This CpG methylation is an epigenetic modification, which is also known as an epigenetic mark. The chemical group is ‘stuck onto’ DNA but doesn’t actually alter the underlying genetic sequence. The C has been decorated rather than changed. Given that the modification is so small, it’s perhaps surprising that it will come up over and over again in this book, and in any discussion of epigenetics. This is because methylation of DNA has profound effects on how genes are expressed, and ultimately on cellular, tissue and whole-body functions.
    In the early 1980s it was shown that if you injected DNA into mammalian cells, the amount of methylation on the injected DNA affected how well it was transcribed into RNA. The more methylated the injected DNA was, the less transcription that occurred 1 . In other words, high levels of DNA methylation were associated with genes that were switched off. However, it wasn’t clear how significant this was for the genes normally found in the nuclei of cells, rather than ones that were injected into cells.
    The key work in establishing the importance of methylation in mammalian cells came out of the laboratory of Adrian Bird, who has spent most of his scientific career in Edinburgh, Conrad Waddington’s old stomping ground. Professor Bird is a Fellow of the Royal Society and a former Governor of the Wellcome Trust, the enormously influential independent funding agency in UK science. He is one of those traditional British scientific types – understated, soft-spoken, non-flashy and drily funny. His lack of self-promotion is in contrast to his stellar international reputation, where he is widely acknowledged as the godfather of DNA methylation and its role in controlling gene expression.
    In 1985 Adrian Bird published a key paper in Cell showing that most CpG motifs were not randomly distributed throughout the genome. Instead the majority of CpG pairs were concentrated just upstream of certain genes, in the promoter region 2 . Promoters are the stretches of the genome where the DNA transcription complexes bind and start copying DNA to form RNA. Regions where there is a high concentration of CpG motifs are called CpG islands.
    In about 60 per cent of the genes that code for proteins, the promoters lie within CpG islands. When