The Epigenetics Revolution

Yeast have a specific feature that has made them one of the favourite model systems of epigeneticists. Yeast never methylate their DNA, so all epigenetic effects must be caused by histone modifications. There’s also another helpful feature of yeast. Each time a yeast mother cell gives rise to a daughter cell, the bud leaves a scar on the mother. This makes it really easy to work out how many times a cell has divided. There are two types of ageing in yeast and these each have parallels to human ageing, as shown in Figure 13.2.

^{Figure 13.2 The two models of ageing in yeast, relevant for dividing and non-dividing cells.}

Most of the emphasis in ageing research has been on replicative ageing, and trying to understand why cells lose their ability to divide. Replicative ageing in mammals is clearly related to some obvious symptoms of getting older. For example, skeletal muscle contains specialised stem cells called satellite cells. These can only divide a certain number of times. Once they are exhausted, you can’t create new muscle fibres.

Substantial progress has been made in understanding replicative ageing in yeast. One of the key enzymes in controlling this process is called Sir2 and it’s an epigenetic protein. It affects replicative ageing in yeast through two pathways. One seems to be specific to yeast, but the other is found in numerous species right through the evolutionary tree, all the way up to humans.

Sir2 is a histone deacetylase. Mutant yeast that over-express Sir2 have a replicative lifespan that is at least 30 per cent longer than normal[241]. Conversely, yeast that don’t express Sir2 have a reduced lifespan[242], about 50 per cent shorter than usual. In 2009, Professor Shelley Berger, an incredibly dynamic scientist at the University of Pennsylvania whose group has been very influential in molecular epigenetics, published the results of a really elegant set of genetic and molecular experiments in yeast.

Her research showed that the Sir2 protein influences ageing by taking acetyl groups off histone proteins, and not through any other roles this enzyme might carry out[243]. This was a key experiment, because Sir2, like many histone deacetylases, has rather loose molecular morals. It doesn’t just remove acetyl groups from histone proteins. Sir2 will take acetyl groups away from at least 60 other proteins in the cell. Many of these proteins have nothing to do with chromatin or with gene expression. Shelley Berger’s work was crucial for demonstrating that Sir2 influences ageing precisely because of its effects on histone proteins. The altered epigenetic pattern on the histones in turn influenced gene expression.

These data, showing that epigenetic modifications of histones really do have a major influence on ageing, gave scientists in this field a big confidence boost that they were on the right track. The importance of Sir2 doesn’t seem to be restricted to yeast. If we over-express Sir2 in our favourite worm, C. elegans[244], the worm lives longer. Fruit flies that over-expressed Sir2 had up to a 57 per cent increase in lifespan[245]. So, could this gene also be important in human ageing?

There are seven versions of the Sir2 gene in mammals, called SIRT1 through to SIRT7. Much of the attention in the human field has focused on SIRT6, an unusual histone deacetylase. The breakthroughs in this field have come from the laboratory of Katrin Chua, a young Assistant Professor at the Stanford Center on Longevity (and also the sister of Amy Chua who wrote the highly controversial mothering memoir Battle Hymn of the Tiger Mother).

Katrin Chua created mice which never expressed any Sirt6 protein, even during their development (they are known as Sirt6 knockout mice). These animals seemed normal at birth, although they were rather small. But from two weeks of age onwards they developed a whole range of conditions that mimicked the ageing process. These included loss of fat under the skin, spinal curvature, and metabolism deficits. The mice died by one month of age, whereas a normal mouse can live for up to two years under laboratory conditions.