The Epigenetics Revolution

We know that not all transgenerational inheritance happens in the same way. In the agouti mouse the phenotype is transmitted via the mother, but not via the father. In this case, the DNA methylation on the IAP retrotransposon is removed in both males and females during normal primordial germ cell reprogramming. However, mothers whose retrotransposon originally carried DNA methylation pass on a specific histone mark to their offspring. This is a repressive histone modification and it acts as a signal to the DNA methylation machinery. This signal attracts the enzymes that put the repressive DNA methylation onto a specific region on a chromosome. The final outcome is the same – the DNA methylation in the mother is restored in the offspring. Male agouti mice don’t pass on either DNA methylation or repressive histone modifications on their retrotransposon, which is why transmission of the phenotype only occurs through the maternal line[91].

This is a slightly more indirect method of transmitting epigenetic information. Instead of direct carry-over of DNA methylation, an intermediate surrogate (a repressive histone modification) is used instead. This is probably why the maternal transmission of the agouti phenotype is a bit ‘fuzzy’. Not all offspring are exactly the same as the mother, because there is a bit of ‘wriggle-room’ in how DNA methylation gets re-established in the offspring.

In the summer of 2010, there were reports in the British press about cloned farm animals. Meat that had come from the offspring of a cloned cow had entered the human food chain[92]. Not the cloned cow itself, just its offspring, created by conventional animal breeding. Although there were a few alarmist stories about people unwittingly eating ‘Frankenfoods’, the coverage in the mainstream media was pretty balanced.

To some extent, this was probably because of a quite intriguing phenomenon, which has allayed certain fears originally held by scientists about the consequences of cloning. When cloned animals breed, the offspring tend to be healthier than the original clones. This is almost certainly because of primordial germ cell reprogramming. The initial clone was formed by transfer of a somatic nucleus into an egg. This nucleus only went through the first round of reprogramming, the one that normally happens when a sperm fertilises an egg. The likelihood is that this epigenetic reprogramming wasn’t entirely effective – it’s a big ask to get an egg to reprogram a ‘wrong’ nucleus. This is likely to be the reason why clones tend to be unhealthy.

When the cloned animals breed, they pass on either an egg or a sperm. Before the clone produced these gametes, its primordial cells underwent the second round of reprogramming, as part of the normal primordial germ cell pathway. This second reprogramming stage seems to reset the epigenome properly. The gametes lose the abnormal epigenetic modifications of their cloned parent. Epigenetics explains why cloned animals have health issues, but also explains why their offspring don’t. In fact, the offspring are essentially indistinguishable from animals produced naturally.

Assisted reproductive technologies in humans (such as in vitro fertilisation) share certain technical aspects with some of the methods used in cloning. In particular, pluripotent nuclei may be transferred between cells, and cells are cultured in the laboratory before being implanted in the uterus. There is a substantial amount of controversy in the scientific journals about the abnormality rates from these procedures[93]. Some authors claim there is an increased rate of imprinting disorders in pregnancies from assisted reproductive technologies. This would imply that procedures such as culturing fertilised eggs outside the body may disrupt the delicately poised pathways that control reprogramming, especially of imprinted regions. It’s important to note, however, that there is no consensus yet on whether this really is a clinically relevant issue.

All the reprogramming of the genome in early development has multiple effects. It allows two highly differentiated cell types to fuse and form one pluripotent cell. It balances out the competing demands of the maternal and paternal genomes, and ensures that this balancing act can be re-established in every generation. Reprogramming also prevents inappropriate epigenetic modifications being passed from parent to offspring. This means that even if cells have accumulated potentially dangerous epigenetic changes, these will be removed before they are passed on.