The Power of Nutrition (Part 4): Epigenetics – Influencing Genes through Lifestyle

Provided that our genes determine our growth, our appearance, our functioning, and the development of disease – how is it possible that two people with the same genetic disposition, e.g. identical twins, do not always share the same looks or even the same illnesses?
The underlying cause is the interaction of our environment and lifestyle with our genome.
Even though every single person’s genetic code itself is unalterable (apart from mutations), the way it is expressed can be influenced by our environment.
This is what we call epigenetics: heritable changes in gene expression that are not accompanied by alterations in DNA sequence.


How does epigenetics work?

While genetics describe the passing of the DNA sequence within a gene to the next generation, epigenetics can be viewed as passing on the way genes are used. To make an analogy, think of a concert: While genetics describes the instruments you inherit, epigenetics describes the music that is played with them. It describes processes that affect which genes are switched-on, or speaking in molecular terms, which are “expressed.”

We know that one mechanism of how epigenetics works is by adding and removing methyl groups to the DNA, which gives information about whether the gene should be switched on or off. The methyl group is used to modify cytosine, one of the four bases that make up the genetic code of our DNA. Cytosine is methylated by enzymes called DNA methyl transferases (DNMTs) and is then called 5-methyl cytosine. In general, we can say that a high number of methylated Cs in the DNA of a gene switches it off, meaning it will not be expressed.

The DNA of plant and animal cells is packed around proteins, and this complex is called chromatin. Within the chromatin, the DNA double helix is wrapped around histone proteins, and this structure is referred to as a nucleosome. The chromatin is made of a string of nucleosomes that is folded and held together by further proteins. Another epigenetic mechanism is the modification of histones through acetyl groups or methyl groups, and some forms of RNA, such as microRNAs (mRNAs) and small interfering RNAs (siRNAs), are involved in the modification of chromatin structure, which decides whether an underlying gene is switched on or off. Similar to the regulation of methylation, acetylation is regulated by enzymes: histone acetyl transferases that add acetyl groups and histone deacetylases (HDACs) that remove them.

By an epigenetic process, such as methylation or acetylation, one of the two alleles of a typical gene pair can be silenced, meaning it will not be expressed. This becomes a problem if the expressed allele is damaged or contains a variant that increases the organism’s vulnerability to certain environmental factors. DNA methylation has been found to be involved in various illnesses and health conditions including cancer.

Many other types of epigenetic processes have been identified so far. They include not only methylation and acetylation, but e.g. also phosphorylation, ubiquitination, and SUMOylation.

Where exactly is the link between genetics and our environment?

Today, a wide variety of illnesses and behaviors are linked with epigenetic mechanisms, including cancer, cognitive dysfunction, cardiovascular disease, reproductive dysfunctions, autoimmune diseases, and neurological illnesses. Environmental agents such as heavy metals, pesticides, tobacco smoke, polycyclic aromatic hydrocarbons, hormones, radioactivity, viruses, and bacteria are known or suspected drivers behind epigenetic processes and also include nutrients and secondary plant compounds.

For a long time, it was thought that our genes determine our health, and that once we know our genetic code, genetic disease would become a thing of the past. It was estimated that there would be at least 100,000 genes that make up for the complexity of human beings, but with the completion of the human genome project, the researchers found that there are only about 20,000 genes in humans – a very small number considering that nematode worms have about 20,000 too, grapes have about 30,000 and tomatoes have nearly 32,000, and that we share 98 percent of our genetic sequence with chimpanzees and 70 percent with acorn worms from the deep sea (approximately 14,000 genes) 1)Simakov O., Kawashima T., Gerhart J. et al. (2015): Hemichordate genomes and deuterostome origins. Nature. 527, 459–465. This was quite a shock, and we had to realize that it is not just genes that determine our development.

The most powerful example for this finding is the development of honey bees 2)Chittka A, Chittka L. (2010): Epigenetics of Royalty. PLoS Biol 8(11): e1000532. . While worker bees and the queen bee are not only different in their phenotype e.g. in size, the queen also lays eggs while worker bees are sterile. Despite this, the queen and workers are genetically identical. But where lies the difference then if not in their genetic code?

The answer is nutrition, or more specifically royal jelly, a secretion that is fed to some developing larvae, which results in these larvae becoming queens rather than workers. To see how this works, we have to come back to acetylation and methylation and their influence on gene expression. It was found that royal jelly contains a histone deacetylase (HDAC) inhibitor stopping the enzymes that normally remove acetyl tags from histones and is thought to be the process which switches on genes required for the development of a queen. But research also discovered another mechanism: when they reduced the amount of the methyl group adding DNMT enzyme in the larvae, they also developed into queens, even if they did not receive royal jelly. In this case fewer methyl tags led to the expression of genes that resulted in the development of the larvae into queens.

Free Honey Bee

How can we influence our genes through diet?

There’s a word for it
The development of honey bees is a powerful example of why nutrition is one of those lifestyle factors that have a huge impact on your genes. Various studies in humans, animals, and cell cultures have demonstrated that macronutrients e.g. fatty acids, micronutrients such as vitamins, and secondary plant compounds (such as flavonoids, carotenoids, coumarins, and phytosterols) naturally occurring in foods are directly involved in metabolic reactions and even regulate gene expression.

This discovery led to the evolution of the field of nutrigenomics: the study of the effects of food and food constituents on gene expression. Not only does food influence our genes, but our individual genetic variations also determine how that food is metabolized. Nutrigenomics tries to find answers on how specific nutrients or dietary regimes may affect human health.

A mother’s starvation and her children’s health
One of the first discussions on the relation of nutrition, genes and disease was started by the observations from the Dutch famine birth cohort, consisting of individuals who were born around the famine during the war in winter 1944/45 and their matched controls 3)Lumey, L. H., et al. (2007a). “Cohort profile: the Dutch Hunger Winter families study.” Int J Epidemiol 36(6): 1196-1204..

With this cohort, it was possible to study how changes in maternal nutrition during pregnancy affect the offspring’s risk for metabolic and cardiovascular disease in adulthood. There were critical time windows found in pregnancy when fetal programming occurs. For example, low birth weight was found for 3rd trimester famine exposure and high birth weight for 1st trimester famine exposure, and prenatal exposure resulted in a higher prevalence of impaired glucose metabolism and type 2 diabetes in adulthood 4)Lumey, L. H., et al. (2007b). “The Dutch Famine of 1944-1945 as a Human Laboratory: Changes in the Early Life Environment and Adult Health.” Int J Early Life Nutrition and Adult Health and Development 3: 1196-1204.. Persistent epigenetic differences were associated with prenatal exposure to famines 5)Heijmans, B. T., et al. (2008). “Persistent epigenetic differences associated with prenatal exposure to famine in humans.” Proc Natl Acad Sci U S A 105(44). Methylation of the insulin-like growth factor 2 (IGF2) gene is a modulator of newborn’s fetal growth and development, and it could be seen that in the famine cohort, less methylation of the IGF2 gene compared to unexposed same sex siblings occurred 6)Roseboom, T. J., et al. (2011). “Hungry in the womb: what are the consequences? Lessons from the Dutch famine.” Maturitas 70(2): 141-145..

Which foods are able to change our epigenetics?
While we do not have an influence on our mother’s diet, the good news is that we seem to be able to induce epigenetic changes ourselves. The Mediterranean diet, which has demonstrated favorable effects on cardiovascular risk, elevated blood pressure, inflammation, and other complications related to obesity, was investigated by a randomized controlled trial to see whether the adherence to this diet is associated with changes in the methylation status from peripheral blood cells. It was found that the adherence to a Mediterranean Diet, high in vegetables, olive oil and low in meat products, is associated with the methylation of the genes related to inflammation with a potential regulatory impact 7)Arpón A, Riezu-Boj JI, Milagro FI, Marti A, Razquin C, Martínez-González MA, Corella D, Estruch R, Casas R, Fitó M, Ros E, Salas-Salvadó J, Martínez JA. (2016): Adherence to Mediterranean diet is associated with methylation changes in inflammation-related genes in peripheral blood cells. J Physiol Biochem. 73(3):445-455.. Another study found that through an intensive change in nutrition and lifestyle, significant epigenetic modulations of protein metabolism and modification, intracellular protein traffic, and protein phosphorylation were detected in men with increased risk of prostate cancer. As these biological processes have critical roles in tumorigenesis, nutrition and lifestyle changes may modulate gene expression in the prostate 8)Ornish D, Magbanua MJM, Weidner G, Weinberg V, Kemp C, Green C, Mattie MD, Marlin R, Simko J, Shinohara K, Haqq CM, Carroll PR. (2008): Changes in prostate gene expression in men undergoing an intensive nutrition and lifestyle intervention. Proc Natl Acad Sci U S A. 105(24): 8369–8374..

But how is this possible?

Some of the biochemicals in foods, e.g. genistein, a component of soy; resveratrol, a phytoalexin, found in red grapes and red wine; or sulforaphane, an isothiocyanate produced by cruciferous vegetables such as broccoli, are ligands for transcription factors and thus directly alter gene expression and influence pathways within the cell cycle. They were found to regulate the expression and enzymatic activity of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), important enzymes activating and silencing specific genes which are involved in aging and cancer formation 9)Sundaram, Madhumitha Kedhari; Ansari, Mohammad Zeeshan; Al Mutery, Abdullah; Ashraf, Maryam; Nasab, Reem; Rai, Sheethal et al. (2018): Genistein Induces Alterations of Epigenetic Modulatory Signatures in Human Cervical Cancer Cells. In: Anti-cancer agents in medicinal chemistry 18 (3), S. 412–421. DOI: 10.2174/1871520617666170918142114.10)Fernandes, Guilherme Felipe Santos; Silva, Gabriel Dalio Bernardes; Pavan, Aline Renata; Chiba, Diego Eidy; Chin, Chung Man; Dos Santos, Jean Leandro (2017): Epigenetic Regulatory Mechanisms Induced by Resveratrol. In: Nutrients 9 (11). DOI: 10.3390/nu9111201.11)Ali Khan, Munawwar; Kedhari Sundaram, Madhumitha; Hamza, Amina; Quraishi, Uzma; Gunasekera, Dian; Ramesh, Laveena et al. (2015): Sulforaphane Reverses the Expression of Various Tumor Suppressor Genes by Targeting DNMT3B and HDAC1 in Human Cervical Cancer Cells. In: Evidence-based complementary and alternative medicine : eCAM 2015, S. 412149. DOI: 10.1155/2015/412149..

How do bacteria influence our epigenome?
But there is yet another mechanism:
Our diet also influences our intestinal microbiome, the amount of bacteria in our gut, and the gut microbiome, on the other hand, modifies dietary exposures in a way that influences its human host. Gut bacteria metabolize macronutrients, either as specialists or in consortia of bacteria, in a variety of diverse metabolic pathways. Microbial metabolites of diet can also be epigenetic activators of gene expression that, for example, may influence colon cancer risk in humans, such as butyrate production from fiber 12)Lazarova DL, Chiaro C, Bordonaro M (2014): Butyrate induced changes in Wnt-signaling specific gene expression in colorectal cancer cells. BMC Res Notes. 2014;7:226. , or by altering the pool of compounds used for modification, or by directly inhibiting enzymes involved in epigenetic pathways. Colonic epithelium is immediately exposed to these metabolites, although some metabolites are also found in systemic circulation.

The human microbiome is remarkably personalized and, thereby, also its influence on host epigenetic processes 13)Turroni S, Rampelli S, Biagi E, et al. Temporal dynamics of the gut microbiome in people sharing a confined environment, a 520-day ground-based space simulation, MARS500. Microbiome. 2017;5(1):39.. This might explain that even when two completely identical organisms are subjected to the same environmental conditions, their epigenetic regulation could still be divergent because of different metabolic activities of their personal microbiomes. There is still little understanding and research on how human microbiome modulates host epigenetic processes directly or indirectly, but there is great potential in studying the two fields together.

In a similar way, researchers are currently trying to provide dietary recommendations to directly influence the microbiome and its effect on human health. An individualized nutrition therapy targeting the epigenome is one desired goal. We are just beginning to uncover the impact certain foods have on epigenetic pathways and the associated pathology.
Exciting research findings are sure to come!

This article is part of the series “The Power of Nutrition”.