The Epigenetics Revolution

Following fusion of the egg and sperm the blastocyst forms, and most regions of the genome become reprogrammed. The cells begin to differentiate, forming the precursors to the placenta and also the various cell types of the body. So, at this point the cells that had been part of the ICM are all marching to the developmental drumbeat, heading down the various troughs in Waddington’s epigenetic landscape. But a very small number (less than 100) begin to march to a different beat. In these cells a gene called Blimp1 switches on. Blimp1 protein sets up a new cascade in signalling, which stops the cells heading towards their somatic dead-ends. These cells start travelling back up Waddington’s trenches[84]. They also lose the imprinted marks which told the cell which parent donated which of a pair of chromosomes.

^{Figure 8.3 Diagram showing how the somatic cells arising from a fertilised zygote all carry the same DNA methylation patterns as each other at imprinted genes, but the imprinting methylation is removed and then re-established in the germ cells. This ensures that females only pass on maternal marks to their offspring, and males only pass on paternal ones.}

The tiny population of cells that carry out this process are know as the primordial germ cells. It’s these cells that will ultimately settle in the developing gonads (testicles or ovaries) and act as the stem cells that produce all the gametes (sperm or eggs respectively). In the stage described in the previous paragraph, the primordial germ cells are reverting to a state more like that of the cells of the inner cell mass (ICM). Essentially, they are becoming pluripotent, and potentially able to code for most of the tissue types in the body. This phase is fleeting. The primordial germ cells quickly get diverted into a new developmental pathway where they differentiate to form stem cells that will give rise to eggs or sperm. To do so, they gain a new set of epigenetic modifications. Some of these modifications are ones that define cellular identity, i.e. switch on the genes that make an egg an egg. But a small number are the ones that serve as parent-of-origin marks, so that in the next generation the imprinted regions of the genome can be recognised with respect to their parent-of-origin.

This seems horribly complicated. If we follow the path from the sperm that fertilised the egg to a new sperm being formed in male offspring, the sequence goes like this:

The sperm that enters the egg has epigenetic modifications on it;

The epigenetic modifications get taken off, except at the imprinted regions (in the immediate post-fertilisation zygote);

Epigenetic modifications get put on (as the cells of the ICM begin to specialise);

The epigenetic modifications get taken off, including at the imprinted regions (as the primordial germ cells break away from the somatic differentiation pathway);

Epigenetic modifications get put on (as the sperm develops).

This could seem like an unnecessarily complicated way to get back to where we started from, but it’s essential.

The modifications that make a sperm a sperm, or an egg an egg, have to come off at stage 2 or the zygote wouldn’t be totipotent. Instead it would have a genome that was half-programmed to be an egg and half-programmed to be a sperm. Development wouldn’t be possible if the inherited modifications stayed on. But to create primordial germ cells, some of the cells from the differentiating ICM have to lose their epigenetic modifications. This is so they can become temporarily more pluripotent, lose their imprinting marks and transfer across into the germ cell lineage.

Once the primordial germ cells have been diverted, epigenetic modifications again get attached to the genome. This is partly because pluripotent cells are potentially extremely dangerous as a multi-cellular organism develops. It might seem like a great idea to have cells in our body that can divide repeatedly and give rise to lots of other cell types, but it’s not. Those sorts of cells are the type that we find in cancer. Evolution has favoured a mechanism where the primordial germ cells can regain pluripotency for a period, but then this pluripotency is re-suppressed by epigenetic modifications. Coupled with this, the wiping out of the imprints means that chromosomes can be marked afresh with their parent-of-origin.