The Epigenetics Revolution

This rearrangement of chromosomes 9 and 22 actually happens relatively frequently in cells of the immune system. In fact it happens so often that this 9:22 hybrid has a specific name. It’s called the Philadelphia chromosome, after the city where it was first described. Ninety-five per cent of people who have a form of cancer called chronic myeloid leukaemia have the Philadelphia chromosome in their cancer cells. This abnormal chromosome causes this cancer in the cells of the immune system because of where the breaking and rejoining happen in the genome. The fusion of the two chromosome regions results in the creation of a hybrid gene called Bcr-Abl. The protein encoded by this hybrid gene drives cell proliferation forwards very aggressively.

Our cells have therefore developed very sophisticated and fast-acting pathways to repair chromosome breaks as rapidly as possible, in order to prevent these sorts of fusions. To do this, our cells must be able to recognise loose ends of DNA. These are created when a chromosome breaks in two.

But there’s a problem. Every chromosome in our cell quite naturally has two loose ends of DNA, one at each end. Something must stop the DNA repair machinery from thinking these ends need to be repaired. That something is a specialised structure called the telomere. There is a telomere at each end of every chromosome, making a total of 92 telomeres per cell in humans. They stop the DNA repair machinery from targeting the ends of chromosomes.

The tail ends

Telomeres play a critical role in control of ageing. The more a cell divides, the smaller its telomeres become. Essentially, as we age, the telomeres get shorter. Eventually, they get so small that they don’t function properly anymore. The cells stop dividing and may even activate their self-destruct mechanisms. The only cells where this is different are the germ cells that ultimately give rise to eggs or sperm. In these cells the telomeres always stay long, so the next generation isn’t short-changed when it comes to longevity. In 2009, the Nobel Prize in Physiology or Medicine was awarded to Elizabeth Blackburn, Carol Greider and Jack Szostak for their work showing how telomeres function.

Since telomeres are so important in ageing, it makes sense to consider how they interact with the epigenetic system. The DNA of vertebrate telomeres consists of hundreds of repeats of the sequence TTAGGG. There are no genes at the telomere. We can also see from the sequence that there are no CpG motifs at the telomeres, so there can’t be any DNA methylation. If there are any epigenetic effects that make a difference at the telomeres they will therefore have to be based on histone modifications.

In between the telomeres and the main parts of the chromosome are stretches of DNA referred to as sub-telomeric regions. These contain lots of runs of repetitive DNA. These repeats are less restricted in sequence than the telomeres. The sub-telomeric regions contain a low frequency of genes. They contain some CpG motifs so these regions can be modified by DNA methylation, in addition to histone modifications.

The types of epigenetic modifications normally found at telomeres and the sub-telomeric regions are the ones that are highly repressive. Because there are so few genes in these regions anyway, these modifications probably aren’t used to switch off individual genes. Instead, these repressive epigenetic modifications are probably involved in ‘squashing down’ the ends of the chromosomes. The epigenetic modifications attract proteins that coat the ends of the chromosomes, and help them to stay as tightly coiled up, and as dense and inaccessible as possible. It’s a little like covering the ends of a pipe in insulation.

It’s potentially a problem for a cell that all its telomeres have the same DNA sequence, because identical sequences in a nucleus tend to find and bind to one another. Such close proximity creates a big risk that the ends of different chromosomes will link up, especially if they get damaged and opened up. This can lead to all sorts of errors as the cell struggles to sort out chains of chromosomes, and may result in ‘mixed-up’ chromosomes similar to the one that causes chronic myeloid leukaemia. By coating the telomeres with repressive modifications that make the ends of the chromosomes really densely packed, there’s less chance that different chromosomes will join up inappropriately.

The cell is, however, stuck with a dilemma, as shown in Figure 13.1.

^{Figure 13.1 Both abnormal shortening and lengthening of telomeres have potentially deleterious consequences for cells.}