The Epigenetics Revolution

There’s a speculative but fascinating case study from Iceland on how diet may epigenetically influence a disease. It concerns a rare genetic disease called hereditary cystatin C amyloid angiopathy, which causes premature death through strokes. In the Icelandic families in which some people suffer from the disease, the patients carry a particular mutation in the key gene. Because of the relatively isolated nature of Icelandic societies, and the country’s excellent record keeping, researchers were able to trace this disease back through the affected families. What they found was quite remarkable. Until about 1820, people with this mutation lived until around the age of 60 before they succumbed to the disease. Between 1820 and 1900, the life expectancy for those with the same disorder dropped to about 30 years of age, which is where it has remained. The scientists speculated in their original paper that an environmental change in the period from 1820 onwards altered the way that cells respond to and control the effects of the mutation[301].

At a conference in Cambridge in 2010, the same authors reported that one of the major environmental changes in Iceland from 1820 to the present day was a shift from a traditional diet to more mainstream European fare[302]. The traditional Icelandic diet contained exceptionally high quantities of dried fish and fermented butter. The latter is very high in butyric acid, the weak histone deacetylase inhibitor. Histone deacetylase inhibitors can alter the function of muscle fibres in blood vessels[303], which is relevant to the type of stroke that patients with this mutation suffer. There is no formal proof yet that it’s the drop in consumption of dietary histone deacetylase inhibitors that has led to the earlier deaths in this patient group, but it’s a fascinating hypothesis.

The fundamental science of epigenetics is the area that is most difficult to make predictions about. One fairly safe bet is that epigenetic mechanisms will continue to crop up in unexpected parts of science. A good recent example of this is in the field of circadian rhythms, the natural 24-hour cycle of physiology and biochemistry found in most living species. A histone acetyltransferase has been shown to be the key protein involved in setting this rhythm[304], and the rhythm is adjusted by at least one other epigenetic enzyme[305].

We are also likely to find that some epigenetic enzymes influence cells in many different ways. That’s because quite a few of these enzymes don’t just modify chromatin. They can also modify other proteins in the cell, so may act on lots of different pathways at once. In fact, it has been proposed that some of the histone modifying genes actually evolved before cells contained histones[306]. This would suggest that these enzymes originally had other functions, and have been press-ganged by evolution into becoming controllers of gene expression. It wouldn’t therefore be surprising to find that some of the enzymes have dual functions in our cells.

Some of the most fundamental issues around the molecular machinery of epigenetics remain very mysterious. Our knowledge of how specific modifications are established at selected positions in the genome is really sketchy. We are starting to see a role for non-coding RNAs in this process, but there are still multiple gaps in our understanding. Similarly we have almost no idea of how histone modifications are transmitted from mother cell to daughter cell. We’re pretty sure this happens, as it is part of the molecular memory of cells that allows them to maintain cell fate, but we don’t know how. When DNA is replicated, the histone proteins get pushed to one side. The new copy of the DNA may end up with relatively few of the modified histones. Instead, it may be coated with virgin histones with hardly any modifications. This is corrected very quickly, but we have almost no understanding of how this happens, even though it is one of the most fundamental issues in the whole field of epigenetics.

It’s possible that we won’t be able to solve this mystery until we have the technology and imagination to stop thinking in two dimensions and move to a three-dimensional world. We have become very used to thinking of the genome in linear terms, as strings of bases that are just read in a straightforward fashion. Yet the reality is that different regions of the genome bend and fold, reaching out to each other to create new combinations and regulatory sub-groups. We think of our genetic material as a normal script, but it’s more like the fold-in from the back of Mad magazine, where folding an image in a particular way created a new picture. Understanding this process may be critical for truly unravelling how epigenetic modifications and gene combinations work together to create the miracle of the worm or the oak or the crocodile.

Or us.