The Epigenetics Revolution

The specialised cell types in the retina and in the bladder are each at the bottom of one of the troughs in Waddington’s epigenetic landscape. The work of both John Gurdon and Shinya Yamanaka showed us that whatever mechanism cells use for staying in these troughs, it’s not anything to do with changing the DNA blueprint of the cell. That remains intact and unchanged. Therefore keeping specific sets of genes turned on or off must happen through some other mechanism, one that can be maintained for a really long time. We know this must be the case because some cells, like the neurons in our brains, are remarkably long-lived. The neurons in the brain of an 85-year-old person, for example, are about 85 years of age. They formed when the individual was very young, and then stayed the same for the rest of their life.

But other cells are different. The top layer of skin cells, the epidermis, is replaced about every five weeks, from constantly dividing stem cells in the deeper layers of that tissue. These stem cells always produce new skin cells, and not, for example, muscle cells. Therefore the system that keeps certain sets of genes switched on or off must also be a mechanism that can be passed on from parent cell to daughter cell every time there is a cell division.

This creates a paradox. Researchers have known since the work of Oswald Avery and colleagues in the mid-1940s that DNA is the material in cells that carries our genetic information. If the DNA stays the same in different cell types in one individual, how can the incredibly precise patterns of gene expression be transmitted down through the generations of cell division?

Our analogy of actors reading a script is again useful. Baz Luhrmann hands Leonardo DiCaprio Shakespeare’s script for Romeo and Juliet, on which the director has written or typed various notes – directions, camera placements and lots of additional technical information. Whenever Leo’s copy of the script is photocopied, Baz Luhrmann’s additional information is copied along with it. Claire Danes also has the script for Romeo and Juliet. The notes on her copy are different from those on her co-star’s, but will also survive photocopying. That’s how epigenetic regulation of gene expression occurs – different cells have the same DNA blueprint (the original author’s script) but carrying varied molecular modifications (the shooting script) which can be transmitted from mother cell to daughter cell during cell division.

These modifications to DNA don’t change the essential nature of the A, C, G and T alphabet of our genetic script, our blueprint. When a gene is switched on and copied to make mRNA, that mRNA has exactly the same sequence, controlled by the base-pairing rules, irrespective of whether or not the gene is carrying an epigenetic addition. Similarly, when the DNA is copied to form new chromosomes for cell division, the same A, C, G and T sequences are copied.

Since epigenetic modifications don’t change what a gene codes for, what do they do? Basically, they can dramatically change how well a gene is expressed, or if it is expressed at all. Epigenetic modifications can also be passed on when a cell divides, so this provides a mechanism for how control of gene expression stays consistent from mother cell to daughter cell. That’s why skin stem cells only give rise to more skin cells, not to any other cell type.

Sticking a grape on DNA

The first 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.

^{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.}