EPIGENETICS AND HEALTH: THE ENVIRONMENT SHAPING OUR GENES

If you are unaware of how much the environment shapes your health, then it is time to take a look at epigenetics.

In this article, we will delve into the role of epigenetics in health, covering how environmental factors influence our genes for better or for worse, as well as how epigenetics is currently being applied to improve health outcomes.

What is Epigenetics?

Epigenetics is defined as the study of or the way in which environmental factors influence gene expression without altering the DNA sequence itself. The process of using a gene's encoded information to create a functioning product or protein is known as gene expression. It is essential for the development, differentiation, and function of cells and organisms.^[1]

Epigenetics Vs Genetics

Genetics refers to the inherent genetic traits of an organism and its study, while epigenetics looks at changes in gene expression occurring in the chromosome that affect how genes are interpreted.

Genetic and epigenetic modifications differ in that whereas basic genetics are hard to alter, epigenetic modifications happen often and are influenced by environmental factors. Some epigenetic changes are long-lasting and can span several generations in a similar way to that of baseline genetics.

Gene Expression Explained

In order to understand epigenetics a bit better, it is important to know how genes are structured, stored, and retrieved for gene expression when the gene becomes active.

The genome is divided into chromosomes, which can be found in the nucleus of the cells. Each chromosome consists of tightly wound DNA strands made of nucleotides (base proteins) that code for vital cell products. In one chromosome, every segment of the DNA strand is coiled around histones that are cylindrical in shape, resembling beads on a string. These are further packed together in rounds of 8, forming DNA ‘spools’ (nucleosomes) that coil to form chromatin^[2]. Thicker coils of tightly wound chromatin make up a chromosome.

Gene expression occurs when the chromatin unwinds from the chromosome, histones unwind from chromatin, and the section of the gene between histones becomes available for reading or transcription. This allows for messenger RNA to form from free nucleotides and RNA polymerase (an enzyme) based on the DNA sequence presented (transcription)^[3]. After some processing, the messenger RNA takes the gene script to the ribosome (another cell organelle), where it is read (translated) and used as a formula for creating complex cellular proteins.

With epigenetic factors, gene expression can be regulated during most of its stages, including transcription, translation, and post-translational modification. Most epigenetic effects revolve around silencing (repressing) or expressing (activating) a gene by allowing or preventing it from being read (transcribed or translated), serving as either an ‘on’ or ‘off’ switch.

What are Epigenetic Changes?

Epigenetic changes are reversible modifications that change the way genes are expressed and do not change the DNA sequence. The full spectrum or collection of epigenetic changes that are present in an organism is called the epigenome.

What triggers gene expression arising from epigenetic changes is not entirely understood and is still an active part of the study of both genetics and epigenetics. However, it can be boiled down to our experiences and perceptions, as well as the chemical changes they create, which leave a lasting impact on the expression of our genes.^[4]

Gene expression is determined by several factors, including:

• Temperature
• Humidity
• Light
• Nutrients
• Toxins
• Stress
• Metabolic factors
• Pressure
• Exercise

The list goes on. Most of these factors are environmental and linked to physical perceptions. However, psychological, emotional, and mental factors may also trigger epigenetic changes and gene expression as well.

When interpreted by cells, exposures, and experiences lead to a cascade of chemical reactions specific to the event that signals to the cell or tissue what’s going on and how to respond. The signals and metabolic changes that result are thought to cause enzymes and proteins involved in regulating gene expression to function differently, giving rise to epigenetic changes.

Very stable epigenetic changes can additionally be passed down from one generation to the next. Other epigenetic changes are caused by inherited or acquired mutations in the genes that regulate epigenetic mechanisms.

In this way, researchers have managed to couple environmental events with specific epigenetic changes and gene expression. Our health can be significantly impacted by epigenetic modifications. Some epigenetic changes and gene expression overlap with those seen across various health conditions, illnesses, and disorders, highlighting how various environmental conditions and events may be disease-promoting, while others may facilitate prevention, treatment, or health. Research has demonstrated that epigenetic modifications can raise one's risk of heart disease, cancer, and a host of other conditions. They have also been linked to mental health conditions such as depression and anxiety.

How Does an Epigenetic Change Differ from a Mutation?

A mutation is a permanent change to the genome, often a gene deletion or a change to the basic gene sequence. Mutations can be hereditary, occur during embryonic development, or in faulty cells (often leading to cancer). Epigenetic changes affect the way the gene is expressed, read, or used and can occur at any point of development due to environmental factors.

Epigenetic Modifications that Lead to Altered Gene Expression

A few major mechanisms of epigenetic genome modification include DNA methylation, histone modification, and non-coding RNA^[5]. These are briefly explained below.

DNA Methylation. This process involves adding a chemical methyl group to DNA that can activate or repress genes. Methyl groups allow for other proteins to attach to them, giving rise to further epigenetic changes to gene expression.

Histone Modification. This involves adding or removing chemical groups from histones to switch genes on or off depending on the gene. Acetylation and deacetylation are some of the most straightforward histone modifications.

• Acetylation means that the histone loosens up the DNA wound around it, switching genes ‘on’ and allowing for more of the gene sequence to be read. Deacetylation is the opposite and refers to the tightening of the DNA strand around the histone, causing less to be available for transcription and switching genes ‘off.’
• Other histone modifications include phosphorylation, ubiquitylation, and methylation. Phosphorylation plays a specific role in initiating gene repair, while the other two are more complex and either activate or repress genes depending on specific conditions.

Non-Coding RNA Interference. Over and above these epigenetic changes, there are many RNA molecules (single-stranded DNA) that can exert epigenetic effects on the genome. These were previously thought to have no true purpose, referred to as part of ‘junk DNA’ as they were not particularly involved in transcription. In recent years, more than 20,000 of them have been shown to be subtle yet potent regulators of gene expression. Non-coding RNA has been further classified according to its length and potential, including subtypes such as microRNA (miRNA), short interfering RNA (siRNA), and long non-coding RNA (lncRNA). siRNA and lncRNA can repress chromatin expression and promote gene silencing by blocking DNA transcription.

Environmental factors that lead to all of the above epigenetic changes are occurring all the time in order to shape the effect our genes have on our biology. These modifications, known as epigenetic markers, are transferred to newly formed cells during cell division.

The Environmental Influence on Gene Expression

Epigenetics has blown the lid off of personalized medicine, revealing just how unique we all are in terms of our genes, the way they interact with the environment, and how these interact to affect overall health and well-being.

However, interactions between genes and epigenetic factors are not straightforward and can be different even between people who carry the same copy of a gene or who live in the same environment with the same exposures. There is a lot more to consider in terms of how these interactions play out on an individual basis and how they may affect our health for better or for worse.^[6]

To explain interindividual differences, scientists look at the effect of a genetic or environmental factor on a trait or disease and its dependency on the presence or absence of other factors. These interactions can be used to assess different epigenetic aspects and effects and have been divided into several types:

• Gene-environment interaction is the way in which the environment interacts with individual genes to influence health.

For instance, research indicates that smokers have an increased risk of developing bladder cancer. In smokers who have a specific variation in their baseline genetics (NAT2), smoking (an environmental factor) poses a much higher risk for bladder cancer. This is due to the way in which epigenetic changes from smoking interact with this specific baseline gene.^[7]

• Scientists are also looking at the genotype-environment interaction, which refers to the way the environment interacts with whole genomes to influence health and vice versa.

These studies demonstrate how different people might react differently to the same life exposures and how genotype-environment interactions cannot be inferred by combining individual gene-environment interactions together.

• This phenomenon, referred to as a gene-by-environment interaction, can cause variations in the way that the environment influences the expression of a gene.

For example, a person may carry a gene that increases their risk for diabetes, yet that gene may only get switched on when another gene is presently being expressed and when they also consume a high-sugar diet.

• As mentioned above, the comparison of genomes and how they fare in response to different environmental exposures cannot be calculated by looking at individual gene-by-environment interactions. Instead, one needs to look at genotype-by-environment interactions.

Going back to the previous example, if two people carried the same diabetes risk gene, the gene it depended upon, as well as consumed a high-sugar diet, it is possible for one to contract diabetes and for the other to remain relatively healthy. These two people may not express their risk gene or the gene it depends upon, even when exposed to the same environmental factors (like a high-sugar diet) due to other genetic factors that are unique to them. In some cases, other genetic factors can make a person more resilient and less likely to acquire a disease or trait.

Genotype-by-environment interactions are the main reason why the entire genome ought to be taken into consideration when going for genetic counseling or testing.

Gene-Environment Interactions Throughout the Lifespan

Throughout our lives, a multitude of factors contribute to our biological growth and development, including genetic and environmental factors and their interactions.^[8] Some examples of epigenetics that shape the course of our lives include:

Growth and Development. Epigenetic changes are the reason why all cells in the body can have the same genome yet are all different due to expressing different genetic traits. This is how an embryo develops into a fetus, and eventually, an infant. It is also how the body is able to regenerate through cell turnover from stem cells, how cells are able to adapt to different environmental conditions, and how we are able to learn new things.^[9]

Cell Memory. Changes in epigenetics can be inherited through cell division from parent cells to daughter cells, which is precisely how new cells maintain their cell type. It is also involved in perpetuating cellular memory, which explains much of how the immune system remembers and refines its response to specific threats. This can be seen during an infection where the immune system becomes sensitized to patterns of danger signals released by the pathogen and surrounding cells. These signals activate cell receptors that lead to epigenetic modifications, such as methylation and demethylation in different parts of the genome, activating or repressing gene expression in response. Cells exposed to these factors retain these epigenetic marks, allowing them to act quicker and refine their defenses during future infections.^[10]

Aging. Cell senescence, or the aging of cells, is caused by changes in gene expression. Aged cells have a different shape, produce more inflammation, are hormonally altered, and tend to have reduced functionality or be completely non-functional. Studies have shown that our diets, lifestyles, and degree of major life stress can all contribute towards aging, and epigenetics explains why and how. Senescence occurs also as a result of epigenetic marks or changes accumulated throughout the lifespan. These contribute towards altered patterns of gene expression, often arising from gene silencing or mutation and genomic instability. Gene-environment interactions can leave lasting epigenetic effects that can even affect the lifespan of one’s children and the way in which they age as well.^[11]

Pregnancy. A whole host of complex epigenetic changes occur during pregnancy that allow for the womb to develop and for the mother to further influence the fetus and vice versa. One active area of research pertains to the exchange of microRNAs between the mother and fetus. Some of these epigenetic marks promote miscarriage, while others remain after birth with the child and have been associated with increases and decreases in disease risk. These include post-pregnancy complications a mother might experience, such as post-partum depression or cardiovascular disease onset influenced by miscarriage^[12]. The epigenetic state of the sperm and egg cell prior to conception has also been proven to affect fetal development and influence the risk of miscarriage or success substantially.^[13]

Stressful Life Events. Stress is known to pose many effects on the epigenome, which differ depending on the type of stress (e.g., chronic vs acute stress), the time in life at which it occurs, and what other environmental factors are present. These changes correlate with known stress-related changes, such as the benefits of mild or acute stress vs the disadvantages of suffering chronic or traumatic stress.^[14] The epigenetics mark left due to childhood adversity has been shown to be long-lasting, affecting brain development and increasing the risk for neurodegenerative disease.

Epigenetics in Psychology

Epigenetics has also been linked to psychology, highlighting the mind-body connection. What we think and feel shares a relationship with our overall health and the state of our genes. For instance, stressful life events induce epigenetic changes that can increase the risk of depression and give rise to negative thoughts and feelings^[15]. Similarly, epigenetic effects induced by happiness and life satisfaction can lower the expression of inflammatory factors associated with heart disease^[16].

While research has yet to confirm whether our thoughts can alter our epigenome, there are several studies that highlight how the epigenome is involved in governing our level of emotional intelligence^[17], our ability to bond socially and empathize^[18], and our psychological resilience towards stress. Many activities that enhance these psychological factors exert epigenetic changes as well, such as exercise, meditation, and socializing in a loving environment. Psychotherapy can also beneficially alter gene expression related to stress^[19] and in blood cells^[20], leading to improved mental well-being.

Epigenetic Diseases and Therapies: Current Uses and Future Applications

In recent years, the concept that inflammation is a component of all diseases has gained popularity. Chronic inflammation leads to changes that cause tissues and organs to eventually become dysfunctional. At the heart of both chronic inflammation and faulty tissues are epigenetic marks that change the expression of genes and lead to chronic imbalances. Epigenetic marks can be used in the future to diagnose disease, assess disease risk, calculate which environmental factors might trigger or promote disease, onset and monitor overall health.

Specific epigenetic therapies are currently being explored for their potential to significantly expand, improve, and personalize treatment options. While a few epigenetic medications have been approved for use to treat aggressive types of cancer, epigenetic treatment options are still in their infancy.

Two of the most common epigenetic therapies being explored include DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi), which lower methylation and improve histone acetylation, respectively. These can counter epigenetic changes and regulate gene expression, helping to improve symptoms and slow disease progression.

Many currently used medications and therapies have also been shown to exert epigenetic effects that explain both their benefits and side effects and why they do not work for everyone with the same condition.

A few examples of how epigenetics contributes to disease risk, onset, progression, and prevention are described below.

The Common Cold

Exposure to infections can pose different effects on different people and explains why some may acquire lifelong illnesses or sensitivities following an infection while others recover without any further issues.

Upon infection, many viral infections, including the common cold (rhinovirus family), induce epigenetic changes, such as hypermethylation and histone modifications, that suppress genes associated with immune function^[21]. Vitamin C is a well-known antiviral home remedy that supports immune function. Studies reveal it is required for regulating methylation and can possibly enhance immune function during viral infection by combating viral-induced epigenetic changes.^[22]

Depression

The serotonin transporter gene (SLC6A4), which is involved in serotonin reuptake, has a hypermethylated promoter region that raises the risk of depression. Research has shown that this epigenetic change can occur with chronic stress exposure or severe trauma, which supports findings in observational studies.

Commonly prescribed for depression, Serotonin Reuptake Inhibitors (SSRIs) may be beneficial for enhancing the expression and function of the serotonin transporter through the epigenetic changes they exert on SLC6A4. However, people who carry the S allele variant of SLC6A4 (instead of the L allele) are genetically incompatible with SSRIs. While SSRIs increase serotonin reuptake, those with the S allele naturally have a reduced expression of the serotonin transporter and cannot take up as much serotonin. Side effects of SSRIs, including suicidal ideation, are much more common for those with the S allele.^[23]

Heart Enlargement (Dilated Cardiomyopathy)

Dilated cardiomyopathy (DCM) is the most prevalent kind of cardiomyopathy, characterized by weakening heart walls and expansion of the heart chambers. 

An epigenetic mark that has been reported to contribute to the development and progression of DCM includes the downregulation of the histone acetyltransferase p300. This has been shown to impair the expression of genes that are involved in cardiac remodeling and contractility, leading to DCM. The use of HDACi has been shown to improve cardiac function and reduce fibrosis in animal models of DCM and may enhance current therapies in the future.

Beta-blockers are currently a common treatment option for DCM. Studies have uncovered that they can reduce DNA methylation and histone acetylation in genes that regulate the heart’s functions.^[24] In doing so, beta-blockers may suppress inflammatory changes in the heart, slow down DCM progression, and improve outcomes.

Breast Cancer

An elevated risk of breast cancer has been linked to the hypermethylation of the BRCA1 gene's promoter region. This means that a portion of this gene has been silenced due to methylation. As BRCA1 is responsible for DNA repair and tumor suppression, keeping it active through preventing excessive methylation is important for breast cancer prevention. DNA methyltransferase inhibitors (DNMTi) have been shown to reactivate BRCA1 gene expression and reduce the proliferation of breast cancer cells.

In recent years, epigenetic factors have been shown to play a role in women who are non-responsive to the widely used treatment, tamoxifen. Future modifications to this chemo drug may enhance its efficacy by altering gene expression in tumors that do not respond^[25].

Metabolic Syndrome

Metabolic syndrome is a cluster of metabolic abnormalities that increase the risk of cardiovascular disease and type 2 diabetes. Epigenetic changes are known to promote metabolic syndrome, such as the hypermethylation of the promoter region of the peroxisome proliferator-activated receptor gamma (PPARγ) gene, which helps regulate weight gain and insulin sensitivity.^[26]

Regular exercise is well known to help lower metabolic disease risk. It helps to lower the methylation of PPARy in muscle and other tissues, enhance overall metabolism, and reduce the risk for metabolic syndrome.

DNMTis may be used in the future to enhance PPARy expression. This can improve insulin sensitivity, glucose metabolism, regulate weight gain, lower inflammation, and enhance current therapies. Metformin is a standard drug prescribed to treat metabolic syndrome and related diseases. It increases methylation and lowers the gene expression of complementary genes that promote excessive glucose production related to metabolic syndrome.

Conclusion

To sum up, epigenetics is a fascinating area of research that could fundamentally alter how we perceive health and illness. We can learn more about the ways in which our environment impacts our health by investigating the ways in which environmental influences can modify gene expression. Epigenetics has already provided us with valuable insights into the causes of many diseases and will continue to be an important area of research in the years to come.

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