Epigenetics is a natural and regular process by which environmental and behavioral factors affect the expression and activity of genes, independently of alterations in DNA sequences (genotype), such as during genetic mutations. These modifications can be transmitted to daughter cells and are influenced by several factors, including age, the environment, lifestyles, and disease states.
These factors can modify DNA through mechanisms involving cytosine methylation and hydroxymethylation or via modifications of histones that regulate the level of DNA availability for transcriptional events .
They can also promote or prevent the translation of proteins that are involved in the different physiological and pathological processes through mechanisms involving other types of RNAs and non-coding RNAs (ncRNAs), including microRNAs (miRNAs), small interfering RNA (siRNAs), Piwi-interacting RNA (piRNAs), Circular RNAs (circRNAs), and long non-coding RNA (LncRNAs) .
Although there are genetic differences that are more favorable to certain groups of people compared to others, such as people who are more resistant to certain types of diseases (e.g., cancer), modulating the factors that control epigenetics could prevent or slow down the effects of the inherited genetic background.
Epigenetics Management of the Master Regulator of Cytoprotection
NrF2 (nuclear factor erythroid-2-related factor 2) is a master regulator of detoxification, anti-inflammation, and antioxidation processes within the cells. NrF2 acts on metallothionein genes that play important detoxification roles through chelating, transporting, and excreting essential and toxic metals, including cadmium, mercury, lead, and arsenic .
Its antioxidant effects are mediated through the induction of the cis-acting element, ARE, that is found in the promoters of genes encoding the two major detoxication enzymes, GSTA2 (glutathione S-transferase A2) and NQO1 (NADPH: quinone oxidoreductase 1) .
Its anti-inflammatory effect is associated with the activation of a wide variety of anti-inflammatory effects through lowering the activity of NF-κB and a series of inflammatory mediators, such as cytokines, chemokines, adhesion molecules, COX-2, MMP-9, and iNOS .
In addition, several studies on NrF2 gain and loss of function in the brain have suggested that the Nrf2 higher level of expression can reduce neurodegeneration, whereas Nrf2 deficiency exacerbates neurodegenerative phenotypes .
Other studies have shown that raising the expression of NrF2 can be useful in preventing and/or treatment of several diseases, including cancer, cardiovascular diseases (e.g., atherosclerosis and heart failure), metabolic diseases (e.g., type 2 diabetes), inflammatory diseases (e.g., inflammatory bowel disease and auto-immune diseases) in animal models and/or humans .
Interestingly, several nutrients have been shown to promote NrF2 activity, including phenolic antioxidants, gamma- and delta-tocopherols and tocotrienols, long-chain omega-3 fatty acids DHA and EPA, carotenoids (e.g., lycopene), isothiocyanates from cruciferous vegetables, sulfur compounds from allium vegetables, and terpenoids.
Other factors that promote NrF2 activity include exercise and caloric restriction .
Although the mechanisms by which factors such as healthy food, exercise, environment, and caloric restriction regulate the expression and activity of NrF2 expression through modulating epigenetics, are not well known, it is becoming clear that overcoming hereditary genetic disadvantages that are associated with some diseases could be achieved through better epigenetics that is promoted by healthy lifestyles and environment.
 Pall, M.L. and Levine, S., 2015. Nrf2, a master regulator of detoxification and also antioxidant, anti-inflammatory and other cytoprotective mechanisms, is raised by health promoting factors. Sheng Li Xue Bao, 67(1), pp.1-18.
 Nguyen, T., Nioi, P. and Pickett, C.B., 2009. The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. Journal of biological chemistry, 284(20), pp.13291-13295.
 Ahmed, S.M.U., Luo, L., Namani, A., Wang, X.J. and Tang, X., 2017. Nrf2 signaling pathway: Pivotal roles in inflammation. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 1863(2), pp.585-597.