Epigenetics is a new frontier in the search for treatments of human diseases. Epigenetics refers to modifications to DNA or the proteins associated with DNA, such as histones, which in turn determine whether a gene is on or off or whether its activity is high or low. The level of activity of a gene will in many cases mean the difference between a healthy normal physiological effect and a disease.
The modifications to the DNA or the proteins associated with DNA include among others acetylation, methylation and phosphorylation. These modifications are added to histones by enzymes called “writers” and removed by enzymes called “erasers”. Examples of writers include protein kinases, histone acetyltransferases and histone methyltransferases and examples of erasers include histone deacetylases and histone demethylases.
Other proteins, called “readers”, do not alter the histone modifications but rather recognize a specific pattern of modifications by binding to them and recruiting additional proteins to regulate gene activity. A number of protein domains have been identified which recognize and bind to such modifications, including bromodomains. Differences in the pattern of modifications occur between different cells and organs of the body or in response to different physiological stimuli. There is now substantial evidence that alterations in these patterns underlie multiple diseases. For these reasons, epigenetics has become an exciting forefront for the discovery of new medicines.
We are focusing on the BET (Bromodomain and ExtraTerminal domain) proteins. Amongst the four members of this family (BRD2, BRD3, BRD4 and BRDT), BRD4 has been associated with the regulation of some medically important genes in areas such as cancer, autoimmune diseases and cardiovascular disease.