Sunday, 9 September 2012

The Epigenetics Revolution: Nutrition

Some further extracts from Nessa Carey's excellent The Epigenetics Revolution

The Agouti mouse is no stranger to those who have spent any time in the paleosphere.  Epigeneticists have used these mice to uncover some pretty intriguing phenomena:
  • [Emman Whitelaw changed the expression of epigenetic proteins]. No matter how tightly scientists control the environment for the [agouti] mice and especially their access to food, identical mice from inbred mouse strains don't all have exactly the same body weight. Experiments carried out over many years have shown that only about 20-30 per cent of the variations in body weights can be attibuted to the post natal environment. This leaves the question of what causes the other 70-80 per cent of variation in body weight. Since it isn't being caused by genetics (all the mice are identical) or by the environment, there has to be another source for the variation.
We need to be careful extrapolating too much from mice to humans (especially given the recent research looking at CR and longevity), but this is interesting stuff:
  • These experiments suggested that certain epigenetic proteins act as a kind of dampening field. 'Naked' DNA is rather prone to being switched on somewhat randomly, and the overall effect is like having a lot of background chatter in our cells. This is called transcriptional noise. The epigenetic proteins act to turn down the volume of this random chat. They do this by covering the histones with modifications that reduce the genes' expression. It's likely that different epigenetic prteins are important for supressing different genes in some tissues rather than in others.

    It's clear that this suppression isn't total. If it were, then all inbred mice would be identical in every aspect of their phenotype and we know this isn't the case. There is variation in body weight even in the inbred [identical] strains, it's just that there's even more variation in the mice with the depressed levels of the epigenetic proteins.

    The sophisticated balancing act, in which epigenetic proteins dampen down transcriptional noise but don't entirely repress gene expression, is a cellular compromise. It leaves cells with enough flexibility of gene expression to be able to respond to new signals - be these hormones or nutrients, pollutants or sunlight - but without the genes being constantly ready to fire up just for the heck of it. Epigenetics allows cells to perform the difficult compromise between becoming (and remaining) different cell types with a variety of functions, and not being so locked into a single pattern of gene expression that they become incapable of responding to changes in their environment.
It is this flexibility, a kind of Lamarkism (if I understand it correctly), that is crucial to understanding epigenetics.  Darwin was right about natural selection, but there is subtlety here.  A subtlety that is influenced by your experiences (particularly during developmental phases), and also those of your forefathers.   One last section that I will quote from Carey regards nutrition,  
  • Nutrition in general is one area where we can predict epigenetics will come to the fore in the next ten years. Here are just a few examples of what we know at the moment.Folic acid is one of the supplements recommended for pregnant women. Increasing the supply of folic acid in the very early stages of pregnancy has been a public health triumph, as it has led to a mahor drop in the incidence of spina bifida in new borns. Folic acid is required for the production of a chemical called SAM (S-adenosyl methionine). SAM is the molecule that donates the methyl group when DNA methyltransferases modify DNA. If baby rats are fed a diet that is low in folic acid, they develop abnormal regulation of imprinted regions of the genome. We are only just beginning to unravel how many of the beneficial effects of folic acid may be mediated through epigenetic mechanisms.Histone deacetylase inhibitors in our diets may also play useful roles in preventing cancer and possibly other disorders. The data are relatively speculative at the moment. Sodium butyrate in cheese, sulphoraphane in broccoli and diallyl disulphide in garlic are all weak inhibitors of histone deacetylases. Researchers have hypothesised that the release of these compounds from food during digestion may help to modulate gene expression and cell proliferation in the gut. In theory, this could lower the risk of developing cancerous changes in the colon. The bacteria in our intestines also naturally produce butyrate from the breakdown of foodstuffs, especially plant-derived materials, which is another good reason to eat our greens.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.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 mainstrean European fare. 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, 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 the consumption of dietary histone deacetylase inhibitors that has led to the earlier deaths in this patient group, but it's a fascinating hypothesis.
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