Introduction

Epigenetics shows how the environment and our own habits influence our genetics and our predisposition to disease. The main external factors that can influence our epigenetics are diet, exercise and stress. In this article we will explore the connection between epigenetics, disease, exercise and nutrition.

How does epigenetics affect you?

Epigenetics and diseases

In 1996, two identical twins who carried the same mutation in a region of the X chromosome developed different disease progressions. Only one of them developed blindness, balance problems and loss of myelin in the brain: all signs of the neurological disease adrenoleukodystrophy (ALD). At that time, the researchers who reported the case concluded that non-genetic factors must be the cause of the different ALD phenotypes. Today we know that this was actually the case and that the causes lay in the twins' different epigenomes.

Similar cases were subsequently reported. Since epigenetics plays an important role in regulating the expression of genes, it is not surprising that it plays a role in numerous diseases. Since epigenetics can suppress or enhance the expression of “good” and/or “bad” genes, epigenetic defects can be associated with or cause diseases such as cancer, autoimmune diseases, metabolic syndromes, neuropsychiatric disorders or even asthma and (cardio)vascular diseases. Some of these cases are presented as examples in the next few lines.

Genomic imprinting

Genomic imprinting is an epigenetic mechanism that determines whether the maternal or paternal copy of a gene is expressed in the offspring. In each generation, the parent-specific imprints must be deleted, reset and preserved. If one of the copies is “turned off” and the other copy is defective (e.g. due to a mutation), this can have serious consequences for the individual. A number of diseases and disorders have been linked to genetic imprinting, e.g. B. Angelman syndrome, Prader-Willi syndrome and Beckwith-Wiedemann syndrome.

Protein mutation

Another group of epigenetic diseases is caused by mutations in proteins that are essential for chromatin modification. These proteins are directly involved in the post-translational modification of histones and in the methylation of DNA or as reader molecules of these modifications. For example, mutations in the histone acetyltransferases CREBBP and EP300 are associated with Rubinstein-Taybi syndrome. Mutations in the DNMT3B and ZBTB24 genes, which are required for DNA methylation, result in immunodeficiency syndrome, centromeric instability, and facial anomalies. And mutations in the histone modification reader MECP2 cause Rett syndrome.

Epigenetic markers

A number of epigenetic biomarkers are associated with cancer and used for various clinical applications. For example, CpG methylation at a number of genomic sites has been used preclinically to classify gastric cancer subtypes and colorectal cancer subtypes. DNA methylation at certain genes, such as BMP3, NDRG4, SEPT9, has been approved by the FDA as a marker for the diagnosis of colorectal cancer. Histone markers have been used preclinically for the diagnosis of pancreatic cancer, e.g. B. H3K4 dimethylation, H3K9 acetylation and H3K27 trimethylation.

In neurology, a number of epigenetic markers are in the preclinical phase. For example, methylation of the SNCA gene for the diagnosis of Parkinson's disease and the trimethylation of H3K9 for the diagnosis of Alzheimer's disease. Or the methylation of the genes APP, BACE1, LRP1 and SORL1 for the prognosis of Alzheimer's disease.

In autoimmune diseases, epigenetic markers could be used for disease prognosis in the future. For example, methylation of interferon and interleukin genes is used to predict lupus.

Epigenetics is also linked to metabolic disorders such as type 2 diabetes and obesity. Diet can greatly influence our epigenetics. More about this in the blog post "The effect of fasting on epigenetics".

As previously mentioned, identifying specific epigenetic markers associated with specific diseases may provide a means to diagnose, monitor, and develop interventions that may reduce the risk or burden of the disease. MoleQlar Analytics supports the pharmaceutical industry in discovering new epigenetic biomarkers and assessing the impact of drugs and treatments on people's epigenetics.

How do you influence epigenetics?

Epigenetics and sport

Have you ever wondered why some of our bodies react differently than others, even when performing the exact same exercise? Genetic makeup has been shown to play a large role when untrained individuals perform certain physical activities, with some performing better and others performing worse [1].

Transcriptomics (the study of RNA transcripts) and proteomics (the study of proteins) studies have shown that our gene expression patterns adapt to the type of exercise we do [1]. For example, people who train for endurance appear to have different gene expression patterns in skeletal muscle than people who train for strength [1]. But it's not just about our genetic code.

To shed more light on the molecular and systemic effects of physical exercise, an important aspect must be taken into account: epigenetics. Exercise has been shown to have effects on histone modifications in muscle and brain tissue, as well as on DNA methylation status in muscle tissue [2, 3]. For example, it has been suggested that physical activity leads to DNA methylation of genes involved in chronic inflammation and tumor suppression[4].

To return to the example of skeletal muscles: Histone deacetylases (HDAC), enzymes that remove an acetyl group from a histone, are primarily responsible for the epigenetic changes to the histones [2]. HDACs act to suppress the transcription factor myocyte enhancer factor 2 (MEF-2), which in turn suppresses the formation of slow-twitch oxidative myofibers [2]. However, overexpression of MEF-2 by selectively depleting HDACs in skeletal muscle of mice promoted the formation of slow myofibers and improved running endurance, allowing these transgenic mice to run almost twice as far as wild-type mice [2].

Other studies have shown that exercise increases the expression of glucose transporter (GLUT4) genes and proteins in human skeletal muscle, which generally enhances insulin action throughout the body [5]. After exercise, nuclear HDACs were reduced by more than half, and the association of HDACs with MEF-2 was reduced by more than a quarter [5].

There are several epigenetic changes that have been linked to physical activity. They therefore represent potential therapeutic targets for various diseases (e.g. regulation of GLUT4 expression in diseases such as type 2 diabetes). Together with partners, MoleQlar Analytics aims to deepen our understanding of the effects of physical activity on us and our epigenetic properties.

Epigenetics and nutrition

Consuming food can cause changes in our epigenetics and thereby impact individual health by affecting the catalytic activities of the enzymes responsible for Write, delete and read epigenetic changes are responsible.

A number of dietary metabolites are known (with more or less scientific evidence) to influence DNA methylation and histone modifications;

For example, consumption of Concord grape juice has been shown to reduce depression levels in mice, which is due to the presence of dihydrocaffeic acid (DHCA) in this drink. DHCA is an inhibitor of DNMT1, a recorder of DNA methylation of the gene IL-6, which when methylated increases depression levels.

Another ingredient in the Concord drink is malvidin-3'-O-glucoside (Mal-Gluc), which lowers stress levels. Mal-gluc is an inhibitor of HDAC2, a so-called eraser for histone H3 acetylations on the Rac1 gene. When H3 acetylation at this gene is high, stress levels in mice decrease.

Another example of how diet affects our epigenetics was found in a common food preservative: sodium benzoate. Sodium benzoate is metabolically converted into benzoyl-CoA in our body. This derivative of writer molecules has been shown to be used to increase histone benzoylation. The effects of this epigenetic change are still unknown.

As shown in the table above, some other metabolites can also cause changes in the epigenome. At MoleQlar Analytics, we work with business partners in the nutraceutical industry to assess the impact of diet and supplements on individuals' epigenetics.