Epigenetics and Human Health

Epigenetics and Human Health
Paige M. Breedon and Austin A. Mardon

Epigenetics refers to heritable changes that affect gene expression but are not due to the underlying genetic code [2]. Such changes may include alterations in methylation patterns of DNA and histones that ultimately affect DNA packaging and gene expression [2]. Intuitively if DNA is more tightly packed, it can be challenging to facilitate transcription because transcription factors cannot bind to the DNA where they are required to, and methylation of DNA can result in decreased transcription. Modification by methylation or acetylation of terminal amino acids of histones can also change gene expression [2]. These different patterns of methylation and chromatin modifications can lead to cellular diversity and affect the future of an individual's phenotype [1]. Environmental factors that can affect diseases by inducing changes to the epigenome include where one lives, stress, nutrition, toxicants, alcohol, lifestyle, climate, and exposure to chemicals, bacteria, heavy metals, and viruses [1]. Most of these factors do not influence the genome but rather result in modifications to the DNA methylation patterns and affect the packing of DNA, thus resulting in altered expression patterns. 

Epigenetics and Aging 
The transgenerational effect of epigenetics places a key emphasis on individuals' lifestyle choices ahead of reproduction; in addition to genetics, parenting styles and the psychological conditions one experiences through their upbringing, epigenetics serves as another avenue in which parents can have an impact on the future health of their children. A common question is then whether epigenetics is reversible or not? Initially, epigenetics was thought to be irreversible. However, more studies have suggested otherwise. Specifically, López-León & Goya (2017) reviewed the evidence for the pluripotency of gene-based cell reprogramming, erasing epigenetic marks of aging and rejuvenating cells, this type of research is promising for individuals and potential therapies to come. More interestingly, the evidence discussed in this study supports an emerging view of aging as a reversible process because of the association between progressive epigenetic dysregulation and organismal aging, which can be challenging to explain the confines of aging as an irresistible process. Therefore, epigenetics plays a significant role in human health and can hold the key to increased health and prolonged life through further investigation.

The Dutch Hunger Winter: A Milestone for Epigenetics
 Since the introduction of the concept of epigenetics in the mid-20th century, it has sparked much attention and debate. However, one of the most historically relevant examples of epigenetics' role in human health was the Dutch Hunger Winter which specifically was demonstrated in individuals who were deprived of food during 1944-1945: a period towards the end of World War II in which there was a food ban imposed on individuals in The Western Netherlands [3]. Through careful registration of pregnant women at the time and documentation of official food rations, scientists have been able to link the environment to offspring's epigenome and health [3].
 A paper by Heijmans et al. (2008) attempted to investigate if prenatal exposure to famine is associated with heritable differences in methylation of the insulin-like growth factor II (IGF2) gene, specifically a region which is maternally inherited known as the differentially methylated region (DMR). IGF2 is of particular interest because it is a well-characterized locus, a critical factor in human growth and development, and epigenetically regulated [3]. The analysis results showed that pre-conceptual exposure to famine during the Dutch Hunger Winter was associated with lower methylation of IGF2 DMR 60 years later. This study was the first evidence of short-lived environmental conditions occurring from early preconception leading to persisting changes in the epigenome [3].
 To elaborate, a meta-analysis by Yohannes (2015) attempted to shed some light on the role of genetic and epigenetic influences in the etiology of type-2-diabetes thus expanding on the Dutch Hunger Winter families cohort studies, which previously suggested the involvement of prenatal epigenetic insulin in type-2 diabetes mellitus (T2DM). The analysis showed that epigenetic insults are significantly linked to the first trimester instead of the mid-second and least to any time beyond the mid-second trimester [6]. Regardless, the meta-analysis furthers the possibility of such a link between T2DM and the prenatal environment. It is hypothesized that such environmental factors include vitamin D or melatonin levels and fetal toxicity due to products of surface water chlorine treatments (Yohannes, 2015). Overall, the Dutch Hunger Winter study demonstrates the power of environmental factors on future phenotypes of offspring through the epigenome. 

Epigenetic Therapies
In addition to genetics, epigenetics can cause or be associated with many different diseases and therefore, it is of scientific interest to investigate potential therapies that can help alleviate these diseases. Understandably, epigenetic mechanisms are essential for normal development, and if certain environmental factors result in the change to epigenetic patterns, one can develop or be more susceptible to developing the disease. Examples of epigenetic therapy medicines are DNA methyltransferase (DNMT) inhibitors and Histone Deacetylase (HDAC) inhibitors for cancer [5]. These technologies work by inhibiting the enzymes that catalyze modifications to the epigenome that change chromatin structures and gene inactivation. In cancer specifically, overexpression of DNMTs is observed and might be involved in carcinogenesis; also, when gene targeting technologies are used to deplete DNMTs, more extensive demethylation of genes is observed, thus demonstrating the importance of this enzyme in tumour progression [5]. Therefore, DNMT is an optimal target for anticancer therapy development [5]. So far, many different inhibitors have been developed, and resulting anticancer effects have been observed, which is promising and why the study of epigenetics should continue.

Future Outlook
    Given substantial evidence for epigenetics supporting the association between environmental conditions and one's phenotype despite the underlying genetic sequence, epigenetics should continue to be investigated and researched thoroughly. This research should bring more information about human health and how diseases can be treated and prevented. Additionally, the link between aging and the epigenome is also of interest to scientists and the future of humankind, and some may argue that considering aging as an epigenetic consequence may open up the possibilities for aging to be considered a reversible process, know how this will be utilized and understood is far from the current investigation. However, it emphasizes a promising future in light of understanding how the 
epigenome works. Finally, knowledge of epigenetics emphasizes the transgenerational impact of daily lifestyle choices, which can have applicability’s today in the form of educating individuals on how their current daily lives can impact the future of their bloodline.

REFERENCES
[1]     Bai, Z.-T., Bai, B., Zhu, J., Di, C.-X., Li, X., & Zhou, W.-C. (2018). Epigenetic actions of
environmental factors and promising drugs for cancer therapy. Oncology Letters, 15(2),
2049–2056. https://doi.org/10.3892/ol.2017.7597

[2]     Dupont, C., Armant, D. R., & Brenner, C. A. (2009). Epigenetics: definition,
mechanisms and clinical perspective. Seminars in reproductive medicine,    27(5), 351–357. https://doi.org/10.1055/s-0029-1237423

[3]    Heijmans, B. T., Tobi, E. W., Stein, A. D., Putter, H., Blauw, G. J., Susser, E. S., … Lumey, L.H.
(2008). Persistent Epigenetic Differences Associated with Prenatal Exposure to Famine
in Humans. Proceedings of the National Academy of Sciences - PNAS, 105(44), 17046–17049. https://doi.org/10.1073/pnas.0806560105

[4]     López-León, M., & Goya, R. G. (2017). The Emerging View of Aging as a Reversible

Epigenetic Process. Gerontology (Basel), 63(5), 426–431.    https://doi.org/10.1159/000477209

[5]     Song, S.-H., Han, S.-W., & Bang, Y.-J. (2012). Epigenetic-Based Therapies in Cancer: Progress
to Date. Drugs (New York, N.Y.), 71(18), 2391–2403.
https://doi.org/10.2165/11596690-000000000-00000

[6]     Yohannes, S. (2015). Dermatoglyphic meta-analysis indicates early epigenetic outcomes &
possible implications on genomic zygosity in type-2 diabetes. F1000 Research, 4,
617–617. https://doi.org/10.12688/f1000research.6923.1

About the Authors
Paige Breedon is a second-year medical sciences undergraduate student at the University of Western Ontario with an interest in epidemiology, public health, and the biological sciences.
Dr. Austin Mardon is a geographer, author, researcher, assistant adjunct professor at the University of Alberta and the founder and director of the Antarctic Institute of Canada.