Rapid progress is being made on all fronts and a relatively new field, epigenetics, is often in the spotlight. Epigenetic changes are not of the ‘classical’ genetic kind, caused by mutations in genes, but arise instead from changes in regulation that switch genes on or off without changing the underlying DNA sequence. Epigenetics is revolutionizing the way we view how gene expression is controlled, and now deeply influences the research that we perform and how we tackle some key diseases. It has also changed how we view the impact our lifestyle has on our own bodies and, remarkably, even on the generations that follow us. Because epigenetic changes are actually heritable.
In this two-part series we will look out how epigenetics was discovered and how it is affecting the way we look at health and the treatment of disease. To gain a better perspective on what epigenetics is about, we will start by moving back 200 years, to a small village in Northern Sweden.
Looking at the 1905 birth cohort, he found that grandsons of Överkalix boys who had experienced good harvests and could gorge themselves when they were pre-puberty (when sperm are maturing) had on average a life expectancy 6 years less than grandsons of Överkalix boys who had experienced famine. Once the data were controlled for socioeconomic variations, the difference in longevity jumped to an amazing 32 years. The reduced life expectancy was frequently caused by diabetes.The first year of the 19th century saw a total crop failure in Överkalix, Northern Sweden, and harvests varied greatly for many years after. This resulted in periods of crop failure and famine followed by massive harvests that enabled the population to gorge themselves for months. In 1984, Lars Olov Bygren, who has roots in this area and is a preventative-health and nutrition expert at Sweden’s renowned Karolinska Institute, became interested in the health of the Överkalix population and used the historical records to reconstruct the nutritional status of several generations. Bygren made a remarkable discovery.
It appeared that Överkalix grandfathers were passing down an experience of starvation (or gluttony) to their grandsons. Later work showed that, in contrast, the granddaughters of women who experienced famine when they were in the womb or just born had a shorter life expectancy. Again, an example of what Bygren called “early influences that give late replies”.
It took many years for Bygren to find acceptance for his results, since they questioned the universally accepted principle that traits are passed down through the DNA whereas experiences die with the individual. It was only when the concept of epigenetics became widely accepted that his results received the recognition they deserved.
Different cells in the body have different functions that are controlled by molecular switches that turn the expression of genes on or off. Epigenetics (from the Greek epi – over, outside of, around) is the study of heritable changes in gene expression that occur without changes in DNA sequence (such as mutations and deletions). Examples of mechanisms that produce such epigenetic changes in gene regulation include DNA methylation and histone modification – histones are proteins around which DNA is wound more or less tightly to regulate gene expression. There are also epigenetic regulators that modify genetic regions to change their expression levels. All these epigenetic changes define cellular identity such that each cell has a specific epigenetic profile that tailors gene expression to match its function.
These epigenetic changes may be retained during the cell’s life and during cell division, and may even be passed on to multiple generations. Of particular interest is the role of epigenetics in reproduction – a role that can readily explain the results observed by Bygren in the Överkalix population.
During embryonic development, the fertilized egg divides multiple times, blossoming from a single cell into a blastocyst comprised of embryonic pluripotent stem cells whose epigenetic slate has been wiped clean. These embryonic stem cells have the potential to form any cell type in the body. As embryonic development continues, female fetuses will form ovaries and egg cells while still in the womb. Astoundingly, this means that at one point in pregnancy three generations are in essence simultaneously exposed to the same environmental stressors, such as famine or gluttony, which can affect epigenetic markers: the pregnant grandmother bears a daughter whose ovaries are under development, with eggs ready to conceive children later in life.
In contrast, boys form sperm first during puberty. So it is not until this point when the environment can start imprinting epigenetic marks on genes in the male, Y-chromosome. Bygren’s results indicate that the famine or gluttony experienced by Överkalix grandfathers during puberty was passed on to grandsons in this way. Remarkable insights such as these and tireless research to connect the molecular dots between basic biology, human development, metabolism, and health have paved the way to new discoveries in nutritional medicine.
Research on asthma by pediatrician Dr Kari Nadeau, MD, now at California-based Stanford University, also led her along a path towards epigenetics. Dr Nadeau was concerned with pollutants in the air – pollutants that lead to the development of asthma. In studying communities in the Fresno area, she discovered that children were more likely to develop asthma due to genetic changes rather than to lung damage itself. These changes included two genes that are crucial to preventing the immune system from overreacting to harmless agents through inflammatory mechanisms, leading to potentially fatal asthma.
Dr. Nadeau suspected that immune cells called regulatory T-cells (Tregs), which control the activity of T helper cells, were involved in asthma. The T helper cells kick off the immune response to potential invaders, but overreaction and proliferation of these cells leads to coughing, airway constriction and other asthma symptoms. When comparing patients from different areas in California, Nadeau found that those from Fresno had particular problems with Tregs activation and discovered the link to air pollution. She finally pinned this down to changes in the regulation of Foxp3, a gene that stimulates immature T cells into becoming Tregs. Air pollution changed the epigenetic methylation tag on Foxp3, switching off the development of Tregs, and allowing T helper cells to run amok, causing asthma. Dr. Nadeau identified a trend in increasing methylation of Foxp3, from children without asthma in Palo Alto, a clean-air region, through asthma-sufferers in the same area, continuing to children in the heavily polluted Fresno area who were non-asthmatics, and finally to asthmatics.
Bearing in mind the insights gained in recent years into epigenetics, Kari Nadeau now attributes exposure to excessive air pollution with asthma-inducing epigenetic changes that can last a lifetime and even be passed on to future generations. Asthma is indeed heritable, and mothers who have been exposed to environmental stress (such as air pollution or cigarette smoke) are more likely to pass on the condition to their children, and even grandchildren, than are fathers exposed in a similar way. Researchers are seeing similar links between air pollution and asthma in other cities and countries.
The insights into the link between epigenetics and, for example, asthma emphasize the impact our lifestyles have on not only ourselves, but also our children and even generations to come. Smoking certainly affects our lungs, and it also potentially affects the health of our as-yet unborn children. Similarly, bad eating habits can affect future generations, just as they did in Överkalix. Most unfortunately, all of this bad behavior and toxic exposure is carried forward by unwittingly passing on the epigenetic tags, good and bad. Even if recent research suggests that epigenetic changes may in fact wear off after a period of time, we still have more responsibility for the health and well-being of future generations than we previously realized.
In the second and final part of this series we will look at how our knowledge of epigenetics is powering basic research and the development of innovative therapy regimes.