The Epigenetics Revolution

The egg is a wonderful thing, honed through hundreds of millions of years of evolution to be extraordinarily effective at generating vast quantities of epigenetic change, across billions of base-pairs. None of the artificial means of reprogramming cells comes close to the natural process in terms of speed or efficiency. But the egg probably doesn’t quite do everything unaided. At the very least, the pattern of epigenetic modifications in sperm is one that allows the male pronucleus to be reprogrammed relatively easily. The sperm epigenome is primed to be reprogrammed[58].

Unfortunately, these priming chromatin modifications (and many other features of the sperm nucleus), are missing if an adult nucleus is reprogrammed by transferring it into a fertilised egg. That’s also true when an adult nucleus is reprogrammed by treating it with the four Yamanaka factors to create iPS cells. In both these circumstances, it’s a real challenge to completely reset the epigenome of the adult nucleus. It’s just too big a task.

This is probably why so many cloned animals have abnormalities and shortened lifespans. The defects that are seen in these cloned animals are another demonstration that if early epigenetic modifications go wrong, they may stay wrong for life. The abnormal epigenetic modification patterns result in permanently inappropriate gene expression, and long-term ill-health.

All this reprogramming of the genome in normal early development changes the epigenome of the gametes and creates the new epigenome of the zygote. This ensures that the gene expression patterns of eggs and sperm are replaced by the gene expression patterns of the zygote and the subsequent developmental stages. But this reprogramming also has another effect. Cells can accumulate inappropriate or abnormal epigenetic modifications at various genes. These disrupt normal gene expression and can even contribute to disease, as we shall see later in this book. The reprogramming of the egg and the sperm prevent them from passing on from parent to offspring any inappropriate epigenetic modifications they have accumulated. Not so much wiping the slate clean, more like re-installing the operating system.

Making the switch

But this creates a paradox. Azim Surani’s experiments showed that the male and female pro-nuclei aren’t functionally equivalent; we need one of each to create a new mammal. This is known as a parent-of-origin effect, because it essentially shows that there are ways for a zygote and its daughter cells to distinguish between chromosomes from the mother and father. This isn’t a genetic effect, it is an epigenetic one, and so there must be some epigenetic modifications that do get transmitted from one generation to the next.

In 1987 the Surani lab published one of the first papers to give an insight into this mechanism. They hypothesised that parent-of-origin effects could be caused by DNA methylation. At that time, this was really the only chromatin modification that had been identified, so it was an excellent place to start. The researchers created genetically modified mice. These mice contained an extra piece of DNA that could get inserted randomly anywhere in the genome. The DNA sequence of this extra bit wasn’t particularly important to the experimenters. What was important was that they could easily measure how much DNA methylation was present on this sequence, and whether the amount of methylation was transmitted faithfully from parent to offspring.

Azim Surani and his colleagues examined seven lines of mice with this random insertion. In one of the seven lines, something very odd happened. When a mother passed on the inserted DNA, it was always heavily methylated in her offspring. But when a male mouse passed it on to his offspring, the mouse pups always ended up with low methylation of this foreign DNA. Figure 7.3 demonstrates this.