What is Epigenetics?
The term epigenetics comes from Greek and literally means 'above genetics.' The term was originally defined by Conrad Waddington (1). Epigenetics encompasses a range of mechanisms of heritable changes in gene activity that are not caused by changes in the DNA sequence itself. These mechanisms function like molecular switches that determine which genes are turned on or off at a given time and in which tissue.
Three Main Mechanisms of Epigenetics
DNA Methylation
DNA methylation is one of the best-researched epigenetic mechanisms. Here, methyl groups are attached to specific sites on the DNA. This chemical modification works like a lock or brake. It generally leads to the suppression of gene activity.
Histone Modifications
The DNA in the cell nucleus is wrapped around proteins called histones, forming chromatin. The ends (or 'tails') of these histones can undergo various chemical modifications. These modifications affect how loosely or tightly the chromatin is packed, which, in turn, influences gene activity. Generally, tighter packing leads to lower gene expression, while looser packing leads to higher gene expression.
Non-coding RNAs
Non-coding RNAs, especially microRNAs and long non-coding RNAs, play an important role in epigenetic regulation. They can influence gene expression in various ways, such as by binding to mRNA and promoting its degradation. For the discovery of this mechanism, the Nobel Prize in Medicine was awarded in 2024 to researchers Victor Ambros and Gary Ruvkun (2).
Environmental Factors and Epigenetics
One of the most exciting findings in epigenetics is that environmental factors can influence epigenetic changes (3). Diet, stress, physical activity, environmental toxins, and other external factors can alter epigenetic patterns and thus affect gene expression. Studies have shown that these environmentally induced epigenetic changes can even be passed on across generations, challenging the traditional understanding of inheritance (3). A well-known example is the Dutch Hunger Winter study, which showed that children whose mothers were exposed to famine during pregnancy had a higher risk of certain diseases and displayed epigenetic changes (4).
It has also been demonstrated in animal studies that a mother's diet can impact the epigenetic signature of her offspring. Experiments with mice have revealed the mechanisms behind this: the experiment with the so-called Agouti mice is one of the classic epigenetics experiments (3). In Agouti mice, the Agouti gene, which is responsible for coat color, is altered so that the mice have a yellowish coat instead of the typical dark brown. The gene encodes an enzyme that influences pigment production. However, this activity can be suppressed through methylation of the gene. The researchers wanted to test whether they could alter the methylation of the gene through the mice's diet so that the gene's activity would change. They fed pregnant mice substances that promote methylation, such as folic acid and vitamin B12. The offspring of these mice were born with brown fur. Molecular studies on the mice showed that the Agouti gene in the newborn mice was inactivated by additional methylation, which is why they had brown fur instead of yellow (3).
Insights into Current Research
Development of Organisms
Epigenetic mechanisms play an important role in the development of organisms. Researchers have found, for example, that epigenetic markings on DNA change during embryonic development. It has been shown that if a gene responsible for epigenetic regulation of chromatin is switched off, eggs and embryos cannot develop properly (5). A detailed map of the epigenetic mechanisms that govern the development of eggs and embryos is currently being studied (6).
Inheritance from One Generation to the Next
As mentioned, epigenetic information is transmitted from one generation to the next. The patterns of how epigenetic information is passed from the mother to the next generation have already been extensively studied (7). It turns out that a specific set of defined molecular mechanisms is involved, such as chromatin (7). Epigenetic information is also passed from the father via the DNA of sperm. In mice, for example, it has been found that defects in the epigenetic signature of DNA in sperm can lead to developmental disorders in subsequent generations (8).
Epigenetics in the Clinic
Insights from epigenetics have fundamentally changed the way we view the genome and have had a lasting influence on basic research. But what do these findings mean in a clinical context? How can results be used to improve treatments and impact patients’ lives?
Clinically, epigenetics is now used, for example, in cancer diagnosis and treatment. Diagnosis can be improved based on epigenetic markers on the DNA of cancer cells. For example, these patterns can help detect cancer at an early stage, since the epigenetic signature of cancer cells differs from that of healthy cells (9). Clinically approved tests are available for a number of cancers, such as colon, liver, or lung cancer (9). These tests can also better track how cancer progresses and how well therapy is working (9). Another rapidly developing research field is the development of so-called epidrugs, that is, pharmaceuticals that act on the mechanisms of epigenetics. These can alter the epigenetic markers of cancer cells to make them cytotoxic, causing the cells to die. Some of these cancer drugs have already been approved by the US FDA (9).
Sources
1. Noble D. Conrad Waddington and the origin of epigenetics. J Exp Biol. March 15, 2015;218(6):816–8.
2. NobelPrize.org [Internet]. [cited May 16, 2025]. Press release: The Nobel Prize in Physiology or Medicine 2024. Available at: https://www.nobelprize.org/prizes/medicine/2024/press-release/
3. Spork P. Der zweite Code. Epigenetik oder: Wie wir unser Erbgut steuern können. Hamburg: Rowohlt Taschenbuch Verlag; 2010.
4. De Rooij SR, Bleker, Laura S., Painter, Rebecca C., Ravelli, Anita C., and Roseboom TJ. Lessons learned from 25 Years of Research into Long term Consequences of Prenatal Exposure to the Dutch famine 1944–45: The Dutch famine Birth Cohort. Int J Environ Health Res. July 3, 2022;32(7):1432–46.
5. Eymery A, Liu Z, Ozonov EA, Stadler MB, Peters AHFM. The methyltransferase Setdb1 is essential for meiosis and mitosis in mouse oocytes and early embryos. Development. August 1, 2016;143(15):2767–79.
6. Du Z, Zheng H, Kawamura YK, Zhang K, Gassler J, Powell S, et al. Polycomb Group Proteins Regulate Chromatin Architecture in Mouse Oocytes and Early Embryos. Mol Cell. February 20, 2020;77(4):825-839.e7.
7. Stäubli A, Peters AH. Mechanisms of maternal intergenerational epigenetic inheritance. Curr Opin Genet Dev. April 2021;67:151–62.
8. Siklenka K, Erkek S, Godmann M, Lambrot R, McGraw S, Lafleur C, et al. Disruption of histone methylation in developing sperm impairs offspring health transgenerationally. Science. November 6, 2015;350(6261):aab2006.
9. Davalos V, Esteller M. Cancer epigenetics in clinical practice. CA Cancer J Clin. 2023;73(4):376–424.
