Precision medicine and biohacking have become buzzwords as each of us seeks to get ahead of biomedical research with cutting-edge data and self-experimentation. Among these datasets include nutrigenomics and the gut microbiome. However, another key piece of data to take into account is epigenetics, another dimension that dials gene function in response to the environment.
Epigenetics is a relatively new field in molecular biology, and new ways of controlling gene function are still being discovered. Given its complexity, many of the general public and even healthcare practitioners misunderstand it. In this article, I will explain to you a few ways epigenetics happen inside your cells. Then, I’ll share examples of how it affects our health.
By definition, epigenetics refers to any means by which gene function can be changed without actually changing the genetic sequence.
To understand epigenetics, it’s helpful to understand the Central Dogma of how genes get read (transcribed) and then, in many cases, translated into proteins.
Epigenetic changes can affect transcription, mRNA levels, translation, and even protein stability.
Some of the epigenetic changes are heritable or somewhat heritable. These changes are often a result of the environment, such as diet, lifestyle, and the microbiome.
Types of Epigenetic Changes
There are many types of epigenetic changes including the following:
Adding and Removing Chemical Tags From DNA, Such as DNA Methylation
DNA methylation is the addition of a methyl group to the nucleotide cytosine. Demethylation is the removal of the methyl group. In most cases, having more methylation inside or near a gene tends to dial down the rate at which the gene is read from (also called “silencing”). Sometimes, the methylation also results in the chromosome winding tighter, which also silences the gene.
It is important to keep in mind that DNA methylation is not the only way that epigenetics occurs. In addition, having more DNA methylation isn’t good or bad on its own. Cancer cells often have high levels of DNA methylation near genes that can stop cancer growth (tumor-suppressor genes). 1. On the other hand, it’s also possible to have high levels of DNA methylation near genes that promote cancer growth (proto-oncogenes), which reduce the risk of cancers. The general answer of whether methylation is good or bad depends on the genes that the methylation ends up affecting.
Adding and Removing Chemical Tags From Histones
Histones are proteins that help pack your main (genomic) DNA into the nucleus of your cells.
There are five types of histones, four of them spherical and one of them more rod-shaped. Different tags, such as methyl, acetyl, phosphate, ubiquitin, citrulline, and sumoyl can be added to histone tails at different amino acid residues.
Image caption: Different types of histone modifications
Image source 2.
Unique combinations of these chemical tags work like codes that determine whether a genomic region gets read into mRNA or silenced and packed away. In most cases, histone acetylation activates the genes, while histone methylation can either activate or silent the genes, depending on the methylated amino acid.
Swapping or Positioning Histones
Histones typically have to be moved out of the way for genes to be read, so if a gene is wound more tightly around histones, the chance of it getting read will be smaller.
Image source: 3.
Certain alternative versions of histones, such as H2A.Z and H3, can also get swapped in to turn genes on or off.4
Image source 4.
Factors That Affect mRNA Stability and Translation
mRNA, which are transcripts that are read out from genes, are typically very unstable molecules. Many factors determine whether mRNA is then “translated” into proteins or destroyed in the cell. Preserving mRNA typically increases the gene function, whereas degrading mRNA typically reduces the gene function.
Other RNA molecules may increase RNA degradation, such as RNA interference and microRNA. miRNAs may also inhibit translation from the mRNA molecule.
Take home message: There are numerous epigenetic mechanisms going on inside your cells at any given time, and they are typically in the right balance given the context. It is not possible, nor is it a good idea, to attempt to manipulate each of your epigenetic pathways. Targeting a single mechanism, such as methylation, with supplements tends to miss the forest for the trees because there are numerous other ongoing epigenetic processes. Instead, you want to address the total output of the system (e.g., the symptoms or lab tests) instead.
Examples of Epigenetics in Human Health
Lifestyle factors, food, dietary supplements, life events, and even infections affect our health by changing our epigenetic marks and working with our gut microbiome.
How Your Gut Bacteria Influence Epigenetics
Our gut microbiota influences our health in numerous ways, and it appears that these microorganisms do so by influencing our epigenetics.
Example 1: Some bacteria strains communicate with our organs through long RNAs that don’t get translated into proteins. 5.
Example 2: Lactobacillus and Bifidobacteria produce methyl donors such as folate, which influence DNA methylation. 6.
Example 3: Butyrate, one of the most beneficial postbiotics from the fermentation of dietary fibers, inhibits the removal of acetyl groups from histone. 7.
Adverse Childhood Experiences
Adverse childhood experiences (ACEs) can result in traumatic memories that are stored in our epigenome, which influence health risks and stress responses decades after the experience occurred. In some cases, the epigenetic memory may even get transmitted to the next generations.
Example 1: The severity, frequency, and type of trauma correlate with more methylation of the NRC31 gene (which encodes the cortisol receptor). In other words, the cells of traumatized children and adults respond less strongly to cortisol compared to those who are not traumatized. 8.
Example 2: The Dutch Famine study showed that men whose mothers went through a famine during their third semester of pregnancy were less likely to become obese. Whereas, if their pregnant mothers went through the famine during the first half of pregnancy, they were more likely to become obese. 9.
Example 3: Mice traumatized early in life have different microRNAs than non-traumatized mice. In addition, their sperms produce offspring that have different behaviors and metabolism. The traumatized mice were more anxious and produced less insulin. 10.
Polycystic Ovarian Syndrome
Polycystic ovarian syndrome (PCOS) is a hormonal and metabolic disorder that may have both genetic and epigenetic components.
Example 1: Female rats exposed to dioxins have progenies that develop polycystic ovaries. It appeared that dioxins and other hormone disruptors can cause DNA methylation patterns that result in ovarian diseases in future generations. 11.
Example 2: In a rat study, elevated anti-mullerian hormone during pregnancy can result in reduced DNA methylation patterns that cause PCOS for three generations. In these animals, treatment of methyl donor (S-adenosylmethionine) appeared to resolve PCOS traits. 12.
These animal studies demonstrate that PCOS is mediated by heritable epigenetic changes that can be inherited through generations. The results remain to be confirmed in humans, which is hindered by the fact that multi-generational clinical studies are more difficult.
How Molecular Hydrogen Works in the Cell
Molecular hydrogen works by influencing epigenetics and activating proteins that activate other genes (transcription factors), especially ones that counteract oxidative stress.
Example 1: Molecular hydrogen activates Nrf2. Then Nrf2 orchestrates genes that protect the cells and create their own internal antioxidants like glutathione. 13.
Example 2: Hydrogen gas changes gene expression by increasing the methylation of histone H3 at the amino acid lysine 27 (H3K27). It also activates the mitochondria’s unfolded protein response, which has a longevity-promoting effect. 14.
Example 3: Obese mice on a high-fat diet (equivalent to human junk food) fed with hydrogen water have an increase in the PGC-1alpha gene, which is important for fatty acid metabolism and mitochondrial health. As a result, these mice had less plasma triglyceride levels and lived longer than the control group. 15.
Conclusion
Epigenetics allows for changes in gene function without changing the genetic sequence itself. There are numerous ways that our cells perform epigenetics, many of which remain to be discovered or studied. Thanks to next-generation sequencing technologies, it’s relatively simple to test for genome-wide DNA methylation, making it the best-studied type of epigenetic mark. However, there are many other types of epigenetic marks, many of which could be more impactful than DNA methylation. For cutting-edge biohackers, it is more useful to take into account the whole picture of health rather than to manipulate individual types of epigenetic marks.
References
1. Wajed, S. A., Laird, P. W., & DeMeester, T. R. (2001). DNA methylation: An alternative pathway to cancer. Annals of Surgery, 234(1): 10–20.
2. Rodríguez-Paredes, M. & Esteller, M. (2011). Cancer epigenetics reaches mainstream oncology. Nature Medicine, 17(3): 330–39.
3. Sha, K., & Boyer, L. A. (2009). Figure 1, [The Basic Unit of Chromatin…]. Harvard Stem Cell Institute.
4. Liang, L., Ai, L., Qian, J., Fang, J.-Y., & Xu, J. (2015). Long noncoding RNA expression profiles in gut tissues constitute molecular signatures that reflect the types of microbes. Scientific Reports, 5, 11763.
5. Rossi, M., Amaretti, A., & Raimondi, S. (2011). Folate production by probiotic bacteria. Nutrients, 3(1) : 118–34.
6. Davie, J. R. Inhibition of histone deacetylase activity by butyrate. The Journal of Nutrition, 133 (7): 2485S–2493S.
7. Perroud, N., Paoloni-Giacobino, P., Prada, P., Olié, E., Salzmann, A., Nicastro, R., Guillaume, S., et al. (2011). Increased methylation of glucocorticoid receptor gene (NR3C1) in adults with a history of childhood maltreatment: A link with the severity and type of trauma. Translational Psychiatry, 1, e59.
8. Ravelli, G. P., Stein, Z. A., & M. W. Susser.(1976). Obesity in young men after famine exposure in utero and early infancy. The New England Journal of Medicine, 295(7): 349–53.
9. Gapp, K., Jawaid, A., Sarkies, P., Bohacek, J., Pelczar, P., Prados, J., Farinelli, L., Miska, E., & Mansuy, I. M. (2014). The implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice. Nature Neuroscience, 17(5): 667–69.
10. Mimouni, N. E. H., Paiva, I., Barbotin,A.-L., Ezzahra Timzoura, F., Plassard, D., Le Gras, S., Ternier, G., et al. (2021). Polycystic ovary syndrome is transmitted via a transgenerational epigenetic process. Cell Metabolism, 33(3): 513–30.e8.
11. Kawamura, T., Wakabayashi, N., Shigemura, N., Huang, C.-S., Masutani, K., Tanaka, Y., Noda, K., et al. (2013). Hydrogen gas reduces hyperoxic lung injury via the Nrf2 pathway in vivo. American Journal of Physiology. Lung Cellular and Molecular Physiology, 304(10): L646–56.
12. Sobue, S., Inoue, C., Hori, F., Qiao, S., Murate, T., & Ichihara, M. (2017). Molecular Hydrogen Modulates Gene Expression via Histone Modification and Induces the Mitochondrial Unfolded Protein Response. Biochemical and Biophysical Research Communications, 493(1): 318–24.
13. Kamimura, N., Ichimiya, H., Iuchi, K., & Ohta, S. (2016). Molecular hydrogen stimulates the gene expression of transcriptional coactivator PGC-1α to enhance fatty acid metabolism. NPJ Aging and Mechanisms of Disease, 2, 16008.
1 Comments
nice one ALEX KEEP RAISINGTHE BAR The pocast with Nick Pinault set us up to expect great things . It would be good to hear The Dr give a few personal pointers to help bring alinement into closer focus .