The Epigenetics Revolution

Imagine a chromosome as the trunk of a very big Christmas tree. The branches sticking out all over the tree are the histone tails and these can be decorated with epigenetic modifications. We pick up the purple baubles and we put one, two or three purple baubles on some of the branches. We also have green icicle decorations and we can put either one or two of these on some branches, some of which already have purple baubles on them. Then we pick up the red stars but are told we can’t put these on a branch if the adjacent branch has any purple baubles. The gold snowflakes and green icicles can’t be present on the same branch. And so it goes on, with increasingly complex rules and patterns. Eventually, we’ve used all our decorations and we wind the lights around the tree. The bulbs represent individual genes. By a magical piece of software programming, the brightness of each bulb is determined by the precise conformation of the decorations surrounding it. The likelihood is that we would really struggle to predict the brightness of most of the bulbs because the pattern of Christmas decorations is so complicated.

That’s where scientists currently are in terms of predicting how all the various histone modification combinations work together to influence gene expression. It’s reasonably clear in many cases what individual modifications can do, but it’s not yet possible to make accurate predictions from complex combinations.

There are major efforts being made to learn how to understand this code, with multiple labs throughout the world collaborating or competing in the use of the fastest and most complex technologies to address this problem. The reason for this is that although we may not be able to read the code properly yet, we know enough about it to understand that it’s extremely important.

Build a better mousetrap

Some of the key evidence comes from developmental biology, the field from which so many great epigenetic investigators have emerged. As we have already described, the single-celled zygote divides, and very quickly daughter cells start to take on discrete functions. The first noticeable event is that the cells of the early embryo split into the inner cell mass (ICM) and the trophoectoderm. The ICM cells in particular start to differentiate to form an increasing number of different cell types. This rolling of the cells down the epigenetic landscape is, to quite a large degree, a self-perpetuating system.

The key concept to grasp at this stage is the way that waves of gene expression and epigenetic modifications follow on from each other. A useful analogy for this is the game of Mousetrap, first produced in the early 1960s and still on sale today. Players have to build an insanely complex mouse trap during the course of the game. The trap is activated at one end by the simple act of releasing a ball. This ball passes down and through all sorts of contraptions including a slide, a kicking boot, a flight of steps and a man jumping off a diving board. As long as the pieces have been put together properly, the whole ridiculous cascade operates perfectly, and the toy mice get caught under a net. If one of the pieces is just slightly mis-aligned, the crazy sequence judders to a halt and the trap doesn’t work.

The developing embryo is like Mousetrap. The zygote is pre-loaded with certain proteins, mainly from the egg cytoplasm. These egg-derived proteins move into the nucleus and bind to target genes, which we’ll call Boots (in honour of Mousetrap), and regulate their expression. They also attract a select few epigenetic enzymes to the Boots genes. These epigenetic enzymes may also have been ‘donated’ from the egg cytoplasm and they set up longer-lasting modifications to the DNA and histone proteins of chromatin, also influencing how these Boots genes are switched on or off. The Boots proteins bind to the Divers genes, and switch these on. Some of these Divers genes may themselves encode epigenetic enzymes, which will form complexes on members of the Slides family of genes, and so on. The genetic and epigenetic proteins work together in a seamless orderly procession, just like the events in Mousetrap once the ball has been released. Sometimes a cell will express a little more or a little less of a key factor, one whose expression is on a finely balanced threshold. This has the potential to alter the developmental path that the cell takes, as if twenty Mousetrap games had been connected up. Slight deviations in how the pieces were fitted together, or how the ball rolled at critical moments, would trigger one trap and not another.