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Epigenetics: beyond DNA sequences

For decades, the study of genetics focused primarily on the DNA sequence, considering it as the blueprint of life. However, recent scientific advancements have unveiled a fascinating field known as epigenetics. Epigenetics explores the changes in gene expression that occur without altering the underlying DNA sequence. It sheds light on how environmental factors and lifestyle choices can influence gene activity, impacting our health, development, and even the passing of traits to future generations. In this article, we will explain the mechanisms and relevance of epigenetics in the regulation of gene expression.



Epigenetics mechanisms

Epigenetics refers to different modifications and processes that can alter gene expression without changing the DNA sequence itself. The DNA is composed of four molecules named adenine (A), thymine (T), cytosine (C), and guanine (G), and the combination of them make all the DNA sequences, think of it as a code, and the molecules ATCG are the letters that form it. The epigenetic modifications occur on the DNA molecule or the proteins around which DNA is wrapped, named histones, influencing how genes are expressed without changing the underlying sequence. Epigenetic changes can modulate cellular function and overall organismal development by modifying gene expression, so they can be activated or inhibited to produce more or less proteins. Epigenetic modifications occur through various mechanisms, with DNA methylation and histone modifications being the most extensively studied (Zhang et al., 2020).


DNA methylation is one of the most extensively studied epigenetic modifications. It involves the addition of a methyl group (-CH3) to the DNA molecule (Figure 1), typically at specific sites called CpG islands. CpG islands are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide, and when these regions are methylated normally, the genes on those regions are repressed, being less active. The enzymes responsible for DNA methylation are called DNA methyltransferases (DNMTs). DNMTs add a methyl group to the carbon 5 position of the cytosine ring, forming 5-methylcytosine (5mC) (Figure 1). DNA methylation patterns are established during early development and are then maintained in most cells throughout an organism's life. However, they can also undergo changes in response to environmental stimuli or during specific developmental processes (Mattei et al., 2022).

Figure 1. The mechanism of DNA methylation (Heikkinen 2022).

Histones are proteins around which DNA wraps, they help package DNA into a compact form known as chromatin. There are different types of chemical modifications that can occur on histones. These modifications can change the structure of chromatin, making it more open or more condensed, which in turn affects the expression of genes. (Zhang et al., 2021). You can think of histones as the "spools" around which the DNA is wound. They help package DNA into a compact and organized structure, which is necessary to fit the long DNA molecules inside the tiny nucleus of a cell.


Acetylation and methylation are the most widely studied histone modifications (Figure 2). Acetylation involves the addition of an acetyl group to specific regions on histone, relaxing the chromatin and making the genes more accessible to increase their expression (Figure 2). Histone acetyltransferases add acetyl groups, while histone deacetylases remove them (Marmorstein & Zhou, 2014). Similar to acetylation, methylation involves the addition of a methyl group to specific regions of histones, depending on the specific regions that are being modified, the methyl addition will have different effects on gene expression, but normally they are more related to the condensation of the chromatin, making the genes more inaccessible and repressing them (Figure 2). Histone methyltransferases (HMTs) add methyl groups, while histone demethylases (HDMs) remove them (Gong & Miller, 2019). These histone modifications provide a dynamic and reversible mechanism for regulating gene expression beyond altering the DNA sequence itself.

Figure 2. Types of histone modifications (Wise 2016).

Environmental and lifestyle influences on Epigenetics

Epigenetic modifications are not only formed when we are born but are also influenced by environmental factors and lifestyle choices (Figure 3). Certain nutrients and dietary factors can influence epigenetic modifications (Carlberg & Velleuer, 2023). Inadequate folate intake has been associated with alterations in DNA methylation patterns. Other nutrients, such as vitamin B12, choline, and various micronutrients, also contribute to epigenetic regulation.


Environmental exposures, including exposure to pollutants, chemicals, and toxins, can induce epigenetic modifications. For example, prenatal exposure to cigarette smoke has been associated with DNA methylation changes in newborns. Similarly, exposure to environmental toxins, such as heavy metals, pesticides, and endocrine-disrupting chemicals, has been linked to alterations in DNA methylation and histone modifications. These changes can perturb normal gene expression patterns and contribute to the development of diseases such as cancer, metabolic disorders, and reproductive abnormalities (Cavalli & Heard, 2019).


Chronic stress and mental health disorders have also been associated with epigenetic changes, particularly in genes involved in stress response, mood regulation, and brain function. Moreover, socioeconomic status has also been linked to differences in epigenetic patterns. Individuals from disadvantaged backgrounds often experience higher levels of chronic stress, poorer nutrition, and exposure to environmental toxins (Gottschalk et al., 2020). These factors can lead to epigenetic modifications that may contribute to health disparities observed across different socioeconomic groups.

Figure 3. Environmental and lifestyle epigenetic influences (Healthylife CapeTown)

Epigenetic inheritance

One of the most remarkable aspects of epigenetics is its potential for transgenerational inheritance, whereby epigenetic marks can be passed from one generation to another. This phenomenon challenges the traditional understanding of genetics, as it suggests that acquired traits and environmental influences can be inherited (Figure 4) (Bošković & Rando, 2018). Experimental studies on animals, including mice and rats, have provided evidence for transgenerational epigenetic effects. These studies have shown that exposure to certain environmental factors or interventions can lead to changes in epigenetic marks that persist across multiple generations. These changes can subsequently affect the health and disease susceptibility of not only the exposed generation but also their descendants. Similarly, stress experienced by parents has been associated with altered DNA methylation patterns in their offspring, potentially influencing their stress response and mental health. The mechanisms underlying transgenerational epigenetic inheritance are still being actively investigated. One proposed mechanism involves the transmission of epigenetic information through germline cells, such as sperm and eggs. Epigenetic marks present in these cells can be carried forward into the next generation and influence gene expression in offspring.

Figure 4. Epigenetic inheritance (LearnGenetics).

Conclusions

Epigenetics provides a revolutionary perspective on how our genes interact with the environment. It highlights the dynamic nature of gene expression and the potential for reversible changes that can impact our health and well-being. Understanding the mechanisms and implications of epigenetics opens up new avenues for personalized medicine, disease prevention, and therapeutic interventions. By unraveling the hidden influences on genetic expression, we gain valuable insights into the complex interplay between nature and nurture. As research in epigenetics progresses, it is essential to consider the ethical implications and societal impacts of this field. The knowledge gained must be used responsibly and with sensitivity to ensure equitable access to healthcare and promote a better understanding of the intergenerational effects of social and environmental factors. Epigenetics invites us to revisit our understanding of genetics, challenging the notion of predetermined destiny. It empowers us to recognize the profound influence of our choices, lifestyles, and environment on our genetic expression and inspires us to embrace a holistic approach to health and well-being.


Bibliographical References

Bošković, A., and Rando, O.J. (2018). Transgenerational Epigenetic Inheritance. Annu. Rev. Genet. 52, 21–41. https://www.annualreviews.org/doi/10.1146/annurev-genet-120417-031404 Carlberg, C., and Velleuer, E. (2023). Nutrition and epigenetic programming. Curr. Opin. Clin. Nutr. Metab. Care 26, 259–265. https://journals.lww.com/co-clinicalnutrition/Abstract/2023/05000/Nutrition_and_epigenetic_programming.10.aspx Cavalli, G., and Heard, E. (2019). Advances in epigenetics link genetics to the environment and disease. Nature 571, 489–499. https://www.nature.com/articles/s41586-019-1411-0 Gong, F., and Miller, K.M. (2019). Histone methylation and the DNA damage response. Mutat. Res. Rev. Mutat. Res. 780, 37–47. https://linkinghub.elsevier.com/retrieve/pii/S1383574217300418 Gottschalk, M.G., Domschke, K., and Schiele, M.A. (2020). Epigenetics Underlying Susceptibility and Resilience Relating to Daily Life Stress, Work Stress, and Socioeconomic Status. Front. Psychiatry 11, 163. https://www.frontiersin.org/articles/10.3389/fpsyt.2020.00163/full Marmorstein, R., and Zhou, M.-M. (2014). Writers and readers of histone acetylation: structure, mechanism, and inhibition. Cold Spring Harb. Perspect. Biol. 6, a018762. https://cshperspectives.cshlp.org/content/6/7/a018762 Mattei, A.L., Bailly, N., and Meissner, A. (2022). DNA methylation: a historical perspective. Trends Genet. 38, 676–707. https://www.cell.com/trends/genetics/fulltext/S0168-9525(22)00071-3?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0168952522000713%3Fshowall%3Dtrue Zhang, L., Lu, Q., and Chang, C. (2020). Epigenetics in Health and Disease. Adv. Exp. Med. Biol. 1253, 3–55. https://link.springer.com/chapter/10.1007/978-981-15-3449-2_1 Zhang, Y., Sun, Z., Jia, J., Du, T., Zhang, N., Tang, Y., Fang, Y., and Fang, D. (2021). Overview of Histone Modification. Adv. Exp. Med. Biol. 1283, 1–16. https://link.springer.com/chapter/10.1007/978-981-15-8104-5_1


Visual Sources

Cover Image. DNA’s Histone Spools Hint at How Complex Cells Evolved (2021) [Image]. Jason Lyan for Quanta Magazine. Retrieved July 06th, 2023, from https://www.quantamagazine.org/dnas-histone-spools-hint-at-how-complex-cells-evolved-20210510/ Figure 1. The mechanism of DNA methylation. Heikkinen et al. (2022) [Image]. The potential of DNA methylation as a biomarker for obesity and smoking. Journal of Internal Medicine. Retrieved July 06th, 2023, from https://onlinelibrary.wiley.com/doi/full/10.1111/joim.13496 Figure 2. Histone modification. Wise and Charchar (2016). [Image]. Epigenetic Modifications in Essential Hypertension. International Journal of Molecular Science. Retrieved July 06th, 2023, from https://www.mdpi.com/1422-0067/17/4/451 Figure 3. Epigenetic influences that can switch genes off or on. [Image]. Your diet and your genes. HelathyLife CapeTown. Retrieved July 06th, 2023, from https://healthylifecapetown.co.za/my-genes-and-genes-testing-nutrigenomics/ Figure 4. Three generations at once are exposed to the same environmental conditions (diet, toxins, hormones, etc.). [Image]. Epigenetics & Inheritance. Learn.Genetics. Retrieved July 06th, 2023, from https://learn.genetics.utah.edu/content/epigenetics/inheritance





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