Unlocking Epigenetics

The field of Epigenetics stands at the interface of the genome, development, and environmental exposure. The Epigenome itself consists of nuclear information that is heritable during cell division, this information controls development, tissue differentiation and cellular responsiveness.

This exciting field attempts to explain how the same DNA present in all the cells of the body allows different organs and tissues to serve vastly different functions and at the same time retain its identity as cells undergo division.

Epigenetics was defined by the embryologist Conrad Waddington in the 1950’s as the branch of biology that studies the interactions between genes and their products that bring phenotype into being. However a major shift in thinking came to light over the last decade and currently it is thought that the environment has a profound effect on developmental plasticity, specifically as it pertains to aging and susceptibility to common diseases.

Check the 5 minute video below on a brief overview of what is epigenetics

The Epigenetic code

There are two “biological codes” that are important in growth, health and sickness.

The genetic code is the sequence of DNA (nucleotide base pairs) that informs a cell how to build proteins, the essential building blocks of life. More than 99.9% of the genetic code is the same for all of us, and the remaining 0.1% variation is important in unique health traits such as height, weight and eye and skin color. Genetic variation can also explain individual susceptibility to various diseases , including the thousands of rare “genetic diseases” such as sickle cell disease and cystic fibrosis where single mutations (genetic changes) can have detrimental effects on health and disease.

The epigenetic code (literally means “above” the genome) does not affect the information contained in DNA sequence, but controls when and where this information is available to cells. The epigenetic code is determined by several mechanisms that affect gene expression, the most well-known of which is DNA methylation (See Figure 1), also modifications of histones in the form of acetylation, methylation, phosphorylation and ubiquitination play a major role. There are also RNA-mediated modifications that are responsible about turning on or off certain genes. The epigenetic code can be altered by environmental exposures such as chemicals, nutrition and stress, especially in early life. Such exposures can have a profound and long lasting impact on gene expression across generations.

Most of our knowledge about epigenetics comes from experimental studies. In humans, epigenetic changes in cancer are among the best characterized. Epigenetics can also be involved in certain birth defects that can be affected by nutritional factors such as folic acid deficiency.

Figure 1

Experimental studies were rigorously undertaken on Agouti mice (Figure 2). They took two mice with identical genetic codes (as with identical twins). In the yellow mouse, a region of the DNA is unmethylated which makes the nearby Agouti gene turned on all the time, while in the brown mouse, the region is methylated and the Agouti gene is turned off. The turning on of this gene leads not only to changes in coat color but to predisposition to all kinds of metabolic diseases including obesity and diabetes.

Environmental exposures can influence whether or not this gene is turned on or off. For example, when pregnant mice are fed bisphenol A (BPA),a chemical present in many commonly used products, the number of offspring with the yellow obese coat color increases dramatically. This happens because BPA decreases DNA methylation so that more offspring have unmethylated Agouti genes. Thus, BPA exposure is associated with a higher number of yellow mice predisposed to obesity and diabetes. When pregnant mice are exposed to BPA along with a vitamin B cocktail (including B12 and folic acid) which increase methylation of the Agouti gene, the offspring are no longer predominantly yellow and obese. Folic acid is important in growth and development and is recommended for women in the prevention of selected birth defects (notably neural tube defects such as spina bifida). Humans have many regions of the genome that are susceptible to epigenetic regulation (see figure 3).

Figure 3

There is also strong suspicion that cumulative epigenetic changes due to environmental exposures and stressors can help explain health disparities in the burden of various diseases among disadvantaged populations. Measuring neighborhood-specific epigenetic alterations potentially can be used to investigate the mechanisms underlying health disparities.

We can use epigenetic information to understand and prevent human disease through environmental modifications (reducing exposures, dietary changes and medication use). The utility of epigenetic information in improving health should follow evidence-based approaches such as the one laid out by CDC ACGE framework and developed further by the EGAPP working group for using genomic tests (Check below some titles of clinical evidence based journals available in the market on the field of epigenetics)

Clinical journals of Epigenetics in the literature and the use of Evidence based medicine

Broad areas of inquiry include 1) assessing accuracy of measurement of epigenetic alterations and their transmission (analytic validity), 2) assessing the relationship between epigenetic alterations to environmental exposures as well as health outcomes (clinical validity); and 3) evaluating the use of epigenetic biomarkers in environmental risk assessment and interventions.

To succeed in identifying epigenetic mechanisms that can lead to human diseases, public health researchers must integrate animal models with clinical and epidemiologic studies, focusing on accuracy of measurements, cell and organ-specific epigenetic patterns as well as windows of vulnerability for epigenetic phenomena in relation to environmental exposures in large prospective studies.

The potential of impact of epigenetic knowledge will be specific to each health outcome. Effective prevention and treatment await a more complete understanding of the causes of human disease and the role that epigenetic modifications can play in improving the health of individuals and populations.

Epigenetics and Health

Epigenetic changes can affect human health in different ways:

1. Infections
   Germs can change an individual epigenetics to weaken his immune system. This helps the germ survive.

Example: Mycobacterium tuberculosis

Mycobacterium tuberculosis causes tuberculosis. Infections with these germs can cause changes to histones in some of the immune cells that result in turning “off” the IL-12B gene. Turning “off” the IL-12B gene weakens the immune system and improves the survival of Mycobacterium tuberculosis .

2. Cancer
Certain mutations make people more likely to develop cancer. Likewise, some epigenetic changes increase cancer risk. For example, having a mutation in the BRCA1 gene that prevents it from working properly makes females more likely to get breast and other cancers. Similarly, increased DNA methylation that results in decreased BRCA1 gene expression raises the risk for breast and other cancers .While cancer cells have increased DNA methylation at certain genes, overall DNA methylation levels are lower in cancer cells compared with normal cells (Figure 4). Different types of cancer that look alike can have different DNA methylation patterns. Epigenetics can be used to help determine which type of cancer a person has or can help to find hard to detect cancers earlier. Epigenetics alone cannot diagnose cancer, and cancers would need to be confirmed with further screening tests.

Figure 4

Example: Colorectal Cancer

Colorectal cancers have increased methylation at the SEPT9 gene. Some commercial epigenetic-based tests for colorectal cancer look at DNA methylation levels at the SEPT9 gene. When used with other diagnostic screening tests, these epigenetic based tests can help find cancer early .

3. Nutrition During Pregnancy
A pregnant woman’s environment and behavior during pregnancy, such as whether she eats healthy food, can change the baby’s epigenetics. Some of these changes can remain for decades and might make the child more likely to get certain diseases (figure 5).

Figure 5

Example: Dutch Hunger Winter Famine (1944–1945)

People whose mothers were pregnant with them during the famine were more likely to develop certain diseases such as heart disease, schizophrenia, and type 2 diabetes. Around 60 years after the famine, researchers looked at methylation levels in people whose mothers were pregnant with them during the famine. These people had increased methylation at some genes and decreased methylation at other genes compared with their siblings who were not exposed to famine before their birth . These differences in methylation could help explain why these people had an increased likelihood for certain diseases later in life.

Why is Epigenetic research important

Finally, epigenetic analysis might be used in completely novel ways that have received almost no attention to date. For example, it could be used to predict therapeutic response in ways that purely genetic analysis cannot do, because epigenetic analysis measures the effect of the genome and the patient’s existing environmental load. Epigenetic analysis could also be used to assess in utero and transgenerational effects. For example, we already know that epigenetic changes are found in the offspring of women who smoke during pregnancy and that there are methylation changes in the sperm of fathers of children with autism who have subsequent children with autism. Epigenetics can lead us at last to an era of comprehensive medical understanding, unlocking the relationships among the patient’s genome, environment, prenatal exposure, and disease risk in time for us to prevent diseases or mitigate their effects before they take their toll on health.

References:

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