Epigenetics & Nurture

Epigenetics is the study of any heritable changes in gene expression (i.e. which genes are active vs inactive) that do not involve changes in the underlying DNA sequence – a change in phenotype but not genotype. These changes in gene expression can be passed onto daughter cells, although the is growing evidence that these changes can be reversed.

The term ‘epigenetics’ was coined by Waddington in 1942 and is derived from the Greek word “epigenesis”, which originally described the influence of genetic processes on development. In the 1990s Waddington observed that environmental stress caused genetic assimilation of certain phenotypic characteristics in Drosophila fruit flies. Whilst there are many different types of epigenetic modification, the most commonly studied at present is DNA methylation, which has been linked to many health issues and diseases; one of the most intensively researched being cancer.

Lifestyle can have a significant impact on gene expression and these changes can even be passed down to future generations. Human epidemiological studies have shown that prenatal and early postnatal environmental factors influence the adult risk of developing various diseases and behavioral disorders. Studies have shown that children born during the period of the Dutch famine from 1944-1945 have increased rates of coronary heart disease and obesity after maternal exposure to famine during early pregnancy, compared to those with mothers not exposed to famine (Painter et al., 2005).

Similarly, exposure of a mother to famine is also associated with an increased risk of schizophrenia in offspring  Likewise, adults that were prenatally exposed to stress and famine have also been reported to have significantly higher incidence of schizophrenia (St Clair et al., 2005, van Os & Selten, 1998).

Gene control

Signals from the outside world can work through the epigenome to change a cell’s gene expression. Here is an interactive look at gene control.

During our development from foetus to human, our differentiated cells fine-tune their functions through changes in gene expression, which allows us to remain adaptable to our changing environment; a skill essential to survival.

Screen Shot 2016-07-06 at 10.02.57

Image Source: learn.genetics.utah.edu

In the womb a baby is affected by the signals it receives from the mother and is susceptible to epigenetic changes as a result of the mother’s nutrition and also stress hormones. After birth factors such as social interactions, exercise, nutrition and other environmental signals can also cause epigenetic changes in cell functions. For example, hormones trigger signals during puberty, which lead to significant physical changes. Such signals are also critical for repairing damage to the body if injured. The cell’s experiences of these signals are transferred to the epigenome, where they shut down and activate different genes. To read more about how the epigenome learns from experience check out this link.

Epigenetics and inheritance

We know know that epigenetic tags exist, which can be passed down from generation to generation through offspring. This process is know as epigenetic inheritance. Usually when an egg is fertilised, the embryo undergoes ‘reprogramming’, whereby any genetic tags conferred by the sperm and egg cells are erased of theeir epigenetic tags to form a ‘blank slate’. Some of these epigenetic tags, however, make it through this process and are passed from parent to offspring.

Reprogramming

Image Source: learn.genetics.utah.edu

The Effects of Nurture

Scientists have studied rats (of course!) and discovered that highly nurtured rats, who have been licked, groomed and nursed frequently by their mother, grow up to be calm adults. In contrast, pups who are ignored by their mother and receive little nurturing grow up to be anxious. The difference between a calm and anxious rat is not genetic, but rather epigenetic. How a rat is nurtured during its first weeks of life shapes its epigenomes right into adulthood.

At a first glance this fundamentally seems like an evolutionary disadvantage to the un-nurtured rat. However, imagine the circumstances in which a rat pup may be devoid of care – in a risky environment. The anxiety this rat then develops as an adult may actually confer a survival advantage over a calm rat, if they are subsequently more cautious of danger.

This pattern tends to pass down through generations – a high nurturing rat tends to raise high-nurturing offspring and vice versa. This epigenetic code affords the genome the flexibility and sensitivity to adapt to changing environmental conditions, without having to wait for the much slower processes of random genetic mutation and natural selection.

Incredibly though, epigenetic codes conferred to offspring are actually reversible too. It is possible to inject a low-nurtured rat with a drug that removes methyl groups, and make it will become calm, just like a highly-nurtured rat. The GR gene becomes switched back on, cells make more GR protein, and the rat becomes moe relaxed.

Nutrition and the epigenome

pathway

Image Source: learn.genetics.utah.edu

It is much easier to study how food impacts on epigenetic changes, rather than other environmental influences, such as stress.F ood can have a direct impact on methylation in the body; high methylation is critical for disease prevention. Many B vitamins impact significantly on the methylation process (including B12 and folic acid) and a diet high in these nutrients can effect gene expression positively; especially during early development.

A mother’s diet during pregnancy is therefore critical to an infant’s epigenomes well into adulthood. If the mother’s diet lacks important methyl-donating folate of choline, certain regions of the genome to be under-methylated for life. Adults can also alter their gene expression if they eat an under-methylated diet, however, luckily any changes are reversible when methyl is added back into the diet.

How do we know about the effects of methyl of epigenetics? It is easy for scientists to manipulate diet in animals such as rats, in order to conduct relatively controlled studies. Rat studies show that mothers who eat an under-methylated diet tend to have offspring who are obese and more likely to die of diabetes and cancer. However, if one of these ‘unhealthy’ rats is given methyl supplements, such as choline, folic acid, betaine and vitamin B12 during pregnancy, their offspring will be born a healthy colour and size. Proper nutrient supplementation can therefore negate the effects of prior epigenetic changes (Dolinoy et al., 2006).

mice

Image Source: learn.genetics.utah.edu

Even more interestingly, a study has shown that if a father is forced to eat a restricted diet (i.e. due to a poor harvest), their grandchildren are more likely to live for longer (less likely to die from obesity-related diseases linked to food abundance) (Kaati et al., 2007).

Did you know that in bee colonies, the Queen bee is also genetically similar to workers; the only difference is that the Queen will eat a diet of ‘Royal Jelly’, causing her to develop the behavioural characteristics and size on a Queen! (Kucharski et al., 2008)

Epigenetics and the Human Brain

Epigenetic errors can lead to a range of adult psychiatric disorders, such as schizophrenia, autism, mood and degenerative disorders. Reports have shown that over-expression of a gene called DNMT1 can lead to hypermethylation, affecting normal neurotransmission, memory formation and plasticity, as seen in the brain tissues of individuals with schizophrenia and bipolar disorder.

Recent research has revealed that epigenetic processes are critical to complex brain functions, such as memory. Mice with a dysfunction in epigenetic components relating to histone proteins and enzymes that modify DNA have an impaired long-term memory. Interestingly though, these problems can be reversed by administering drugs to correct the defective epigenetic components. These findings may have an important application in neurodegenerative disorders in humans, as drugs that modulate histone-modifying enzymes may slow cognitive decline or even delay the onset on Alzheimer’s disease. Epigenetic marks may also be used in the future for diagnostic purposes. Detection of epigenetic marks (via blood tests) might act as a warning indicator for a potential pathology, which an individual might then be able to prevent or delay via proper nutrition, supplements or drug therapy.

Issues with epigenetic research

It is worth noting, however, that there is recent criticism of studies into epigenetics; particularly those which study generational effects of epigenetic markers. It has been argued that these studies are poorly designed, with a distinct lack of ability to establish cause and effect (clearly scientists are unable to control the IV in these studies and must rely on naturally occurring variables). Some studies, for example, have claimed that an epigenetic marker on a gene called HIF3A causes obesity. Richmond et al (2016) discovered that these genetic markers actually occur after subjects put on weight, indicating that that the epigenetic changes were the result, not the cause, of illness.

To overcome the cause and effect issues above though, longitudinal studies, which involve collecting blood and genetic samples from healthy individuals, prior to the onset of illness, needs to be the next main step. The process of analysis is a lot more complex than it might seem though (check out this article for a discussion of the difficulties faced). At present, however, findings in the field of epigenetic research need to be treated with caution.

References

A big thank you to the University of Utah, whose presentation of research formed the basis of this article.

Dolinoy D.C., Weidman J.R., Waterland R.A., Jirtle R.L. (2006). Maternal Genistein Alters Coat Color and Protects Avy Mouse Offspring from Obesity by Modifying the Fetal Epigenome. Environmental Health Perspectives, 114:567-572.

Kaati G., Bygren L.O., Pembrey M., Sjostrom M. (2007). Transgenerational response to nutrition, early life circumstances and longevity. European Journal of Human Genetics, 15: 784-790.

Kucharski R., Maleszka J., Foret S., Maleszka R. Nutritional Control of Reproductive Status in Honeybees via DNA Methylation (2008). Science, 319: 1827-1830 (registration required).

Painter R.C., Roseboom T.J., Bleker O.P. Prenatal exposure to the Dutch famine and disease in later life: an overview. Reproductive Toxicology 20, 345-52 (2005).

St Clair D., Xu M., Wang P., Yu Y., Fang Y., Zhang F., Zheng X., Gu N., Feng G., Sham P., and He L. Rates of Adult Schizophrenia Following Prenatal Exposure to the Chinese Famine of 1959-1961. JAMA 294(5):557-562 (2005).

van Os J, Selten JP. Prenatal exposure to maternal stress and subsequent schizophrenia. The May 1940 invasion of The Netherlands. Br J Psychiatry 172:324-6 (1998).

Waddington C.H. (1942). “The epigenotype”. Endeavour 1: 18–20

Weaver, I.C.G, Cervoni, N., Champagne, F.A., D’Alessio, A.C., Sharma, S., Seckl, J.R., Dymov, S., Szyf, M., & Meaney, M. (2004). Epigenetic programming by maternal behavior. Nature Neuroscience, 7, 847-854


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