The Epigenetics Revolution

The impact of imprinting varies from tissue to tissue. The placenta is particularly rich in expression of imprinted genes. This is what we would expect from our model of imprinting as a means of balancing out the demand on maternal resources. The brain also appears to be very susceptible to imprinting effects. It’s not so clear why this should be the case. It’s harder to reconcile parent-of-origin control of gene expression in the brain with the battle for nutrients we’ve been considering so far. Professor Gudrun Moore of University College London has made an intriguing suggestion. She has proposed that the high levels of imprinting in the brain represent a post-natal continuation of the war of the sexes. She has speculated that some brain imprints are an attempt by the paternal genome to promote behaviour in young offspring that will stimulate the mother to continue to drain her own resources, for example by prolonged breast-feeding[83].

The number of imprinted genes is quite low, rather less than 1 per cent of all protein-coding genes. Even this small percentage won’t be imprinted in all tissues. In many cells the expression from the maternally and paternally-derived copies will be the same. This is not because the methylation pattern is different between the tissues but because cells vary in the ways that they ‘read’ this methylation.

The DNA methylation patterns on the imprinting control regions are present in all the cells of the body, and show which parent transmitted which copy of a chromosome. This tells us something very revealing about imprinted regions. They must evade the reprogramming that takes place after the sperm and egg fuse to form the zygote. Otherwise, the methylation modifications would be stripped off and there would be no way for the cell to work out which parent had donated which chromosome. Just as the IAP retrotransposons stay methylated during zygotic reprogramming, mechanisms have evolved to protect imprinted regions from this broad-brush removal of methylation. It’s not really very clear how this happens, but it’s essential for normal development and health.

You put your imprint on, you take your imprint off …

Yet this presents us with a bit of a problem. If imprinted DNA methylation marks are so stable, how do they change as they are transmitted from parent to offspring? We know that they do, because of Azim Surani’s experiments with mice that we encountered in the previous chapter. These showed how methylation of a sequence monitored for experimental purposes changed as it was passed down the generations. This was the experiment that was described using the mice with ‘black’ and ‘white’ DNA in the previous chapter.

In fact, once scientists recognised that parent-of-origin effects exist, they predicted that there must be a way to reset the epigenetic marks, even before they knew what these marks were. Let’s consider chromosome 15, for example. I inherited one copy from my mother and one from my father. The UBE3A imprinting control region from my mother was unmethylated, whereas the same region on the chromosome from my father was methylated. This ensured appropriate expression patterns of UBE3A protein in my brain.

When my ovaries produce eggs, each egg inherits just one copy of chromosome 15, which I will pass on to a child. Because I’m a woman, each copy of chromosome 15 must carry a maternal mark on UBE3A. But one of my copies of chromosome 15 has been carrying the paternally-derived mark I inherited from my father. The only way I can make sure that I pass on chromosome 15 with the correct maternal mark to my children is if my cells have a way of removing the paternal mark and replacing it with a maternal one.

A very similar process would have to take place when males produce sperm. All maternally-derived modifications would need to be stripped off the imprinted genes, and paternally derived ones put on in their place. This is indeed exactly what happens. It’s a very restricted process which only takes place in the cells that give rise to the germ line.

The general principle is shown diagrammatically in Figure 8.3.