How diet can change your epigenome and affect cancer and chromatin of DNA

Food that shapes you: how diet can change your epigenome

You are what you eat – quite literally. Our diet can influence the tiny changes in our genome that underlie several diseases, including cancer and obesity.

DNA helix
Image courtesy of mstroeck /
Wikimedia Commons

When you look at yourself in the mirror you may ask, ‘How, given that all the cells in my body carry the same DNA, can my organs look so unlike and function so differently?’ With the recent progress in epigenetics, we are beginning to understand. We now know that cells use their genetic material in different ways: genes are switched on and off, resulting in the astonishing level of differentiation within our bodies.

Epigenetics describes the cellular processes that determine whether a certain gene will be transcribed and translated into its corresponding protein. The message can be conveyed through small and reversible chemical modifications to chromatin (figure 1). For example, the addition of acetyl groups (acetylation) to DNA scaffold proteins (histones) enhances transcription. In contrast, the addition of methyl groups (methylation) to some regulatory regions of the DNA itself reduces gene transcription. These modifications, together with other regulatory mechanisms, are particularly important during development – when the exact timing of gene activation is crucial to ensure accurate cellular differentiation – but continue to have an effect into adulthood.

Epigenetic modifications can occur in response to environmental stimuli, one of the most important of which is diet. The mechanisms by which diet affects epigenetics are not fully understood, but some clear examples are well known.

Figure 1: Epigenetic changes
to the chromatin structure
involve mainly histone
acetylation – which enhances
transcription – and DNA
methylation, whereby methyl
groups are covalently bound
to cytosine, making the
chromatin structure less
accessible. These changes are
reversible, allowing gene
activity to be adapted to
changing environmental
conditions or signals.
This image was updated on the
13 May 2014.

Image courtesy of Cristina Florean

During the winter of 1944–1945, the Netherlands suffered a terrible famine as a result of the German occupation, and the population’s nutritional intake dropped to fewer than 1000 calories per day. Women continued to conceive and give birth during these hard times, and these children are now adults in their sixties. Recent studies have revealed that these individuals – exposed to calorie restrictions while in their mother’s uterus – have a higher rate of chronic conditions such as diabetes, cardiovascular disease and obesity than their siblings. The first months of pregnancy seem to have had the greatest effect on disease risk.

How can something that happened before you were even born influence your life as much as 60 years later? The answer appears to lie in the epigenetic adaptations made by the foetus in response to the limited supply of nutrients. The exact epigenetic alterations are still not clear, but it was discovered that people who were exposed to famine in utero have a lower degree of methylation of a gene implicated in insulin metabolism (the insulin-like growth factor II gene) than their unexposed siblings (Heijmans et al., 2008). This has some startling implications: although epigenetic changes are in theory reversible, useful changes that take place during embryonic development can nonetheless persist in adult life, even when they are no longer useful and could even be detrimental. Some of these changes may even persist through generations, affecting the grandchildren of the exposed women (Painter et al., 2008).

Figure 2: Two queen
honeybee larvae floating in
royal jelly in their queen cell.
Queen larvae are fed
exclusively with royal jelly,
which triggers the
development of the queen
phenotype, allowing
reproduction 

Image courtesy of Waugsberg /
Wikimedia Commons

The effects of early diet on epigenetics are also clearly visible among honeybees. What differentiates the sterile worker bees from the fertile queen is not genetics, but the diet that they follow as larvae (figure 2). Larvae designated to become queens are fed exclusively with royal jelly, a substance secreted by worker bees, which switches on the gene programme that results in the bee becoming fertile.

Another striking example of how nutrition influences epigenetics during development is found in mice. Individuals with an active agouti gene have a yellow coat and a propensity to become obese. This gene, however, can be switched off by DNA methylation. If a pregnant agouti mouse receives dietary supplements that can release methyl groups – such as folic acid or choline – the pups’ agouti genes become methylated and thus inactive. These pups still carry the agouti gene but they lose the agouti phenotype: they have brown fur and no increased tendency towards obesity (figure 3).

Figure 3: The agouti mouse
model. The phenotype
depends on the mother’s diet
during pregnancy. A:
Normally, the agouti gene is
associated with yellow fur
and a tendency towards
obesity. B: Mice born to a
mother receiving dietary
supplements of methyl
donors, however, have a
methylated and thus
inactivated agouti gene,
resulting in a thin, brown-
fur phenotype.

Image courtesy of Cristina
Florean

An insufficient uptake of folic acid is also implicated in developmental conditions in humans, such as spina bifida and other neural tube defects. To prevent such problems, folic acid supplements are widely recommended for pregnant women and for those hoping to conceive (see Hayes et al., 2009).

What about the dietary effect on epigenetics in adult life? Many components of food have the potential to cause epigenetic changes in humans. For example, broccoli and other cruciferous vegetables contain isothiocyanates, which are able to increase histone acetylation. Soya, on the other hand, is a source of the isoflavone genistein, which is thought to decrease DNA methylation in certain genes. Found in green tea, the polyphenol compound epigallocatechin-3-gallate has many biological activities, including the inhibition of DNA methylation. Curcumin, a compound found in turmeric (Curcuma longa), can have multiple effects on gene activation, because it inhibits DNA methylation but also modulates histone acetylation. Figure 4 shows further examples of epigenetically active molecules.

Fruit market in Spain
Image courtesy of Marcel
Theisen / Wikimedia Commons

Most of the data collected so far about these compounds come from in vitro experiments. The purified molecules were tested on cellular lines, and their effects on epigenetic targets were measured. It remains to be proved if eating the corresponding foods has the same detectable effect as has been seen in cellular models (Gerhauser, 2013).

Epidemiological studies, however, suggest that populations that consume large amounts of some of these foods appear to be less prone to certain diseases (Siddiqui et al., 2007). However, most of these compounds not only have epigenetic effects but also affect other biological functions. A food may contain many different biologically active molecules, making it difficult to draw a direct correlation between epigenetic activity and the overall effect on the body. Finally, all foods undergo many transformations in our digestive system, so it is not clear how much of the active compounds actually reach their molecular targets.

As a result of their far-reaching effects, epigenetic changes are involved in the development of many illnesses, including some cancers and neurological diseases. As cells become malignant, or cancerous, epigenetic modifications can deactivate tumour suppressor genes, which prevent excessive cell proliferation (Esteller, 2007). Because these epigenetic modifications are reversible, there is great interest in finding molecules – especially dietary sources – that might undo these damaging changes and prevent the development of the tumour.

We all know that a diet rich in fruit and vegetables is healthy for our everyday life, but it is becoming increasingly clear that it might be much more important than that, having significant implications for our long-term health and life expectancy.

References

Resources

Connie’s Comments:

  • Eat colored fruits and Veggies.
  • For quality supplementation that resets your gene expression to a younger you:
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Stevens–Johnson syndrome and supplementation after healing

Stevens–Johnson syndrome (SJS) is a type of severe skin reaction. Together with toxic epidermal necrolysis(TEN) it forms a spectrum of disease, with SJS being less severe. Early symptoms include fever and flu-like symptoms. A few days later the skin begins to blister and peel forming painful raw areas. Mucous membranes, such as the mouth, are also typically involved. Complications include dehydrationsepsispneumonia, and multiple organ failure.[2]

The most common cause is certain medications such as lamotriginecarbamazepineallopurinolsulfonamide antibiotics, and nevirapine.[2] Other causes can include infections such as Mycoplasma pneumoniae and cytomegalovirus or the cause may remain unknown.[1][2] Risk factors include HIV/AIDS and systemic lupus erythematosus. The diagnosis is based on involvement of less than 10% of the skin.[1] It is known as TEN when more than 30% of the skin is involved and an intermediate form with 10 to 30% involvement.[3] Erythema multiforme (EM) is generally considered a separate condition.[4]

Treatment typically takes place in hospital such as in a burn unit or intensive care unit. Efforts may include stopping the cause, pain medicationantihistaminesantibioticsintravenous immunoglobulins, or corticosteroids.[1] Together with TEN it affects 1 to 2 people per million per year.[2] It is twice as common in males as females. Typical onset is under the age of 30. Skin usually regrows over two to three weeks; however, complete recovery can take months.


Connie’s comments:

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Weak control of inflammation by genes, linked to Alzheimer’s development

A team of researchers from the University of Cambridge has studied data from healthy human brain tissue, revealing a signature of proteins in specific areas of the brain that could dictate vulnerability to damage in Alzheimer’s. The findings help to explain the characteristic spread of damage across the brain that is observed in the disease and the findings could help to inform future drug discovery efforts. The results are published on 10 August in the journal Science Advances.

Alzheimer’s disease is characterised by the abnormal build-up of two proteins in the brain called amyloid and tau. Initially, the damage inflicted by both proteins is confined to specific areas of the brain – particularly those involved in controlling memory and navigation. Over time, the damage caused by these proteins spreads across the brain, affecting new areas and causing symptoms to worsen and diversify. This spread of damage is not random and for many years researchers have observed a predictable pattern of spread between particularly vulnerable areas of the brain. But researchers have long questioned why these areas are most susceptible to Alzheimer’s.

The Cambridge team suggested that one explanation for this vulnerability could lie in the pattern of proteins expressed in a particular brain area. If a region of the brain expresses a signature of proteins, which are inherently more prone to clumping together, then it could be more susceptible to the damage triggered when the amyloid and tau proteins start to build up.

To explore their hypothesis they used data from existing databases to compare the levels of almost 20,000 genes and corresponding proteins from 500 different brain areas taken from six healthy people aged 24 to 57 years. They gave a vulnerability score to each brain region that was higher if that area expressed more proteins that were prone to clumping together. They then looked to see whether these protein signatures corresponded to the areas of the brain known to be most susceptible to damage in Alzheimer’s.

The scientists found a link between areas of the brain known to be vulnerable to damage in Alzheimer’s and specific signatures of genes and proteins in those areas. The gene signature corresponded to proteins that either clump together with amyloid and tau, or influence the brain’s ability to clear the two culprit proteins. He and his colleagues conducted a transcriptome-wide microarray analysis of more than 500 healthy brain tissues from the Allen Brain Atlas and characterized the progression of disease using Braak staging. After developing their vulnerability score, the researchers noted that brain regions where Alzheimer’s disease is typically first noticed had elevated expression levels of proteins that co-aggregate in plaques and tangles.

But as these co-aggregating proteins were still present at fairly high levels across the brain, the researchers also examined the role of the protein homeostasis components that regulate them. These components, they found, are typically expressed at lower levels in vulnerable tissues, suggesting a role for them in amyloid and tau deposition.

“Vulnerability to Alzheimer’s disease isn’t dictated by abnormal levels of the aggregation-prone proteins that form the characteristic deposits in disease, but rather by the weaker control of these proteins in the specific brain tissues that first succumb to the disease,” Vendruscolo added.

The vulnerable tissues also exhibited lower expression of genes associated with autoimmune response, which lends further credence to theories that inflammation plays a role in Alzheimer’s disease development.

The researchers repeated their tissue vulnerability analysis for aggregation sets linked to amyotrophic lateral sclerosis, ALS, finding a significant difference between the scores for each disease.

Vendruscolo and his colleagues then used single-cell human mRNA data to zoom in on cells most vulnerable to aggregation by evaluating the levels of amyloid beta and tau in various brain cell types. Their relative expression was highest in neurons, the researchers reported.

“The results of this particular study provide a clear link between the key factors that we have identified as underlying the aggregation phenomenon and the order in which the effects of Alzheimer’s disease are known to spread through the different regions of the brain,” co-author Christopher Dobson, also at Cambridge, said in the statement. ”


Connie’s notes: Reading, using the brain more, exercise, sleep, whole foods and being out in the sun (Vit D helps in absorption of calcium and magnesium) help in slowing the progression of Alzheimer’s (as we age, we move less, our body function slowly, so we need to energize our body more).