The Epigenetics Revolution

^{Figure 7.3 Mice generated in which a particular foreign piece of DNA was either methylated or not methylated. Black represents methylated DNA, and white represents unmethylated. When a mother passed on this foreign DNA, the DNA was always heavily methylated (black) in her offspring, regardless of whether she herself had been ‘black’ or ‘white’. The opposite was found for males, whose offspring always had unmethylated ‘white’ DNA. This was the first experimental demonstration that some regions of the genome can be marked to indicate if they were inherited via the maternal or the paternal line.}

Black represents the methylated inserted DNA, whereas white represents unmethylated DNA. Fathers always give their offspring white, unmethylated DNA whereas mothers always give their offspring black, methylated DNA. In other words, the methylation in the offspring is dependent on the sex of the parent who passed the inserted DNA onto them. It’s not dependent on what the methylation was like in the parent. For example, a ‘black’ male will always have offspring with ‘white’ DNA.

What this paper from Azim Surani[59], and another published at the same time[60], demonstrated was that when mammals create eggs and sperm, they somehow manage to barcode the DNA in these cells. It’s as if the chromosomes carry little flags. The chromosomes in sperm carry little flags that say, ‘I’m from Dad’ and the chromosomes in eggs carry little flags that say, ‘I’m from Mum’. DNA methylation is the fabric that these flags are made from.

The description that is used for this is imprinting – the chromosomes have been imprinted with information about which parent they came from originally. Imprinting and parent-of-origin effects are something we will explore in more detail in the next chapter.

What was happening to the foreign DNA in the experiments, which kept changing its methylation status as it was transmitted from parent to offspring? It had, quite by chance, got inserted into a region of the mouse DNA that carried one of these flags. As a consequence, the foreign DNA also started getting DNA methylation flags stuck to it when it was passed down the generations.

The fact that only one of seven mouse lines showed this effect suggested that not all of the genome carries these flags. If the whole genome was marked in this way, we would have expected that all the lines that were tested would show the effect. In fact, the one in seven rate suggests that these flagged regions are the exception, not the rule.

In Chapter 6 we saw that sometimes animals do inherit acquired characteristics from their parents. The work of Emma Whitelaw, amongst others, shows us that some epigenetic modifications do indeed get passed between parent and offspring, via the sperm and the egg. This type of inheritance is pretty rare, but it does strengthen our belief that there must be some epigenetic modifications that are special. They don’t get replaced when the egg and sperm fuse to form the zygote. So, although the vast majority of the mammalian genome does get reset when the egg and the sperm fuse, a small percentage of it is immune from this reprogramming.

The epigenetics arms race

Only 2 per cent of our genome codes for proteins. A massive 42 per cent is composed of retrotransposons. These are very odd sequences of DNA, which probably originated from viruses in our evolutionary past. Some retrotransposons are transcribed to produce RNA and this can affect the expression of neighbouring genes. This can have serious consequences for cells. If it drives up expression of genes that cause cells to proliferate too aggressively, for example, this may nudge cells towards becoming cancerous.

There’s a constant arms race in evolution, and mechanisms have evolved in our cells to control the activity of these types of retrotransposons. One of the major mechanisms that cells use is epigenetic. The retrotransposon DNA gets methylated by the cell, turning off retrotransposon RNA expression. This prevents the RNA disrupting expression of neighbouring genes. One particular class, known as IAP retrotransposons, seems to be a particular target of this control mechanism.