The Epigenetics Revolution

So, although we know that epigenetic modifications change over time, this doesn’t prove that these alterations cause the illnesses and degeneration associated with old age. In theory, the changes could just be random variations with no functional consequences. They could just be changes in the epigenetic background noise in a cell. In many cases, we don’t even yet know whether the altered patterns of epigenetic modifications lead to changes in gene expression. Addressing this question is hugely challenging, and particularly difficult to assess in human populations.

Guilt by more than association

Having said that, there are some epigenetic modifications that are definitely involved in disease initiation or progression. The case for these is strongest in cancer, as we saw in Chapter 11. The evidence includes the epigenetic drugs which can treat certain specific types of cancer. It also includes the substantial amounts of data from experimental systems. These show that altering epigenetic regulation in a cell increases the likelihood of a cell becoming cancerous, or can make an already cancerous cell more aggressive.

One of the areas that we dealt with in Chapter 11 was the increase in DNA methylation that frequently occurs at the promoters of tumour suppressor genes. This increased DNA methylation switches off the expression of the tumour suppressor genes. Oddly enough, this increase in DNA methylation at specific sites is often found against an overall background of decreased DNA methylation in many other areas of the genome in the same cancer cell. This decrease in methylation may be caused by a fall in expression or activity of the maintenance DNA methyltransferase, DNMT1. This decrease in global DNA methylation may also contribute to the development of cancer.

To investigate this, Rudi Jaenisch generated mice which only expressed Dnmt1 protein at about 10 per cent of normal levels in their cells. The levels of DNA methylation in their cells were very low compared with normal mice. In addition to being quite stunted at birth, these Dnmt1 mutant mice developed aggressive tumours of the immune system (T cell lymphomas) when they were between four and eight months of age. This was associated with rearrangements of certain chromosomes, and especially with an extra copy of chromosome 15 in the cancer cells.

Professor Jaenisch speculated that the low levels of DNA methylation made the chromosomes very unstable and prone to breakages. This put the chromosomes at high risk of joining up in inappropriate ways. It’s like snapping a pink stick of rock and a green stick of rock to create four pieces in total. You can join them back together again using melted sugar, to create two full-length items of tooth-rotting confectionery. But if you do this in the dark, you may find that sometimes you have created ‘hybrid’ rock sticks, where one part is pink and the other is green.

The end result of increased chromosome instability in Rudi Jaensich’s mice was abnormal gene expression. This in turn led to too much proliferation of highly invasive and aggressive cells, resulting in cancer[238][239]. These data are one of the reasons why DNMT inhibitors are unlikely to be used as drugs in anything other than cancer. The fear is that the drugs would cause decreased DNA methylation in normal cells, which might pre-dispose some cell types towards cancer.

These data suggest that the DNA methylation level per se is not the critical issue. What matters is where the changes in DNA methylation take place in the genome.

The generalised decrease in DNA methylation levels that comes with age has also been reported in other species than humans and mice, ranging from rats to humpback salmon[240]. It’s not entirely clear why low levels of DNA methylation are associated with instability of the genome. It may be because high levels of DNA methylation can lead to a very compacted DNA structure, which may be more structurally stable. After all, it’s easy to snip through a single extended wire with a pair of cutters, but much harder if that wire has been squashed down into a dense knot of metal.

It’s important to appreciate just how much effort cells put into looking after their chromosomes. If a chromosome breaks, the cell will repair the break if it can. If it can’t, the cell may trigger an auto-destruct mechanism, essentially committing cellular suicide. That’s because damaged chromosomes can be dangerous. It’s better to kill one cell, than for it to survive with damaged genetic material. For instance, imagine one copy of chromosome 9 and one copy of chromosome 22 break in the same cell. They could get repaired properly, but sometimes the repair goes wrong and part of chromosome 9 joins up with part of chromosome 22.