Epigenetics explains how cells are able to use different parts of their DNA at different times. Epigenetic modifications made to our DNA underpin many important processes in our bodies, and can be corrupted in disease.

Our epigenetics researchers aim to unravel how epigenetic changes influence healthy and diseased cells, with a goal of better treatments for diseases.

Our epigenetics research

Our research in the field of epigenetics aims to:

• Discover new proteins that either package or epigenetically modify our DNA.
• Reveal how epigenetic changes control the development and function of different cell types in health and disease.
• Develop new strategies that treat disease by altering the epigenetic control of genes.

What is epigenetics?

Epigenetics examines how our body manages to create all of our different cell types – such as white blood cells, muscle cells and skin cells – from the same genetic code. It studies how chemical changes, called ‘epigenetic modifications’ switch genes on or off.

Our genome, made of DNA, contains the instructions for how our cells behave. Different cells in our body function in distinct ways because of variations in the proteins made by each cell. The proteins are produced under instruction from genes. Switching different genes on or off affects which particular proteins are produced. For example, red blood cells produce haemoglobin to transport oxygen, whereas skin cells make elastin to keep our skin elastic.

DNA consists of four ‘letters’ called bases. It is the sequence of bases that makes the instructions within genes. Changes in the order of the bases changes the proteins that are produced.

Epigenetic modifications are chemical changes to DNA and to certain proteins, called histones, that DNA wraps around. The DNA and histones together are called ‘chromatin’.

Chemical changes influence whether the chromatin is:

• ‘Open’ or packed loosely, allowing genes to be active, or
• ‘Closed’ or packed tightly, inactivating the genes.

Epigenetic modifications are reversible: a cell can switch off a gene at one point in time, and switch it back on later. The trigger to open or close a particular section of DNA can be:

• An external signal received by the cell, such as a hormone binding to a receptor, or a change in a nutrient.
• An internal change in the cell, such as the cell preparing to divide.

When a cell divides, the ‘parent’ cell’s epigenetic state can be maintained in the daughter cells. This means that a trigger at one point in time can influence how a cell behaves at a later time. It also means that when a certain type of cell divides it produces another cell of the same type. Thus, a liver cell divides into two liver cells, not into any other type of cell.

The environment can also influence epigenetic modifications. In particular, it appears that changes to a mother’s diet are experienced by the developing foetus, and can influence how epigenetic modifications are established during development in the womb. This can influence the disease sensitivities of the person into adulthood.

Epigenetic modifiers

The proteins that make epigenetic changes to chromatin are called ‘epigenetic modifiers’. These include:

• Histone acetyltransferases (HATs), histone methyltransferases and histone deacetylases (HDACs) and histone demethylases that modify histone proteins.
• DNA methyltransferases, which modify certain bases in DNA, and a set of proteins including TET proteins that undo these modifications.

Discovering new epigenetic modifiers is a goal of our epigenetics research.

X-inactivation

Male and female mammals differ at the genetic level:

• Female cells contain two X chromosomes.
• Male cells contain one X and one Y chromosome.

Having two X chromosomes active within a cell is toxic. Therefore, during development female cells apply epigenetic changes to permanently close down all the genes on one X chromosome. This process is called ‘X-inactivation’.

Our researchers are using X-inactivation as a model of epigenetic changes, to discover new ways that genes are switched on and off.

Epigenetics and development

Epigenetic changes explain how one cell can give rise to the complex mix of cells in an adult. During embryonic development, different genes are required at different times, and in different cells. Epigenetic modifications are critical for instructing a cell on which genes it should be using.

Epigenetics and disease

Diseases can occur because of errors within cells. Some of these can be traced to certain changes in the cell’s DNA sequence. It is becoming apparent that specific epigenetic modification in a cell can underlie certain diseases. Our researchers are examining this hypothesis in a number of important conditions including cancer.

Epigenetic changes that alter gene expression occur in cancer cells. These enable the cell to divide uncontrollably and become long lived. Some cancer-causing gene mutations have been found in epigenetic modifiers.

Epigenetic cancer therapies

Epigenetic changes to chromatin can enable the growth of a cancer but, unlike genetic mistakes, these epigenetic changes are reversible. Medications that alter a cancer cell’s epigenetic state have been developed. These interfere with epigenetic modifiers such as the HDACs and DNA methyltransferases. Some of these medications are already in use to treat blood cancers, and are being tested in other cancers.

As research reveals more about epigenetics in health and disease, more strategies to treat disease by altering a diseased cell’s epigenetic state will be developed.