Epigenetics: Why Your Genes Aren’t Everything

By: Andrea Savio

Why do identical twins differ despite having the exact same DNA? It’s all about how the DNA is used – read on to learn more about how ‘epigenetics’ controls this.

DNA is the genetic sequence of code that contains all of the instructions required to make all components of our body. However, if two identical twins have the exact same DNA, why do some develop different diseases?  If each cell in our body has the exact same DNA, what makes a brain cell develop into a brain cell, or a skin cell develop into a skin cell?

It all depends on which genes are used – which are turned ‘on’ or ‘off’ – and how much of each gene is used. ‘Epigenetics’ is what regulates this and changes how the DNA instructions are used. Like a dimmer switch on a light bulb, epigenetics can turn a gene all the way on, all the way off, or to a level somewhere in between.

How do epigenetics control how much of each gene is utilized by our cells? First, let’s talk about how our DNA is arranged within our cells. The DNA contained within each cell of our bodies is separated into 23 pairs of chromosomes (with one copy of each inherited from each parent). The DNA contained within the chromosomes in each cell of our body is 2 metres in length. This length of DNA is then coiled, folded, and packaged into a space that is only approximately 6 micrometres in diameter, or six one-thousandths of a millimetre! One way that epigenetics works is by altering how tightly the DNA is packaged. If DNA is in a more ‘open’ state, it is more likely to be turned on. If a gene is turned on, we say that it is being expressed. Conversely, more closed, coiled, and tightly packaged DNA is less likely to be expressed.

Epigenetic regulation of DNA changes over time in response to the environment, our genetics, and the natural aging process. Sometimes, epigenetic changes lead to the wrong genes being turned on or off. In the early 1980s, cancer was the first human disease to be linked to epigenetics (1). Although first studied in colorectal cancer, epigenetic changes have since been found in every type of cancer. When epigenetic and genetic errors accumulate they can cause a normal cell to transform into a cancer cell, including the ability to invade tissues or metastasize (spread) to other areas of the body.

While epigenetic signals can change over time, they are also reversible. This means that if the epigenetics are changed in a tumour cell, it may be possible to change it back to its normal state through epigenetic therapies. This type of cancer treatment has been approved as a first line therapy for several cancer types, including myelodysplastic syndrome and T-cell lymphoma. Numerous studies are underway by researchers and clinicians to discover new therapeutic drugs to increase the number of cancer types that can be treated with this kind of therapy.

A recent study discovered a promising new drug, called MC180295, which can turn epigenetically silenced genes back on (2). This drug was studied in models of colorectal, breast, lung, and ovarian cancers. The drug targets a cellular component (‘protein’) that usually acts in synchrony with other proteins to package DNA into a more compact state. The drug prevents that protein from working, causing the DNA to be found in a more relaxed or open state. In turn, this leads to genes being turned back on and expressed at a higher level. After testing this new drug in a variety of conditions and cancer cell types, the scientists found that treatment with MC180295 enhanced survival in mouse models by inhibiting tumour growth. The next step will be to determine if this effect holds true in patients.

Epigenetic researchers continue to search for therapies that can treat other types of cancers in order to add to our growing arsenal of cancer therapies with improved and more targeted options. Using epigenetic therapy in combination with traditional therapeutics is also being investigated for its potential to achieve superior eradication of disease. Epigenetic changes are essential for the development of cancer, and the possibility of reversing these cancer-associated epigenetic changes is an exciting and rapidly evolving area of research.

Andrea Savio is a technical writer at a scientific and regulatory consulting firm. She graduated with a PhD from the University of Toronto where her thesis focused on the interplay of genetics and epigenetics in colorectal cancer.

 

Resources:

1. Feinberg AP, Vogelstein B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature. 1983:301(5895):89-92.
2. Zhang H, Pandey S, Travers M, Sun H, Morton G, Madzo J, Chung W, Khowsathit J, Perez-Leal O, Barrero CA, Merali C, Okamoto Y, Sato T, Pan J, Garriga J, Bhanu NV, Simithy J, Patel B, Huang J, Raynal NJ, Garcia BA, Jacobson MA, Kadoch C, Merali S, Zhang Y, Childers W, Abou-Gharbia M, Karanicolas J, Bavlin SB, Zahnow CA, Jelinek J, Graña X, Issa JJ. Targeting CDK9 reactivates epigenetically silenced genes in cancer. Cell. 2018;175(5):1244-1258.