The Epigenetics Revolution

The opposite phenotype to Beckwith-Wiedemann syndrome is a condition called Silver-Russell syndrome[79][80]. Children with this disorder are characterised by retarded growth before and after birth and other symptoms associated with late development[81]. Most cases of this condition are also caused by problems in the same region of chromosome 11 as in Beckwith-Wiedemann syndrome, but in Silver-Russell syndrome IGF2 protein expression is depressed, and the growth of the foetus is dampened down.

The epigenetic imprint

So, imprinting refers to a situation where there is expression of only one member of a pair of genes, and the expression may be either maternal or paternal. What controls which gene is switched on? It probably isn’t surprising to learn that DNA methylation plays a really big role in this. DNA methylation switches genes off. Therefore, if a paternally-inherited region of a chromosome is methylated, the paternally-derived genes in this region will be repressed.

Let’s take the example of the UBE3A gene which we encountered in the discussion of Prader-Willi and Angelman syndromes. Normally, the copy inherited from the father contains methylated DNA and the gene is switched off. The copy inherited from the mother doesn’t have this methylation mark, and the gene is switched on. Something similar happens with Igf2r in mice. The paternal version of this is usually methylated, and the gene is inactive. The maternal version is non-methylated and the gene is expressed.

While a role for DNA methylation may not have come as a shock, it may be surprising to learn that it is often not the gene body that is methylated. The part of the gene that codes for protein is epigenetically broadly the same when we compare the maternal and paternal copies of the chromosome. It’s the region of the chromosome that controls the expression of the gene that is differently methylated between the two genomes.

Imagine a night-time summer party in a friend’s garden, beautifully lit by candles scattered between the plants. Unfortunately, this lovely ambience is constantly ruined because the movement of the guests keeps triggering a motion detector on a security system and turning on a floodlight. The floodlight is too high on the wall to be able to cover it, but finally it dawns on the guests that they don’t need to cover the light. They need to cover the sensor that is triggering the light’s activity. This is very much what happens in imprinting.

The methylation, or lack of it, is on regions known as imprinting control regions (ICRs). In some cases, imprinting control is very straightforward to understand. The promoter region of a gene is methylated on the gene inherited from one parent, and not on the one from the other. This methylation keeps a gene switched off. This works when there is a single gene in a chromosome region that is imprinted. But many imprinted genes are arranged in clusters, all very close to one another in a single stretch on one chromosome. Some of the genes in the cluster will be expressed from the maternally-derived chromosome, others from the paternally-derived one. DNA methylation is still the key feature, but other factors help it to carry out its function.

The imprinting control region may operate over long distances, and certain stretches may bind large proteins. These proteins act like roadblocks in a city, insulating different stretches on a chromosome from one another. This gives the imprinting process an additional level of sophistication, by inserting diversions between different genes. Because of this, an imprinting control region may operate over many thousands of base-pairs, but it doesn’t mean that every single gene in those thousands of base-pairs is affected the same way. Different genes in a particular imprinted stretch of chromatin may loop out from their chromosome to form physical associations with each other, so that repressed genes huddle together in a sort of chromatin knot. Activated genes from the same stretch of chromosome may cling together in a different bundle[82].