Epigenetics – from under the radar to over the top?
Does epigenetics represent a new frontier in drug discovery? Nessa Carey looks at the explosion in our understanding
Until about 10 years ago, epigenetics was a bit of a niche discipline in biology, something of a problem child – clearly very clever, but difficult to pin down. To hardcore geneticists it was too fuzzy, with an uncomfortably large gap between outcomes and mechanisms. In the last decade however, there’s been an explosion in our understanding of epigenetics – now recognised as a vital player in cellular function and human health, as well as a source for the development of new drugs.
What is Epigenetics?
How long do you have? There’s a lot of subtly different definitions, and some of the nuances are only of interest to the obsessives. A useful working definition, at a mechanistic level, is that epigenetics refers to heritable modifications to chromatin. These modifications can be present on DNA itself or on the histone proteins with which it associates. They are passed on when cells divide, through mechanisms that in many cases are opaque.
The modifications don’t alter the sequence of genes, but they do influence how and when a gene is expressed. The modifications vary hugely in their stability and the length of time for which they influence expression of a specific gene. At one extreme they can mediate a transient response to an environmental stimulus, of 30 minutes or less. At the other, they define and maintain cellular fate for an entire lifetime. In the past decade the techniques for identifying and analysing these patterns of modifications have improved by orders of magnitude, driving some of the increased interest in this field.
Epigenetic literacy
Epigenetic modifications and their effects on gene expression are mediated by proteins that fall into three linguistic categories. ‘Writer’ enzymes deposit epigenetic modifications on chromatin, whereas ‘Eraser’ enzymes remove them. The consequences of these events are translated by nonenzymatic ‘Reader’ proteins which bind to the different modifications and attract protein complexes, driving the ultimate outcome in terms of gene expression. Together they are encoded by several hundred different genes, representing in turn, hundreds of new potential drug targets. These new targets even include the non-enzymatic Reader proteins, at least some of which have been shown to be exquisitely druggable.
Not too subtle?
These hundreds of epigenetic proteins generate a horrendously complex landscape of interacting epigenetic modifications across the entire genome, which varies with cell type, age and just about every environmental influence you can imagine, with a high degree of stochastic variation thrown in for luck.
So what makes us think that interfering with just one Writer, Eraser or Reader will really have any biological impact? Well, nature itself suggests that abnormal expression of a single epigenetic protein can influence cellular outcomes dramatically.
This is clear from the overt phenotypes seen in children with germline mutations in genes that encode epigenetic proteins. Similarly, somatic mutations in specific epigenetic genes have been shown to be strong drivers of certain cancers.
The future
There are already drugs licensed for clinical use that target epigenetic enzymes.
Often referred to as first generation epigenetic drugs, these are effective at treating (although not necessarily curing) certain haematological cancers.
They target epigeneticenzymes that mediate very wide-ranging modifications and were discovered more or less accidentally – the starting compounds were shown to be anti-tumour before they were shown to be working epigenetically.
Epigenetics does represent a new frontier in drug discovery, potentially opening up opportunities in cancer and a range of chronic diseases
Epigenetics does represent a new frontier in drug discovery, potentially opening up opportunities in cancer and a range of chronic diseases. But frontiers are hazardous places and we will need new approaches to target identification, patient monitoring, dosing and toxicology, to maximise the benefits of this field. To support this improvement, the Royal Society of Chemistry has recently published Epigenetics for Drug Discovery, written by the leading researchers in this field. It is intended as a guide for medicinal chemists or scientists in other fields wishing to know more.
Epigenetics for Drug Discovery is part of the 'RSC Drug Discovery' series of books, which has now reached its 50th volume in five years.
Access the ebook Epigenetics for Drug Discovery; the first chapter is free.